Regioselective Pd-catalyzed aerobic aza-Wacker cyclization for preparation of isoindolinones and isoquinolin-1(2 H)-ones

Article abstract of DOI:10.1021/ol203043h

A switchable regioselective intramolecular aerobic aza-Wacker cyclization catalyzed by palladium is presented. Isoindolinones or isoquinolin-1(2H)-ones could be prepared selectively from the same substrates using different catalysts. The type and steric hindrance of the ligands may be the variables most significant for regiocontrol.

Full text of DOI:10.1021/ol203043h

ORGANIC
LETTERS
2012
Vol. 14, No. 1
268–271
Regioselective Pd-Catalyzed Aerobic
Aza-Wacker Cyclization for Preparation of
Isoindolinones and Isoquinolin-1(2H)-ones
Guoqiang Yang and Wanbin Zhang*
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China
wanbin@sjtu.edu.cn
Received November 11, 2011
ABSTRACT
A switchable regioselective intramolecular aerobic aza-Wacker cyclization catalyzed by palladium is presented. Isoindolinones or isoquinolin-
1(2H)-ones could be prepared selectively from the same substrates using different catalysts. The type and steric hindrance of the ligands may be
the variables most significant for regiocontrol.
Nitrogen-containing heterocycles are the components of
potent drugs and bioactive natural products, therefore con-
siderable effort has been directed toward their synthesis.1
Among the aza-cyclization reactions, oxidative aminations
catalyzed by palladium represent one of the most efficient
methods to build such ring systems under mild conditions.2ꢀ4
Hegedus’ pioneering work opened the study of palladium-
catalyzed aza-Wacker-type reactions.5 After further im-
provement, this reaction became attractive for the constru-
ction of nitrogen-containing heterocycles with dioxygen or
air as the oxidant.3,6
As an important goal in synthetic chemistry, however,
the ability to achieve catalyst-controlled regioselectivity in
coupling reactions with alkenes has rarely been reported.3a
For example, the regioselective Heck reaction has become
feasible only recently.7 A few examples of the palladium-
catalyzed regioselective coupling reactions of oxygen nu-
cleophiles with alkene substrates have also been reported.8
In addition, several reports have described the substrate-
or condition-controlled palladium-catalyzed oxidative re-
gioselective amination of olefins.5a,6a,9 Liu and co-workers
reported the Brønsted base controlled selective prepara-
tion of five- or seven-membered nitrogen-containing het-
erocycles via a palladium-catalyzed intramolecular aerobic
(4) (a) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R.
Organometallics 2004, 23, 5618. (b) Brice, J. L.; Harang, J. E.; Timokhin,
V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868. (c)
Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127,
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Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (h) Wang, B.;
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Du, H.; Shi, Y. Angew. Chem., Int. Ed. 2008, 47, 8224. (i) Muniz, K.;
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Streuff, J.; Chavez, P.; Hovelmann, C. H. Chem.;Asian J. 2008, 3, 1248.
€
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(j) Hovelmann, C. H.; Streuff, J.; Brelot, L.; Muniz, K. Chem. Commun.
(1) (a) Brown, E. G. Ring Nitrogen and Key Biomolecules; Springer:
Boston, MA, 1998. (b) O'Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(c) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213.
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r
10.1021/ol203043h
Published on Web 12/08/2011
2011 American Chemical Society

allylic oxidative amination.10 Importantly, the Brønsted
base modulated regioselective palladium-catalyzed inter-
molecular aerobic aza-Wacker-type reaction has been
developed by Stahl and co-workers.11 However, the anti-
Markovnikov amination is limited in substrate scope in
their reported work. Herein, we report a regioselective
palladium-catalyzed intramolecular aerobic aza-Wacker
cyclization. With this method, isoindolin-1-one and
isoquinolin-1(2H)-one derivatives were prepared in differ-
ent conditions and high yields (Scheme 1).
toluene and THF for the reaction yielding 2a due to the
poor solubility of the correponding palladium complex but
beneficial to the catalysis in MeOH, resulting in an 85%
yield of product (entries 3, 5 vs 7). An opposite behavior
was observed with the quinoline as a monodentate ligand
(entries 2, 4 vs 6). To our surprise, the six-membered ring
3a was afforded as the favored product in the absence of
ligand in MeOH (entry 8). The yield of 3a could be further
enhanced by adding CuCl2 as the cocatalyst and changing
Pd(OAc)2 to (MeCN)2PdCl2 (entries 9, 10). The 3a form-
ing reactions in different solvents gave lower or similar
yields (entries 11, 12). When 20 mol % triethylamine was
added to the system described in entry 10, an excellent yield
of 3a was achieved (entry 13). In addition, CuCl2 could
catalyze neither of the reactions (entry 14).
Scheme 1. Switchable Regioselective Palladium-Catalyzed
Intramolecular Aerobic Aza-Wacker Cyclization
To identify the variables for regiocontrol, we further
screened several reaction conditions.14 A catalytic amount
of PhCO2H had no significant effect on the yield of 3a but
could decrease the yield of 2a dramatically (entries 15, 16).
This means the excess Phen in condition A may also
function as a Brønsted base.11 We have also studied the
effect of the chloride ion (entries 7ꢀ10, 17ꢀ20). Unfortu-
nately, maybe due to the poor solubility, no reaction
happened with or without added CuCl2 when (MeCN)2-
PdCl2 and Phen in situ formed the catalyst in MeOH
(entries 17, 18). Importantly, the cocatalysts Cu(OAc)2
and Cu(OTf)2 could alsoincreasethe yield of 3a(entries 19,
20). These results show that the chloride ion can improve
the activity of the catalyst toward the six-membered ring
product, but it is not the most significant variable for
regiocontrol.15 Similar ligands, Bpy and Phen, gave simi-
lar yields of 2a (entries 7, 21). Interestingly, when the more
sterically hindered ligand NC was used, the regioselectivity
Our initial goal was to develop an enantioselective
aza-Wacker-type cyclization reaction toward the total syn-
thesis of 3-monosubstituted chiral isoindolinone natural
products.12 Although no satisfactory enantioselectivity
was obtained, we discovered that different reaction condi-
tions could provide different products, isoindolin-1-one
derivative 2a or isoquinolin-1(2H)-one derivative 3a
(Table 1).13 We screened the conditions to optimize the
yields of 2a and 3a. The well studied system, pyridine/
Pd(OAc)2/toluene,6bꢀe gave the best yield (68%) of 2a in
toluene under aerobic conditions (Table 1, entries 1ꢀ3).
The bidentate ligand, Phen, was toxic to Pd(OAc)2 in
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(14) Thanks for the reviewers’ gentle suggestions.
Org. Lett., Vol. 14, No. 1, 2012
269

was switched to the six-membered ring product, although
with poor yield (entry 22). This steric effect of ligand on
regioselectivity was also observed when iPr-Pyox and iPr-
Quinox were used as ligands (entries 23ꢀ25). As a con-
sequence of the above-mentioned, we propose that the type
and steric hindrance of the ligands play key roles in regio-
control. The poisoning effect of quinoline to Pd(OAc)2 in
MeOH is still unclear.
Pd(OAc)2 as the palladium source, and MeOH as the
solvent and performing the reaction at 60 °C for 12 h.
On the other hand, 3a could be furnished in nearly quan-
titative yield with (MeCN)2PdCl2 and CuCl2 as the cata-
lytic metal sources and triethylamine as the ligand and/or
base in MeOH at 60 °C for 15 h.
Table 2. Substrate Scopea,b
Table 1. Reaction Conditions Screeninga,b
a Unless otherwise stated, reactions were carried out on a 0.20 mmol
scale using 10 mol % Pd salt, with or without added 20 mol % ligand in
solvent (2.0 mL) under 1 atm of dioxygen at 60 °C for 12 h. When the
solvent was toluene, the reaction temperature was 80 °C. b Isolated yield.
NR = No reaction. ND = trace, not detected. c Phen = 1,10-phenan-
throline. NC = neocuproine. Bpy =2,20-bipyridine. iPr-Pyox = (S)-4-
isopropyl-2-(pyridin-2-yl)-4,5-dihydrooxazole. iPr-Quinox = (S)-4-iso-
propyl-2-(quinolin-2-yl)-4,5-dihydrooxazole. d The reaction time was
15 h. e The corresponding complex showed poor solubility in the solvent.
f The solubility of the corresponding complex in the solvent was not
good. g CuCl2 (10 mol %) was added. h PhCO2H (30 mol % for entry 15,
20 mol % for entry 16) was added. i Cu(OAc)2 (10 mol %) was added.
j Cu(OTf)2 (10 mol %) was added. k The reaction time was 48 h. l With
49% yield of the olefin isomers of 2a obtained; please see Supporting
Information.
a Reaction was conducted at 0.20 mmol scale in 2.0 mL of MeOH
under 1 atm of dioxygen at 60 °C. Condition A: Pd(OAc)2 (10 mol %) and
Phen (20 mol %), 12 h. Condition B: (MeCN)2PdCl2 (10 mol %), CuCl2
(10 mol %), NEt3 (20 mol %), 15 h. b All of the yields were isolated yields.
c Reaction time was 48 h. d Pd(OAc)2 (20 mol %) and Phen (40 mol %),
48 h. e Reaction time was 18 h. f Reaction time was 96 h. g The yield in
parentheses was obtained under the conditions of entry 1 of Table 1.
Based on the above results, the optimal reaction conditions
leading to 2a were found to be when using Phen as the ligand,
With a catalyst set identified, a variety of substrates were
examined (Table 2). For substrates 1aꢀ1g (R0 = Ph), the
electronic and steric properties of substituents affect the
constructions of 2 and 3 in a similar manner (entries 1ꢀ7).
The substrates with electron-rich groups gave better yields
(15) It has been established that the concentration of chloride ion can
affect the stereochemistry of oxypalladation. For a selected recent paper
and review, please see: (a) Hayashi, T.; Yamasaki, K.; Mimura, M.;
Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. (b) Keith, J. A.; Henry,
P. M. Angew. Chem., Int. Ed. 2009, 48, 9038.
270
Org. Lett., Vol. 14, No. 1, 2012

of 2 and 3 than the ones with an electron-withdrawing
group (entries 1ꢀ5 vs 6, 7). A longer reaction time gave a
better yield of 2f (entry 6, 77% vs 58%). The ortho-methyl
group slightlydecreasedtheyields ofboth2 and 3 (entry 2).
Both of the catalyst systems tolerate different aryl sub-
stituents on the nitrogen (R = H, entries 8ꢀ11). However,
the electronic effect of substituents on the benzene ring of
aniline is opposite to that of R.16 An electron-withdrawing
group led to a better yield when compared with the
corresponding electron-rich substrate (entry 8 vs 11). With
a methyl group at the ortho position of aniline, cyclization
of 1 under condition B showed an obvious decrease in
yield. However, this is not the case with condition A (entry
10vs8, 9). WhenR0 was analkyl group, under conditionA,
2l and 2m were produced sluggishly while reactions under
condition B occurred more rapidly to construct 3l and 3m
(entries 12, 13). Two olefin isomers 2n and 2n0 were
obtained when substrate 1n was catalyzed under condition
A. Under condition B, a moderate yield of 3n and 5% yield
of 2n were observed (entry 14). Substitution is not always
permitted at the external vinyl position. For instance,
substrate 1o with a bulky group at this position favored
the six-membered ring product 3o under condition A, and
substrate 1p containing a benzyl group tended to form the
five-membered ring product even under condition B
(entries 15, 16). Substrate 1q, with an aliphatic link instead
of an aromatic functional group, showed poor reactivity
toward both catalytic systems. This also occurred when
using the pyridine/Pd(OAc)2/toluene system (entry 17,
16% yield after 48 h at 80 °C). The trisubstituted olefin
substrate 1r has a tendency to yield 2r, even under condi-
tion B (entry 18).
The 2a forming reaction of 1a under condition A may
proceed through an aminopalladation/β-H elimination
pathway (Wacker-type mechanism)6m,n,17 or an allylic
CꢀH activation/reductive elimination pathway.8c,10,18 If
the oxidative cyclization undercondition A proceeds via an
allylic oxidative substitution mechanism, both 1a and 4
will result in the formation of the same π-allylic-PdII
intermediate 5 and afford the same product 2a (Scheme
2). If the CꢀN forming reaction under condition A follows
an aminopalladation/β-H elimination pathway, the reac-
tion of 4 will give product 3a. The experimental results
showed that 1a favored product 2a while 3a was the
predominant product of the reaction when using 4. There-
fore, we believe that formation of 2 from 1 under condition
A occurs via a Wacker-type mechanism through the inter-
mediate 6. The six-membered ring product 3a was ob-
viously thermodynamically stable, but it was produced
through a more sterically hindered intermediate 7a. We
propose that if a smaller ligand (MeOH, Clꢀ, AcOꢀ) is
used, the steric hindrance between the ligand and reactant
in the intermediates 6 or 7 would be weaker. Thus the
thermodynamic product 3a will be produced. If a larger
ligand (Phen, Bpy, iPr-Pyox) is employed, the steric hin-
drance in 7 would be increased more than that in 6. As a
consequence, the kinetic product 2a will be the major
product. However, more sterically hindered ligands (NC,
iPr-Quinox) could reduce the steric hindrance difference
between 6 and 7, and then the thermodynamic product 3a
will be generated but in low yield. In the cases of substrate
1o or 1r, the steric hindrance difference between 6 and 7
decreased or increased, respectively. Therefore, the ther-
modynamic product 3o or kinetic product 2r was favored.
A detailed mechanism study is being carried out.
Scheme 2. Oxidative CꢀN Forming Reaction of 4
In summary, we have developed a palladium-catalyzed
intramolecular aerobic aza-Wacker cyclization to prepare
isoindolinones and isoquinolin-1(2H)-ones selectively
from the same substrates. The switchable selectivity could
be controlled by using different catalysts. We propose that
the type and steric hindrance of the ligands should be the
most significant variables for regiocontrol.
Acknowledgment. We thank Prof. Tsuneo Imamoto
and Dr. Masashi Sugiya of Nippon Chemical Industrial
Co., Ltd. for helpful discussions. This work was partially
supported by the National Natural Science Foundation of
China (Nos. 20972095 and 21172143) and Science and
Technology Commission of Shanghai Municipality (No.
10dz1910105), and Nippon Chemical Industrial Co., Ltd.
Supporting Information Available. General experimen-
tal procedures and characterization details. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(16) (a) For cyclization-decelerating effect of electron-deficient acyl
group side, see: ref 6m. (b) For cyclization-accelerating effect of electron-
deficient aniline side, see ref 6n.
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Soc. 2011, 133, 18594.
(18) The terminal olefins have been well studied as the substrates for
palladium-catalyzed allylic oxidative substitution probably due to their
high activity. For selected recent papers, see: (a) Yin, G.; Wu, Y.; Liu, G.
J. Am. Chem. Soc. 2010, 132, 11978. (b) Campbell, A. N.; White, P. B.;
Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116. (c)
Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133, 12584.
Org. Lett., Vol. 14, No. 1, 2012
271