Efficient synthesis of hydroxyl isoindolones by a Pd-mediated C-H activation/annulation reaction

Article abstract of DOI:10.1002/chem.201302031

Radical reaction: A convenient synthesis of hydroxyl isoindolones by a Pd-catalyzed C-H activation/annulation reaction with near "click chemistry" efficiency is presented (see scheme; TBHP=tert-butyl hydrogen peroxide). This methodology features short reaction times (10-30 min), high atom economy, wide substrate scope (22 examples), and good reaction yields (up to 93 %). Copyright

Full text of DOI:10.1002/chem.201302031

COMMUNICATION
Radical reaction: A convenient synthe-
sis of hydroxyl isoindolones by a Pd-
Heteroycles
À
catalyzed C H activation/annulation
Q. Yu, N. Zhang, J. Huang,* S. Lu,
reaction with near “click chemistry”
efficiency is presented (see scheme;
TBHP=tert-butyl hydrogen peroxide).
This methodology features short reac-
tion times (10–30 min), high atom
economy, wide substrate scope (22
examples), and good reaction yields
(up to 93%).
Y. Zhu, X. Yu, K. Zhao* . . . &&&& — &&&&
Efficient Synthesis of Hydroxyl Isoin-
À
dolones by a Pd-Mediated C H Acti-
vation/Annulation Reaction
Chem. Eur. J. 2013, 00, 0 – 0
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DOI: 10.1002/chem.201302031
À
Efficient Synthesis of Hydroxyl Isoindolones by a Pd-Mediated C H
Activation/Annulation Reaction
Qingzhen Yu,[a] Nana Zhang,[a] Jianhui Huang,*[a, b] Shaonan Lu,[a] Yi Zhu,[a]
Xiaoxiao Yu,[a] and Kang Zhao*[a]
The construction of heterocycles under transition-metal-
catalyzed bimolecular C<C->H activation/annulation reac-
tions has been very well recognised as one of the most pow-
erful methods in modern synthetic organic chemistry.[1] The
beauty of these approaches is that the syntheses can proceed
in an atom-economic and modular fashion. However, most
of the reactions have employed excess amounts of external
oxidant and require long reaction times. For our on-going
À
research interests, we are keen to develop efficient C H ac-
tivation/annulation reactions for the preparation of hetero-
cycles to mimic click chemistry efficiency.[2,3]
Hydroxyl isoindolones/isopyrrolones are a useful class of
heterocycles that have been found in natural products and
APIs, selected examples are illustrated in Figure 1. Eszopi-
clone,[4] chlortalidone,[5] chilenine,[6] (À)-leuconolam,[7] and
Figure 1. Biologically active compounds with a hydroxyl isoindolone/pyr-
rolone skeleton.
UCN-01 (7-hydroxystaurosporine)[8] are all biologically
active ingredients that contain hydroxyl isoindolone/isopyr-
rolone.
synthesis of hydroxyl isoindolonoes; however, the process
utilized six equivalents of Ag source as the oxidant. Herein,
À
The direct syntheses of aryl ketones by directed C H acti-
vation of arenes and aldehydes have been studied, those re-
actions generally require more than 10 hours;[10] however,
À
the first Pd-catalyzed C H activation/annulation reaction
for the facile preparation of hydroxyl isoindolones with near
“click chemistry” efficiency is presented. This methodology
features environmentally benign reagents, short reaction
times (within 15 min), high atom efficiency (loss of 2 H
atoms), wide scope (22 examples), and good yields (up to
93%; Scheme 1). A gram-scale synthesis with nonchromato-
graphic purification is also demonstrated.
À
the directed C H activation/annulation reaction has less
been exploited. To the best of our knowledge, so far only
Kim and co-workers have reported the synthesis of hydroxyl
isoindolones under Rh-catalyzed double-activation reactions
of benzamides and aldehydes.[9] It was the first C H activa-
À
tion/cyclization protocol for the construction of hydroxyl
isoindolones although the approach is limited with N-iPr
benzamide and the coupling partners have to be aryl alde-
hydes. Their strategy has provided a novel solution for the
The proof of concept was carried out by using N-OMe
benzamide[11] and benzaldehyde as the starting substrates.
[a] Q. Yu, N. Zhang, Prof. Dr. J. Huang, S. Lu, Y. Zhu, X. Yu,
Prof. Dr. K. Zhao
Tianjin Key Laboratory for Modern Drug Delivery &
High-Efficiency, School of Pharmaceutical Science and Technology
Tianjin University, 92 Weijin Road, Nankai District
Tianjin (P. R. China)
Fax : (+86)2227404031
E-mail: jhuang@tju.edu.cn
kangzhao@tju.edu.cn
[b] Prof. Dr. J. Huang
Synergetic Innovation Center of Chemical Science and
Engineering
Tianjin (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302031.
Scheme 1. Hydroxyl isoindolone syntheses.
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Synthesis of Hydroxyl Isoindolones
Table 1. Reaction condition screening.[a]
COMMUNICATION
Table 2. Benzamide scope.[a]
Entry
Cat.
Oxidant
t [min]
Yield [%]
1
2
3
4
5
6
7
Pd
Pd
Pd
N
TBHP
30
30
10
20
10
73
81
91
89
68
69
0
TBHP[b]
TBHP[c]
TBHP[c]
TBHP[c]
TBHP[c]
TBHP[c]
R
G
G
G
40
600
–
[a] Reaction conditions: Benzamide 1a (45 mg, 0.3 mmol), benzaldehyde
(95 mg, 0.9 mmol), Pd catalyst (10 mol%), TBHP (40% in H2O)
(2.0 equiv) at 1008C (1.5 mL, 0.2m), 10 min–5 h. [b] TBHP (3.0 equiv)
was used. [c] TBHP (5.0 equiv) was used. [d] Catalyst (5 mol%) was
used.
Gratifyingly, when benzamide was treated with three equiv-
alents of benzaldehyde in the presence of 10 mol% of Pd-
ACHTUNGTRENNUNG(OAc)2 and two equivalents of tert-butyl hydrogen peroxide
(TBHP) in dioxane at 1008C for 30 min, our desired hydox-
yl isoindolone 1a was successfully isolated in a good 73%
yield (Table 1, entry 1). Solvent screening has shown that di-
oxane is the optimal solvent prior to those polar and nonpo-
lar solvents, such as DMF, AcOH, H2O, BuOH, and toluene
(see the Supporting Information for details). Oxidant evalu-
ations have revealed that K2S2O8 and (NH4)2S2O8 are poor
oxidants for the reaction that failed to provide our desired
product 3a. Oxidants, such as 1,4-benzoquinone (BQ) and
Ag2O, were demonstrated to be unreactive for the reaction,
whereas peroxides, such as meta-chloroperbenzoic acid (m-
CPBA) and H2O2 had shown poor reactivity. The reaction
using azobisisobutyronitrile (AIBN) has also failed to give
the desired isoindolone (see the Supporting Information for
details). The increase of the amount of the cheap readily
available oxidant TBHP resulted in a good 81% yield
(entry 2). Interestingly, when five equivalents of TBHP were
employed the reaction time was reduced to 10 min and the
reaction yield increased to an excellent 91% (entry 3).
Other Pd catalysts, for instance, PdCl2 also produced isoin-
dolone 3a in a good 89% yield, albeit with a slightly longer
[a] Reaction conditions: Benzamide 1 (0.5 mmol), benzaldehyde (159 mg,
1.5 mmol), Pd(OAc)2 (10 mol%), TBHP (5.0 equiv) at 1008C in dioxane
(2.5 mL, 0.2m), 15 min. [b] Reaction time: 30 min.
AHCTUNGTRENNUNG
gave the corresponding hydroxyl isoinodolones 3b–f in good
yields (68–83%), whereas para-OMe benzamide gave our
desired isoindolone in a good 78% yield. Benzamides with
ortho- and meta-substituents are also good substrates for
these reactions; the corresponding hydroxyl isoindolones
(3h–k) were obtained in good to excellent yields. The regio-
À
selectivity of C H activation of amides 1j and 1k is excel-
lent at the less hindered position providing the correspond-
ing products in much higher yields compared to Rh-cata-
[12]
À
lyzed C H activation reactions. Reaction of disubstituted
benzamide with benzaldehyde also underwent the activa-
tion/annulation process fluently and delivered the desired
isoindolone 3l in a good 61% yield. Unfortunately, under
À
our optimal conditions, the C H activation did not occur
reaction time, whereas the reaction using [Pd
N
when heteroamides, such as N-methoxypicolinamide and N-
methoxynicotinamide, were employed.
fluoroacetic acid) required similar short reaction times with
slightly reduced yield (entries 4 and 5). Interestingly, howev-
er, [Pd2ACHTUNGTRENNUNG(dba)3] (dba=dibenzylideneacetone) is also demon-
Under the optimal conditions, reactions with all of the
benzamides possessing electron-withdrawing or -donating
substitutes gave the corresponding products in good to ex-
cellent yields. Benzamides with para-electron withdrawing
substituents gave the corresponding hydroxyl isoinodolones
3b–f in good yields (68-83%), whereas para-OMe benza-
mide gave our desired isoindolone in a good 78% yield.
Benzamides with ortho- and meta-substituents are also good
substrates for these reactions; the corresponding hydroxyl
isoindolones (3h–k) were obtained in good to excellent
yields. Reaction of disubstituted benzamide with benzalde-
hyde also underwent the activation/annulation process flu-
strated to be an efficient catalyst for the reaction albeit with
a slightly longer reaction time and lower yield (entry 6). In
the absence of Pd catalyst, the reaction did not proceed and
only unreacted starting material was recovered (entry 7).
The scope of the Pd-catalyzed reaction with various ben-
zamides with benzaldehyde is summarized in Table 2. Under
the optimal conditions, reactions with all of the benzamides
possessing electron-withdrawing or -donating substituents
gave the corresponding products in good to excellent yields.
Benzamides with para-electron-withdrawing substituents
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J. Huang, K. Zhao et al.
Table 3. Reactions with various aldehydes.[a]
Table 4. Reactions with various N-substituted benzamides.[a]
[a] Reaction conditions: Benzamide 1 (0.5 mmol), benzaldehyde (159 mg,
1.5 mmol), Pd(OAc)2 (10 mol%), TBHP (5.0 equiv) at 1008C in dioxane
AHCTUNGTRENNUNG
(2.5 mL, 0.2m), 15 min. [b] TsOH (0.2 equiv) was added, reaction time:
1 h.
[a] Reaction conditions: Benzamide 1 (0.5 mmol), aldehyde 2 (1.5 mmol),
PdACHTUNGTRENNUNG(OAc)2 (10 mol%), TBHP (5.0 equiv) at 1008C in dioxane (2.5 mL,
Scheme 2. Gram-scale synthesis by using 1 mol% of PdACHTNUTRGNEUNG(OAc)2.
0.2m), 15 min.
complex reaction mixtures due to the sensitive isoindolone
ring system.
ently and delivered the desired isoindolone 3l in a good
61% yield.
To have a better understanding of the reaction mecha-
nism, a series of experiments were carried out to answer the
crucial questions: 1) Whether or not the reaction is a radical
reaction? 2) Whether the nitrogen radical is beneficial for
Unlike Kimꢁs conditions, our reaction is not limited to
aryl aldehyde. The reactions also tolerated aliphatic alde-
hydes well. As depicted in Table 3, reactions of both elec-
tron-deficient and -rich aryl aldehydes underwent the reac-
tion fluently and gave our desired products 3m and 3n in
good 79 and 82% yields. Reactions with both primary and
secondary aldehydes also went fluently and gave our desired
alkyl-substituted hydroxyl isoindolones in good 65% to
88% yields. It is worth noting that reactions with electron-
deficient aldehydes, such as cinnamic aldehyde and ethyl 2-
oxoacetate, failed to give the corresponding hydroxyl isoin-
dolones. Fortunately, when (E)-2-methyl-3-phenylacrylalde-
hyde was untilized instead of cinnamic aldehyde, isoindo-
lone 3s was successfully isolated in 43% yield.
The reactions with both N-alkoxy and N-alkyl-substituted
benzamides have also been evaluated. Both primary and
secondary N-alkoxy have shown good reactivity as the prod-
ucts 3a, 3u, and 3v were obtained in 76–91% yields
(Table 4). In addition, N-methyl hydroxylisoinodolone 3w
was also successfully prepared with the introduction of a
catalytic amount (0.2 equiv) of TsOH.
À
the fast reaction? 3) Whether the C H activation is an oxi-
dative addition process or Friedel–Crafts-type of transfor-
mation? 4) Whether the reductive elimination process oc-
curred before cyclization? See below for a discussion of the
results.
1) Radical processes: Firstly, the radical inhibitor di-tert
butyl methyl phenol was subjected to the reaction mix-
ture.[14] As expected, the reaction was totally retarded
and only 95% of unreacted benzamide 1a was isolated
without the detection of any desired product, which fur-
ther proved that our reaction underwent a radical proc-
ess (Scheme 3, for reaction details see the Supporting In-
formation).
With the good reaction scope, a gram-scale preparation
was also investigated. Pleasingly the reaction can be con-
ducted under similar conditions even with 1 mol% of Pd
catalyst loading, in which our desired product was isolated
by cystallization in a good 65% yield without column chro-
matography (Scheme 2).
Scheme 3. Reaction with radical inhibitor.
2) Nitrogen radical initiation: With respect to the nitrogen
radical generation, we have also isolated ester 4 in 23%
yield together with 69% of our desired isoindolone 3 f
during the reaction of benzamide 1 f and benzaldehyde
À
With respect to the synthesis of N H hydroxyl isoindo-
À
lone, attemps on the N O bond cleavage under both our
NaH conditions[1i] and Fisherꢁs TiCl3 conditions[13] resulted in
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Synthesis of Hydroxyl Isoindolones
COMMUNICATION
no cyclization product was observed and amide 6 was
isolated in 36% yield with 47% of recovered starting
amide 5 (Scheme 7).
Scheme 4. Isolation of ester 4.
Scheme 7. Control experiment.
under our optimal conditions (Scheme 4). The formation
of 4 is believed to be formed by radical dimerization of
4) Reductive elimination: To find out whether the cycliza-
tion occured before Pd catalyst eliminated from the
system, we chose a five-membered thiophene amide 7 as
the substrate. Due to the strained nature as well as elec-
tronic effect of the heteraromatic ring, no cyclized isoin-
dolone 3v was observed and the corresponding ketone
amide 8 was isolated in 65% yield instead.
À
benzamide 1 f followed by the cleavage of the MeO N
bond with the loss of molecular nitrogen. The similar
radical processes have been discussed in Gloverꢁs early
studies of thermal decomposition of N,N-dialkoxya-
mides.[15] To further prove the generation of the nitrogen
radical, we conducted an experiment under similar con-
ditions in the absence of benzaldehyde. We were pleased
to find that the yield of the ester has increased rapidly to
41% after the reaction mixture was heated at 1008C for
7 h (Scheme 5).
With all the experimental evidence in hand, we have pro-
posed a plausible reaction pathway. As demonstrated in
Figure 2, radical activation of benzamide gives the amide ni-
trogen radical that undergoes radical addition[18] to form a
PdIII intermediate A. A benzaldehyde radical could also be
generated in the presence of TBHP and would possibly add
onto Pd intermediate A to provide the active PdIV species B.
As a side pathway, the reductive elimination of Pd inter-
mediate B would give amide 5, which could not be further
transformed into the final product as shown in Scheme 7.
In the main pathway, the formation of palladacycle C
Scheme 5. Radical transmetallation.
À
À
3) C H oxidative addition: The deuterium-labeled competi-
under fast C H activation is supposed to be due to the for-
mation highly reactive high-valent Pd intermediate B by
À
tion reaction has revealed that the C H bond cleavage is
the turnover limiting step as we have observed a kinetic
isotope effect (KIE) value of 3.0:1 (Scheme 6), which is
different from the Rh-catalyzed transformation for which
Kim has reported a KIE value of 1:1 for his hydroxyl
isoindolone synthesis. In these cases of hydroxyl isoindo-
either reductive elimination and oxidative addition onto the
C H bond or a Friedel–Crafts-type of C H acitvation.
[19]
À
À
À
lone synthesis, Pd-catalyzed C H activation is irreversi-
ble,[16] whilst Rh-catalysis is reversible,[12,17] with the low
KIE value. As we have observed the formation of amide
5 (was isolated in 21% yield) during our reaction solvent
screening (see the Supporting Information, Table S1,
entry 1). This suggests benzamide 5 could be a reactive
intermediate in this reaction. To examine the possible
À
C H activation pathway, benzamide 5 was subjected to
the reaction under our standard reaction conditions and
Scheme 6. KIE studies.
Figure 2. Plausible catalytic cycle.
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J. Huang, K. Zhao et al.
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After reductive elimination, a new C C bond can be
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formed with Pd attached with a benzamide nitrogen atom.
Intramolecular cyclization provides PdII intermediate E that
readily undergoes another reductive elimination to give our
desired isoindolone 3 with the loss of Pd0. Pd0 can be reoxi-
dized into PdII for the next catalytic cycle. In thiophene ben-
zamideꢁs case, no further ring closure was obseved at the
stage of PdII intermediate D, instead only reductive elimina-
tion proceeded which provided the ketone benzamide 8
without the generation of hydroxyisoindolone (Scheme 8).
The proposed high oxidation state of Pd intermediate B
À
could be benificial for the fast C H activation processes.
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Scheme 8. Ketone amide formation without ring formation.
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In conclusion, the first Pd-catalyzed fast and convenient
À
synthesis of hydroxyl isoindolone by a C H activation/annu-
lation reaction has been reported. This fast and environmen-
À
tally benign radical C H activation approach has opened up
a potential direction for the future development of fast and
À
efficient C H direct functionalization. Further studies of the
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Experimental Section
Representative procedure: A solution of amide (0.5 mmol), aldehyde
(1.5 mmol), PdACHTUNGTRENNUNG(OAc)2 (10 mol%), and TBHP (40% in H2O, 2.5 mmol)
in 1,4-dioxane (2.5 mL) was heated at reflux under air for 15 min. After
the reaction was completed, the reaction mixture was allowed to cool
down to room temperature and EtOAc (20 mL) was added. The resulting
mixture was washed with saturated aqueous Na2S2O3 (20 mL). The organ-
ic layer was dried over anhydrous Na2SO4, filtered, and the solvent was
removed under reduced pressure to provide the crude product. The puri-
fication was performed by flash column chromatography on silica gel to
give the desired hydroxyl isoindolone 3.
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Acknowledgements
Financial support from the National Natural Science Foundation of
China (grant no. 21342001), Tianjin Natural Science Foundation (grant
no. 13JCQNJC04800), and the Innovation Foundation of Tianjin Univer-
sity (2013XJ-0005) are gratefully acknowledged. Valuable discussions
with Prof. J. Siegel (Tianjin University/University of Zurich) and Prof. Y.
Tang (Tianjin University) are also acknowledged.
[19] A. J. Hickman, M. S. Sanford, Nature 2012, 484, 177–185.
À
Keywords: C H activation/annulation
isoindolones · palladium · radical reaction
·
heterocycles
·
Received: May 27, 2013
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