Pd-catalysed synthesis of isoquinolinones and analogues via C-H and N-H bonds double activation

Article abstract of DOI:10.1039/c2cc17859a

An atom economical synthesis of isoquinolinones and analogues via ligand-free Pd-catalysed C-H and N-H double activation has been developed. A series of isoquinolinones were obtained in good to excellent yields. Good regioselectivities were also observed during the activation reactions with unsymmetrical alkynes. A practical one-pot procedure for the preparation of N-H isoquinolinones is also described. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17859a

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COMMUNICATION
Pd-catalysed synthesis of isoquinolinones and analogues via C–H and
N–H bonds double activationw
Hongban Zhong, Dan Yang, Songqing Wang and Jianhui Huang*
Received 16th December 2011, Accepted 1st February 2012
DOI: 10.1039/c2cc17859a
Table 1 Reaction conditions screening
An atom economical synthesis of isoquinolinones and analogues
via ligand-free Pd-catalysed C–H and N–H double activation
has been developed. A series of isoquinolinones were obtained in
good to excellent yields. Good regioselectivities were also
observed during the activation reactions with unsymmetrical
alkynes. A practical one-pot procedure for the preparation of
N–H isoquinolinones is also described.
Entries
Catalyst
Additive
2a (equiv.)
Yield
Atom economic synthesis has been one of the most popular
topics and attracted great attention in the last decade.1,2 In
particular, directed C–H activation by the use of coordinative
functional groups as directing handles as well as reacting sites
has offered important advantages.3
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
—
CoCl2
CuCl2
NaCl
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
3.0
3.0
27%
42%
31%
65%
72%
86%
74%
93%
47%
o5%
25%
o5%
NaBr
NaIꢀ2H2O
KI
In the past two years, the construction of isoquinolinones
using transition metals such as Rh and Ru has been established.
Rh catalysed reactions pioneered by Guimond/Fagnou,4 Rovis,5
Miura6 and Li7 have been reported. Three types of isoquinolinones
with different N-substituents are reported by utilizing the same
[Cp*RhCl2]2 catalyst.
NaIꢀ2H2O
NaIꢀ2H2O
NaIꢀ2H2O
NaIꢀ2H2O
NaIꢀ2H2O
9
10
11
12
Pd(dppf)Cl2
Pd(MeCN)2Cl2
Pd(OAc)2/dppf
Reaction conditions: benzamide 1a (45 mg, 0.3 mmol), alkyne 2a
(160 mg, 0.9 mmol), Pd catalyst (10 mol%), additive (1.0 equiv.)
at 120 1C in DMF (1.5 mL, 0.2 M), 7–24 h.
While reactions using transition metal Ru have also been
communicated by Ackermann8 and Li/Wang9 groups during
our study of Pd catalysed reactions early this year, however, to
the best of our knowledge, reactions using common transition
metal Pd salt have not been exploited. Herein, we report the
first Pd-catalysed approach for the synthesis of N-alkoxyl
isoquinolinone via N–H and C–H bonds double activation
of N-alkoxyl benzamide. By using this method, a range of
isoquinolinones and derivatives are successfully achieved in
good to excellent yields.
data of the isolated product did not agree with the product
previously reported by Guimond/Fagnou.4,10 Subsequently, the
chemical structure of our isolated product was determined by
X-ray crystallography which unambiguously confirmed the
assignment of the structure of 3a as drawn in Table 1. Reaction
optimization was then carried out. Solvents such as xylenes,
toluene and dichloroethane were ineffective for this transforma-
tion and the reactions only gave low yields (less than 15%),
while polar solvents such as tert-amyl alcohol afforded no
desired product even after the reaction mixture was heated at
reflux for 24 hours. Gratifyingly, polar aprotic solvent, DMF
led us to our desired isoquinolinone 3a in a relatively useful
27% yield. Inspired by these results, further optimizations by
the introduction of additives provided us with encouraging
results and the representative results are shown in Table 1.
A range of additives were evaluated and we were pleased to
find that transition metal salts CoCl2 and CuCl2 are good for the
isoquinolinone formation as shown in Table 1 entries 2 and 3,
the desired product was isolated in 42% and 31% respectively.
Cheap, readily available alkaline metal salts seem to be good
additives for the reaction. When NaCl was employed, the
reaction yield was increased to 65% and the bromide salt gave
We commenced our study with the treatment of a series of
benzamides with diphenyl acetylene in the presence of Pd(OAc)2
as the catalyst. Benzamide, N-methylbenzamide and N-phenyl-
benzamide are less efficient for this transformation as only
trace amounts of products were observed. Interestingly, when
N-methoxybenzamide 1a was treated with diphenyl acetylene,
we were pleased to find that our desired isoquinolinone was
formed in 27% yield (Table 1, entry 1). However, the analytical
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, China. E-mail: jhuang@tju.edu.cn;
Fax: 0086-22-27404031; Tel: 0086-22-27404031
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc17859a
c
3236 Chem. Commun., 2012, 48, 3236–3238
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even better yield. The combination of 10% of PdCl2 with
1.0 equivalent of NaOAc gave comparable results (59%) to the
reaction using Pd(OAc)2 and NaCl. NaIꢀ2H2O is proven to be
the most effective additive possibly due to the soft ligand
exchange processes (86% yield).11 With the excess use of
alkyne (3.0 equivalents), the reaction resulted in excellent
93% yield with the recovery of nearly 1.0 equivalent of the
unreacted alkyne.
3d and 3e were slightly lower. Alkynes with sp3 hybridized
substituents are also efficient for isoquinolinone synthesis as
products 3i and 3o were formed in good 66% and 62% yields.
More interestingly, when furyl and thiophenyl amides were
subjected to the reaction conditions, isoquinolinones 3g and 3h
were obtained in good yields. When the unsymmetrical internal
alkynes were employed, products were isolated in good yields
with good regioselectivity. As shown in Table 2, isoquinolinone
3ja and its regioisomer 3jb were observed in a 5 : 1 ratio which
can be isolated in 60% and 11% yields respectively. The
regiochemistry was determined by the comparison of the
corresponding known N–H isoquinolinone 4ja (see ESIw).4 In
addition, NOE study of product 3ka has further confirmed the
regioselectivity. The regioselectivity outcome is proposed in the
catalytic cycle.13,14 These may lead to the major regioisomer
with the relatively large group close to the nitrogen atom as
shown in 3j and 3k. When N-isopropoxy benzamide was
utilized, the reaction also demonstrated to be effective and
products with electron rich and deficient substituents were
successfully prepared albeit isoquinolinone 3n was given in a
moderate 53% yield. Reaction of N-isopropoxy benzamide and
unsymmetrical alkyne behaves similar to that of the corres-
ponding N-methoxy benzamide which leads to the 2 separated
regioisomers in an overall 70% yield. Unfortunately, attempts
on the reactions with terminal alkynes are not successful with
no obvious products isolated.
Other Pd sources were also examined, PdCl2 showed a
moderate reactivity and Pd(dppf)Cl2 and Pd(MeCN)2Cl2 did
not show better reactivities. The desired product 3a was not
formed when Pd(dppf)Cl2 was used and only 25% yield was
obtained when Pd(MeCN)2Cl2 was employed as the catalyst.
The introduction of external ligand dppf inhibited the reactivity
completely, only a trace amount of the product was obtained. It
is worth noting that during the reaction, no additional oxidant
is needed, air is supposed to be the green oxidant for the
regeneration of active Pd(II) species.12
With the optimal conditions in hand, studies towards the
scope of the reaction were carried out. A range of aryl carbamates
were examined and a series of isoquinolinones were successfully
prepared (Table 2).
For electron rich aromatic benzamides, the reactions are very
successful and the corresponding isoquinolinones 3b and 3c
were obtained in 92% and 76% yields respectively. The
introduction of an electron withdrawing group seems to
partially affect the reactivity as the yields of isoquinolinones
In addition, the removal of the methoxy group15 was also
studied. We were pleased to find that NaH is superior to other
inorganic bases16,17 to give isoquinolinone 4a in greater than
95% yield.
Table 2 Isoquinolinone and derivative synthesis
During the deprotection process, NaH is believed to be
chelated by both oxygen atoms of the amide carbonyl and
methoxy groups and the attack of hydride onto the oxygen atom
to break the N–O bond gave the desired N–H isoquinolinone 4a
as shown in Scheme 1.
Inspired by the deprotection by NaH, a one-pot procedure
was then examined. To our delight, both 1a and 1i were
successfully transformed into the corresponding isoquinolinones
after the standard C–H, N–H activation followed by the addition
of NaH. As described in Scheme 2, the desired product 4a
was isolated in excellent 96% and 92% yields respectively.
Scheme 1 Deprotection of N-methoxyisoquinolinone 3a.
Standard reaction conditions: benzamide 1 (0.3 mmol), alkyne 2a
(160 mg, 0.9 mmol), Pd(OAc)2 (10 mol%), NaIꢀ2H2O (1.0 equiv.) at
120 1C in DMF (1.5 mL, 0.2 M).a Separable regioisomers 3ja and 3jb
were observed in a ratio of 5 : 1 by 1H NMR of the crude reaction
b
mixture and were isolated in 60% and 11% respectively. In a 8 : 1
c
ratio with 76% and 9% isolated yields for the 2 regioisomers. In a
10 : 1 ratio with 64% and 6% yields respectively.
Scheme 2 One-pot synthesis of N–H isoquinolinones.
Chem. Commun., 2012, 48, 3236–3238 3237
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2 For recent reviews about C–H bond functionalizations, see:
(a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc.
Rev., 2011, 40, 5068; (b) J. F. Hartwig, Chem. Soc. Rev., 2011,
40, 1992; (c) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev.,
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(e) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011,
40, 1976; (f) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius,
¨
Chem. Soc. Rev., 2011, 40, 4740; (g) C. S. Yeung and V. M. Dong,
Chem. Rev., 2011, 111, 1215; (h) M. C. Willis, Chem. Rev.,
2010, 110, 725; (i) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem.
Commun., 2010, 46, 677; (j) L. Ackermann, Chem. Commun.,
2010, 46, 4866.
3 (a) F. W. Patureau and F. Glorius, Angew. Chem., Int. Ed., 2011,
50, 1977; (b) T.-T. Yuan, D.-D. Li and G.-W. Wang, Chem.
Commun., 2011, 47, 12789; (c) J. W. Wrigglesworth, B. Cox,
G. C. Lloyd-Jones and K. I. Booker-Milburn, Org. Lett., 2011,
13, 5326; (d) D. A. Colby, R. G. Bergman and J. A. Ellman,
Chem. Rev., 2010, 110, 624; (e) C.-C. Liu, K. Parthasarathy and
C.-H. Cheng, Org. Lett., 2010, 12, 3518; (f) L. Ackermann,
R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009,
48, 9792.
Fig. 1 Proposed catalytic cycle.
The relatively higher overall yields are due to the demethoxylated
isoquinolinone ring construction. The one-pot procedure was
also successfully employed for isoquinolinone 4ka and 4kb
synthesis as shown in Scheme 2.
4 (a) N. Guimond, S. I. Gorelsky and K. Fagnou, J. Am. Chem. Soc.,
2011, 133, 6449; (b) N. Guimond, C. Gouliaras and K. Fagnou,
J. Am. Chem. Soc., 2010, 132, 6908.
5 T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132,
10565.
6 S. Mochida, N. Umeda, K. Hirano, T. Satoh and M. Miura,
Chem. Lett., 2010, 744.
7 G. Song, D. Chen, C.-L. Pan, R. H. Crabtree and X. Li, J. Org.
Chem., 2010, 75, 7487.
8 (a) L. Ackermann and S. Fenner, Org. Lett., 2011, 13, 6548;
(b) L. Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem.,
Int. Ed., 2011, 50, 6379.
9 B. Li, H. Feng, S. Xu and B. Wang, Chem.–Eur. J., 2011,
17, 12573.
10 Under Guimond/Fagnou’s reaction conditions, their proposed
isoquinolinone may possibly be formed by the O-cyclisation and
the product could possibly be 3,4-diphenyl-1H-isochromen-1-one
O-methyl oxime 5a as shown below.
As previously reported in the Rh and Ru-catalysed reactions,
activation of the C–H bond proceeded first and the isoquinolinone
products were generated after the carbometallation and reductive
elimination processes. Analogous to Rh and Ru-mediated
reactions, in our case, active Pd(II) A was possibly formed
first when Pd(OAc)2 was subjected to the reaction system.
Activation of the adjacent C–H bond to the amide via directing
group participation18 with the loss of ligands gives a 5-membered
cyclic Pd adduct B (a similar reactive Pd intermediate had been
previously characterized by Wang19 and co-workers) which
can readily undergo the thermo cycloaddition to afford the
corresponding 7-membered Pd intermediate C.
Pd cycle B0 may also form during the reaction which is
considered to be less reactive with alkynes. The regioselectivity
is due to the addition of aryl-Pd of reactive intermediate B onto
the less hindered alkyne Csp centre which gave amide C in a
regioselective fashion. After reductive elimination the desired
product was obtained and the Pd(0) can be reoxidized by air to
regenerate Pd(II) species for the next catalytic cycle (Fig. 1).
In conclusion, we have developed an efficient approach for
the synthesis of isoquinolinones. A wide range of isoquinolinones
were successfully constructed with moderate to good yields with
good regioselectivity for unsymmetrical alkynes. In addition,
we have also described a novel one-pot synthesis of N–H
isoquinolinones via activation reaction followed by NaH
dealkoxylation. The detailed mechanistic studies are currently
ongoing and the communication will be reported in due course.
The financial support from the Cultivation Foundation for
the New Faculties from Tianjin University (No. 60302010) is
gratefully acknowledged. Acknowledgements are also given to
Professor Joseph P. A. Harrity (University of Sheffield, UK)
for his helpful discussions.
In their studies, O-cyclized product 5a may not be easily converted
into N–H isoquinolinone 4a as described in their control reactions.
11 (a) R. G. Pearson, J. Am. Chem. Soc., 1963, 85, 3533;
(b) R. G. Pearson, Science, 1966, 151, 172.
12 The reaction under a nitrogen atmosphere instead of air only
resulted in less than 50% conversion after the reaction mixture
was heated for 24 hours.
13 S. Cacchi and G. Fabrizi, in Carbopalladation of alkynes followed
by trapping with nucleophilic reagents in Handbook of Organo-
palladium Chemistry for Organic Synthesis, ed. E.-i. Negishi,
Wiley-Interscience, New York, 2002, vol. 1, p. 1335.
14 C. Amatore, S. Bensalem, S. Ghalem and A. Jutand, J. Organomet.
Chem., 2004, 689, 4642.
15 General methods for the cleavage of N–O bond, see: (a) S. P. Y.
Cutulic, J. A. Murphy, H. Farwaha, S.-Z. Zhou and E. Chrystal,
Synlett, 2008, 2132; (b) C. Taillier, V. Bellosta, C. Meyer and
J. Cossy, Org. Lett., 2004, 6, 2145.
16 KOH and K2CO3 were also examined and less than 30% reaction
conversion was observed when 3.0 equivalents of KOH or K2CO3
were used under similar reaction conditions.
17 K. V. Nikitin and N. P. Andryukhova, Mendeleev Commun., 2000,
10, 32.
Notes and references
1 For atom efficiency, see: (a) B. M. Trost, M. U. Frederiksen and
M. T. Rudd, Angew. Chem., Int. Ed., 2005, 44, 6630; (b) B. M. Trost,
Acc. Chem. Res., 2002, 35, 695; (c) B. M. Trost, Angew. Chem., Int.
Ed., 1995, 34, 259; (d) B. M. Trost, Science, 1991, 254, 1471.
18 R. B. Bedford, M. F. Haddow, C. J. Mitchell and R. L. Webster,
Angew. Chem., Int. Ed., 2011, 123, 5638.
19 G.-W. Wang, T.-T. Yuan and D.-D. Li, Angew. Chem., Int. Ed.,
2011, 50, 1380.
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3238 Chem. Commun., 2012, 48, 3236–3238
This journal is The Royal Society of Chemistry 2012