Palladium-catalyzed phthalazinone synthesis using paraformaldehyde as carbon source

Article abstract of DOI:10.1021/ol502498y

A palladium-catalyzed one-pot synthesis of phthalazinones from 2-halomethyl benzoates, paraformaldehyde, and aryl hydrazines is described. Various substituted phthalazinones were selectively obtained in good yields using paraformaldehyde as the cheap carbon source (CH). (Chemical Equation Presented).

Full text of DOI:10.1021/ol502498y

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Phthalazinone Synthesis Using
Paraformaldehyde as Carbon Source
Huamin Wang,† Jinhui Cai,† Huawen Huang,† and Guo-Jun Deng*,†,‡
†Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
‡Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080,
China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed one-pot synthesis of
phthalazinones from 2-halomethyl benzoates, paraformaldehyde,
and aryl hydrazines is described. Various substituted phthalazi-
nones were selectively obtained in good yields using
paraformaldehyde as the cheap carbon source (CH).
itrogen-containing heterocycles are frequently found in
pharmaceutical drugs, agrochemicals, and functional
Scheme 1. Various Procedures for the Phthalazinone
Synthesis
N
materials.1 Among the numerous nitrogen-containing hetero-
cycles, phthalazinones represent a class of annulated six-
membered N-heterocycles and exhibit many important bio-
logical activities. Phthalazinones show great potential in the
treatment of a variety of disorders, such as diabetes,2 hepatitis B,3
asthma,4 and arrhythmia.5 For example, Astelin is an antihist-
amine and is used to treat nasal allergy symptoms (Figure 1, 2008
procedure. Carbon monoxide (CO) is frequently used as the
carbonyl source to construct various carbonyl-containing
compounds such as aldehydes, amides, and esters.11 In 2012,
Beller and co-workers reported a palladium-catalyzed procedure
for the synthesis of phthalazinones from 2-bromobenzaldehydes,
CO, and hydrazines (Scheme 1b).12 In this transformation, a
broad range of substituted phthalazinones were efficiently
prepared using CO as the carbonyl source. To avoid the use of
toxic CO gas, solid metal carbonyl complexes such as Mo(CO)6
and Co2(CO)8 also could be used as the carbonyl source for this
kind of transformation.13 In a similar transformation, the
isocyano group could serve as an efficient carbon source to
afford 4-aminophthalazin-1(2H)-ones using palladium as the
catalyst.14
Figure 1. Selected drugs containing phthalazinone moiety.
sales $0.24 billion).6 Moreover, phthalazinone derivatives are
used as potent inhibitors of poly(-ADP-ribose)polymerase-1
(PARP-inhibitor).7 The phthalazinone moiety can serve as the
key building block for the preparation of the phosphodiesterase-4
(PDE-4) inhibitor.8
Because of their significant value in pharmaceuticals, the
synthesis of phthalazinone and its derivatives has attracted
considerable interest.9 In general, two classes of reactions are
developed to assemble the six-membered heterocycle moiety.
One is based on the two-component cyclocondensation [4 + 2]
of 2-carboxybenzaldehydes and hydrazines generally under
transition-metal-free conditions (Scheme 1a).10 In this process,
the 2-carboxybenzaldehydes afford four carbons and hydrazines
afford two nitrogen atoms. However, the substrate scope based
on 2-carboxybenzaldehydes is very limited. The second-class
reactions are mainly based on the [3 + 2 + 1] three-component
Paraformaldehyde is an abundant, easy to handle, and
inexpensive one carbon source. In recent years, various methods
Received: August 24, 2014
Published: September 29, 2014
© 2014 American Chemical Society
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Letter
have been developed to introduce paraformaldehyde into more
complex molecules as carbonyl or carbon source.15 Very recently,
Beller and co-workers disclosed a palladium-catalyzed carbon-
ylation of aryl bromides to selectively afford aromatic aldehydes
using paraformaldehyde as the CO source.16 Although there are
few other methods available to prepare phthalazinones, efficient
methods for construction of them using readily available and
nontoxic starting materials are highly desirable. Herein, we report
a palladium-catalyzed three-component procedure [3 + 2+1] to
prepare phthalazinones from 2-halomethyl benzoates, aryl
hydrazines and paraformaldehyde (Scheme 1c). Various
substituted phthalazinones were selectively obtained in good
yields using paraformaldehyde as the carbon source (CH).
We began our investigation by subjecting methyl 2-
bromobenzoate (1a), paraformaldehyde, and phenylhydrazine
(2a) to the catalytic system of Pd(OAc)2, 4,5-bis-
(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and
K2CO3 in toluene at 150 °C for 24 h, which gave the target
product 3a in 71% GC yield (Table 1, entry 1). Several other
phosphine ligands were investigated, and lower yields were
observed (entries 2−6). Among the various base investigated,
K2CO3 showed the best efficiency (entries 7−11). The screening
of different palladium salts demonstrated that Pd(TFA)2 was
best for this reaction, and the corresponding product was
obtained in 74% yield (entry 15). Other organic solvents, such as
DMSO, anisole, PhCl, and NMP, did not give any improvement
in the reaction yield (entries 16−19). Gratifyingly, the reaction
yield could be increased to 85% when the reaction was performed
at a slightly elevated temperature (entry 20). When the model
reactions were performed without palladium, ligand or base,
none or a trace amount of the product 3a was observed (entries
21−23).
Having established the optimized reaction conditions (Table
1, entry 20), the scope and generality of the reaction were first
explored by using a series of arylhydrazines. Under the optimized
reactions, the model reaction of 1a and 2a in the presence of
paraformaldehyde afforded 3a in 81% isolated yield (Table 2,
a
Table 2. Reactions of 1a with Various Hydrazines
a
Table 1. Optimization of the Reaction Conditions
a
Conditions: 1a (0.2 mmol), 2 (0.4 mmol), paraformaldehyde (0.4
mmol), Pd(TFA)2 (5 mol %), Xantphos (10 mol %), K2CO3 (0.24
b
mmol), toluene (0.6 mL), 24 h, 160 °C. Isolated yields based on 1a.
entry 1). Phenylhydrazines bearing an alkyl or alkoxyl group at
the para position, such as −CH3, −CH2CH3, −C(CH3)3,
−OCH3, and −OCF3, coupled smoothly with 1a to give the
corresponding products in 78% (3b), 75% (3c), 61% (3d), 75%
(3e), and 76% (3f) yields, respectively. Halogen substituents on
the benzene ring, including F and Cl, were compatible for this
kind of cyclization (entries 7 and 8). An electron-withdrawing
functional group, such as 4-CN (2i), was well tolerated to give
the desired product 3i in 49% yield (entry 9). In addition, a slight
steric effect was observed since the substrates bearing a meta- or
ortho-substituent led to relatively lower yields compared to para-
substituted variant (51%−70% yields, entries 10−13). When 3,5-
dimethylphenylhydrazine (2n) was used, the desired product 3n
could be obtained in 68% yield (entry 14).
a
Subsequently, the reaction scope with respect to ester
substrates is presented in Table 3. In addition to aryl bromides,
aryl chloride 1b and aryl iodide 1c also smoothly reacted with 2a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), paraformaldehyde (0.4
mmol), catalyst (5 mol %), ligand (10 mol %), base (0.24 mmol),
solvent (0.6 mL), 24 h, 150 °C. GC yield. At 160 °C.
b
c
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Letter
a
Table 3. Reactions of 2a with Various Esters
Scheme 2. Control Experiments
possible intermediate product, which as expected coupled well
with 2a under the standard conditions to give 3a in 90% GC yield
(Scheme 2b). Further investigation indicated that Pd(TFA)2 and
K2CO3 could independently promote this condensation
reaction, affording 3a in 70% and 46% yields, respectively
(Scheme 2b). These results suggested that the Pd catalyst
probably played a dual role, as a transition metal to initiate
carbonylation and as a Lewis acid to facilitate condensation.
On the basis of the above observation and previous work by
others,12−14,17 a plausible mechanism for the three-component
reaction is proposed in Scheme 3. The reaction starts with the in
Scheme 3. Possible Reaction Mechanism
a
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), paraformaldehyde (0.4
mmol), Pd(TFA)2 (5 mol %), Xantphos (10 mol %), K2CO3 (0.24
b
mmol), toluene (0.6 mL), 24 h, 160 °C. Isolated yields based on 2a.
situ generation of a Pd(0) species from the Pd(II) catalyst.
Oxidative addition of the carbon−halogen bond of 1a to the
Pd(0) species affords intermediate I. Then, the migratory
insertion of paraformaldehyde into the Ar−Pd bond gives
intermediate II, with a subsequent β-hydrogen elimination to
produce methyl 2-formylbenzoate III and palladium hydro-
bromide complex. Finally, intermolecular [4 + 2] cyclo-
condensation of III and hydrazine 2a delivers the desired
product 3a. The catalytically active Pd(0) is regenerated through
reductive elimination of the PdHBr complex. Alternatively,
Beller16 et al. proposed that paraformaldehyde would be first
converted into CO in the reported carbonylation and
alkoxycarbonylation of aryl bromides. Another possible mech-
anism might be also reasonable. Paraformaldehyde is first
decomposed into CO and H2; subsequently, a typical reductive
carbonylation can occur to generate the aldehyde intermediate
III. Finally, the desired product 3a was generated from
cyclocondensation of III and hydrazine 2a.
and paraformaldehyde to provide the same product 3a in 78%
and 82% yields, respectively (entries 1 and 2). Moreover, ethyl 2-
bromobenzoate (1d) and isopropyl 2-bromobenzoate (1e)
coupled well with 2a to provide 3a in 77% and 61% yields,
respectively (entries 3 and 4). The reaction was generally
practicable with methyl 2-bromobenzoate bearing either
electron-withdrawing or electron-donating substituents. Methyl
(1f, 1j), methoxy (1g), and fluoro (1h, 1i) functionalities were all
tolerated, affording the corresponding products in excellent
yields (78%−88%, entries 5−9). Finally, methyl 2-chloro-4-
nitrobenzoate (1k) was proved to be a less efficient coupling
partner, which resulted in the desired product in only 25% yield
(entry 10).
To define the reaction mechanism, several control reactions
were investigated (Scheme 2). When the model reaction was
performed within 2 h, methyl 2-formylbenzoate (III) and (E)-
methyl 2-((2-phenylhydrazono)methyl)benzoate (IV) were
detected by GC−-MS in 6% and 31% yields, respectively
(Scheme 2a). Then, III was reasonably speculated to be a
In summary, we have discovered an efficient palladium-
catalyzed three-component coupling reaction of 2-halomethyl-
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Letter
J. Appl. Microbiol. Biotechnol. 1998, 49, 445. (f) Franck, P.; Hosty, S.;
benzoates, paraformaldehyde, and hydrazines, providing facile
access to pharmaceutically significant phthalazinones with a
broad functional group tolerance. In this transformation, the use
of paraformaldehyde as a one-carbon source features low toxicity,
low cost, and easy operation. Thus, this protocol should inspire
other cases of one-carbon design in organic synthesis. A detailed
reaction mechanism and further application of this reaction are
underway in our laboratory.
́
́ ́ ́
Dajka-Halasz, B.; Polonka-Balint, A.; Monsieurs, K.; Matyus, P.; Maes,
B. U. W. Tetrahedron 2008, 64, 6030. (g) Li, W.; Li, H.; Li, Z.
Tetrahedron Lett. 2010, 51, 5448. (h) Poli, D.; Catarzi, D.; Colotta, V.;
Vavano, F.; Filacchioni, G.; Daniele, S.; Trincavelli, L.; Martini, C.;
Paoletta, S.; Moro, S. J. Med. Chem. 2011, 54, 2102. (i) Mantovani, A. C.;
Goulart, T. A. C.; Back, D. F.; Zeni, G. Chem.Eur. J. 2014, 20, 12663.
(10) (a) Mitter, P. C.; Sen, J. N. J. Chem. Soc. Trans. 1919, 115, 1145.
(b) Racine, S. Justus Liebigs Ann. Chem. 1887, 239, 84. (c) Seekles, L. Rec.
Trav. Chim. Pays-Bas 1924, 43, 329. (d) Heravi, M. M.; Baghernejad, B.;
Oskooie, H. A.; Bamoharram, F. F. Heterocycl. Commun. 2008, 14, 375.
ASSOCIATED CONTENT
* Supporting Information
■
(e) Outerbridge, V. M.; Landge, S. M.; Tamaki, H.; Torok, B. Synthesis
̈
̈
S
2009, 11, 1801. (f) Shi, L. Y.; Wang, J. Q.; Cao, X. Q.; Gu, H. W. Org.
Lett. 2012, 14, 1876.
General experimental procedure and characterization data of the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) For selected examples, see: (a) Brennfuhrer, A.; Neumann, H.;
̈
Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114. (b) Wu, X. F.;
Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986. (c) Wu, X. F.;
Neumann, H.; Beller, M. ChemSusChem 2013, 6, 229. (d) Liu, Q.;
Zhang, H.; Lei, A. W. Angew. Chem., Int. Ed. 2011, 50, 10788. (e) Wu, X.
F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1. (f) Li, H. Q.;
Neumann, H.; Beller, M.; Wu, X. F. Green Chem. 2014, 16, 1336. (g) He,
L.; Sharif, M.; Neumann, H.; Beller, M.; Wu, X. F. Green Chem. 2014, 16,
3763. (h) Chen, J. B.; Neumann, H.; Beller, M.; Wu, X. F. Org. Biomol.
Chem. 2014, 12, 5835. (i) Chen, J. B.; Natte, K.; Spannenberg, A.;
Neumann, H.; Langer, P.; Beller, M.; Wu, X. F. Angew. Chem., Int. Ed.
2014, 53, 7579. (j) Wu, X. F.; Fang, X. J.; Wu, L. P.; Jackstell, R.;
Neumann, H.; Beller, M. Acc. Chem. Rev. 2014, 47, 1041. (k) Wu, X. F.;
Fang, X. J.; Wu, L. P.; Jackstell, R.; Neumann, H.; Beller, M. ACS Catal.
2014, 4, 2977.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gjdeng@xtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the New Century
Excellent Talents in University from Ministry of Education of
China (NCET-11-0974), and the Scientific Research Founda-
tion for Returned Scholars, Ministry of Education of China
(2011-1568).
(12) Wu, X. F.; Neumann, H.; Neumann, S.; Beller, M. Chem.Eur. J.
2012, 18, 8596.
(13) (a) Rao, K. P.; Basak, A. K.; Deb, P. K.; Sharma, S.; Reddy, L. K.
Tetrahedron Lett. 2013, 54, 3694. (b) Suresh, A. S.; Baburajan, P.;
Ahmed, M. Tetrahedron Lett. 2014, 55, 3482.
(14) Vlaar, T.; Ruijter, E.; Znass, Z.; Janssen, E.; Kanter, F. J. J. D.;
Maes, B. U.W.; Orru, R. V. A. Org. Lett. 2011, 13, 6496.
(15) For recent selected examples, see: (a) Garcia, J. M.; Jones, G. O.;
Virwani, K. Science 2014, 6185, 732. (b) Ganesan, S. S.; Ganesan, A.
Tetrahedron Lett. 2014, 55, 694. (c) Havlik, M.; Ddensky, B.; Jakubek,
M. Eur. J. Org. Chem. 2014, 2014, 2798. (d) Castello, L. M.; Najera, C.;
Sansano, J. M. Synthesis 2014, 7, 967.
(16) Natte, K.; Dumrath, A.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2014, 53, 10090.
(17) Jia, X. F.; Zhang, S. H.; Wang, W. H.; Luo, F.; Cheng, J. Org. Lett.
2009, 11, 3120.
REFERENCES
■
(1) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
VCH: Weinheim, 2003. (b) Katritzky, A. R.; Pozharskii, A. F. Handbook
of Heterocyclic Chemistry, 2nd ed.; Pergamon: Amsterdam, 2000.
(c) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:
Oxford, 2000. (d) Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.;
Zhdankin, V. V. Handbook of Heterocyclic Chemistry, 3rd ed.; Elsevier:
Oxford, 2010. (e) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.;
Longman: Upper Saddle River, NJ, 1997.
(2) Madhavan, G. R.; Chakrabarti, R.; Kumar, S. K. B.; Misra, P.;
Mamidi, R. N. V. S.; Balraju, V.; Kasiram, K.; Babu, R. K.; Suresh, J.;
Lohray, B. B.; Lohray, V. B.; Iqbal, J.; Rajagopalan, R. Eur. J. Med. Chem.
2001, 36, 627.
(3) El Ashry, E. S. H.; Abdel-Rahman, A. A. H.; Rashed, N.; Rasheed,
H. A. Pharmazie 1999, 54, 893.
(4) Ukita, T.; Sugahara, M.; Terakawa, Y.; Kuroda, T.; Wada, K.;
Nakata, A.; Ohmachi, Y.; Kikkawa, H.; Ikezawa, K.; Naito, K. J. Med.
Chem. 1999, 42, 1088.
(5) Engel, J.; Kutscher, B.; Fleischhauer, I.; Szeleny, S.; Metzaenauer,
P.; Werner, U. Eur. Patent EP 590551, 1994; Chem. Abstr. 1994, 121,
50100.
(6) (a) Nakajima, M.; Ohyama, K.; Nakamura, S.; Shimada, N.;
Yamazaki, H.; Yokoi, T. Drug Metab. Dispos. 1999, 27, 792.
(b) McTavish, D.; Sorkin, E. M. Drugs 1989, 38, 778.
(7) Cockcroft, X.; Dillon, K. J.; Dixon, L.; Drzewiecki, J.; Kerrigan, F.;
Loh, V. M.; Martin, N. M. B.; Menear, K. A.; Smith, G. C. M. Bioorg. Med.
Chem. Lett. 2006, 16, 1040.
(8) Van der Mey, M.; Bommele, K. M.; Boss, H.; Hatzelmann, A.; Van
Slingerland, M.; Sterk, G. J.; Timmerman, H. J. Med. Chem. 2003, 46,
2008.
(9) For selected examples, see: (a) Butala, I.; Ruzdija, A.; Kalmar, J.
́
Croat. Chem. Acta 1979, 52, 43. (b) Haider, N.; Kaferbock, J.; Matyus, P.
̈
̈
Heterocycles 1999, 51, 2703. (c) Sato, H.; Horie, S.; Sekikawa, N.; Ono,
H. DE Patent DE2, 632, 656, 1977; Chem. Abstr. 1977, 86, 171487.
(d) Hirayama, T.; Kamada, M. JP Patent JP52, 027,785, 1977; Chem.
Abstr. 1977, 87, 18454. (e) Sutherland, J. B.; Freeman, J. P.; Williams, A.
5327
dx.doi.org/10.1021/ol502498y | Org. Lett. 2014, 16, 5324−5327