Iron-catalyzed selective oxidation of N-methyl amines: highly efficient synthesis of methylene-bridged bis-1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol901751c

Methylene-bridged bis-1,3-dicarbonyl derivatives were synthesized efficiently by Iron-catalyzed oxidative reactions of 1,3-dicarbonyl compounds and N,N-dimethylaniline. Blpyrazoles and substituted 1,4-dlhydropyridlne were obtained by the reactions of bis-1,3-dicarbonyl compounds with hydrazines and ammonium acetate, respectively.

Full text of DOI:10.1021/ol901751c

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4176-4179
Iron-Catalyzed Selective Oxidation of
N-Methyl Amines: Highly Efficient
Synthesis of Methylene-Bridged
bis-1,3-Dicarbonyl Compounds
Haijun Li, Zhiheng He, Xingwei Guo, Wenjuan Li, Xuhui Zhao, and Zhiping Li*
Department of Chemistry, Renmin UniVersity of China, Beijing 100872, China
zhipingli@ruc.edu.cn
Received July 30, 2009
ABSTRACT
Methylene-bridged bis-1,3-dicarbonyl derivatives were synthesized efficiently by iron-catalyzed oxidative reactions of 1,3-dicarbonyl compounds
and N,N-dimethylaniline. Bipyrazoles and substituted 1,4-dihydropyridine were obtained by the reactions of bis-1,3-dicarbonyl compounds
with hydrazines and ammonium acetate, respectively.
The oxidation of amines,1,2 especially N-methyl amines,3 is
an important process and has attracted much interest in
Scheme 1
.
Direct Oxidative Functionalization of N-Methyl
chemistry and biochemistry. Catalytic functionalization of
a C-H bond adjacent to a nitrogen atom presents a direct
and efficient method of synthesizing amine derivatives.4 A
general mechanism for the oxidative functionalization of
N-methyl amine is shown in Scheme 1.5 An iminium species
A is generated by selective oxidation C-H bond adjacent
to nitrogen (Step a). Subsequently, the nucleophilic addition
reaction affords the oxidative Mannich-type products B in
Amines
the presence of a nucleophile (Step b), which were generally
synthesized by the Mannich reaction or the aza-Michael
addition reaction. However, selective double alkylation of
N-methyl amines is virtually unknown (Step c).6
(1) (a) Cytochrome P-450, Structure, Mechanism, and Biochemistry, 2nd
ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995. (b)
Gorrod, J. W. Biological Oxidation of Nitrogen; Elsevier/North Holland
Biomedical Press: New York, 1978
(2) (a) Murahashi, S.-I.; Zhang, D. Chem. Soc. ReV. 2008, 37, 1490. (b)
Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443
.
The application of readily available and nontoxic iron
catalysts instead of expensive and sensitive catalysts is highly
attractive for chemical synthesis.7 Iron-catalyzed oxidation
of N-methyl amines is of considerable interest in synthetic
chemistry.8,9 In conjunction with our recent result on
selective oxidation of C-H bonds adjacent to heteroatoms,10
we herein report a novel and efficient method of synthesizing
.
(3) (a) Yi, C.; Yang, C.-G.; He, C. Acc. Chem. Res. 2009, 42, 519. (b)
Chiavarino, B.; Cipollini, R.; Crestoni, M. E.; Fornarini, S.; Lanucara, F.;
Lapi, A. J. Am. Chem. Soc. 2008, 130, 3208. (c) Baciocchi, E.; Lapi, A.
Tetrahedron Lett. 1999, 40, 5425.
(4) For representative reviews, see: (a) Campos, K. R. Chem. Soc. ReV.
2007, 36, 1069. (b) Godula, K.; Sames, D. Science 2006, 312, 67. (c) Tobisu,
M.; Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683.
(5) For representative reviews, see: (a) Li, C.-J. Acc. Chem. Res. 2009,
42, 335. (b) Li, C.-J.; Li., Z. Pure Appl. Chem. 2006, 78, 935. (c) Murahashi,
S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33, 225. (d) Murahashi, S.-I. Pure
Appl. Chem. 1992, 64, 403.
(6) (a) Murata, S.; Miura, M.; Nomura, M. J. Org. Chem. 1989, 54,
4700. (b) Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc., Chem.
Commun. 1989, 116.
10.1021/ol901751c CCC: $40.75
Published on Web 08/14/2009
 2009 American Chemical Society

bis-1,3-dicarbonyl derivatives11 by the iron-catalyzed reac-
tions of 1,3-dicarbonyl compounds with N-methyl amines
under mild reaction conditions.
The reaction of ethyl 3-oxo-3-phenylpropanoate 1a and
N,N-dimethyl aniline 2a was investigated to examine the
suitable reaction conditions (Table 1). FeCl3, Fe(OAc)2, and
reaction time was one hour (entry 8). Some uncharacterized
byproducts were observed with a prolonged reaction time.
These results demonstrated that low loading catalyst and short
reaction time are essential for the high selectivity of the
present transformation.
Other N-methyl amines were also investigated under the
optimized reaction conditions (Table 2). The reaction of 1a
Table 1. Optimization of the Reaction Conditions
Table 2. Reactions of 1a with Other N-Methyl Amines
1a
2a
yield
entry (mmol) (mmol)
[Fe] (%)a
oxidant (mmol)b (%)a
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
FeCl3 (10)
Fe(OAc)2 (10) (t-BuO)2 (1.5)
FeBr2 (10)
FeCl2 (10)
Fe2(CO)9 (5)
Fe2(CO)9 (5)
(t-BuO)2 (1.5)
5
6
(t-BuO)2 (1.5)
(t-BuO)2 (1.5)
(t-BuO)2 (1.5)
t-BuOOH (1.5)
27
52
39
51
75
86c
Fe2(CO)9 (2.5) t-BuOOH (2.0)
Fe2(CO)9 (2.5) t-BuOOH (2.0)
a Based on 1a. b t-BuOOH (5.5 M in decane). c One hour.
FeBr2 were ineffective catalysts for the formation of 3a
(entries 1-3). The desired product 3a was obtained in 52%
yield when FeCl2 was used as a catalyst (entry 4). Although
Fe2(CO)9 led to 39% yield of 3a at 25 °C,12 a 51% yield of
3a was achieved when tert-butyl hydrogenperoxide (TBHP)
was used instead of di-tert-butyl peroxide (entries 5 and 6).
Importantly, up to 75% yield of 3a was obtained using 2.5
mol % of Fe2(CO)9 and 2.0 equivalents of TBHP (entry 7).
The yield of 3a was further improved to 86% when the
with 4-methyl N,N-dimethyl aniline affords a comparable
yield of the desired product 3a (Table 2, entry 1 vs Table 1,
entry 8), whereas electron-withdrawing substituted aniline
gave 3a in low yields (entries 2 and 3). These results were
consisted with the oxidative activities of 4-X-N,N-dimethy-
lanilines.13 Notably, aliphatic tertiary amines were not
effective methylenic sources (entries 4 and 5).
(7) For representative reviews, see: (a) Sherry, B. D.; Fu¨rstner, A. Acc.
Chem. Res. 2008, 41, 1500. (b) Correa, A.; Manchen˜o, O. G.; Bolm, C.
Chem. Soc. ReV. 2008, 37, 1108. (c) Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem., Int. Ed. 2008, 47, 3317. (d) Fu¨rstner, A.; Martin, R. Chem.
Lett. 2005, 34, 624. (e) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
ReV. 2004, 104, 6217.
Subsequently, the scope of the present transformation was
examined using N,N-dimethyl aniline 2a as a methylenic unit
source. Various 1,3-dicarbonyl compounds were transformed
into the corresponding methylene-bridged bis-1,3-dicarbonyl
products 3a with good to excellent yields under the optimized
conditions (Scheme 2). Not only ꢀ-ketone esters but also
ꢀ-ketone amide and 1,3-diketones reacted smoothly with
N,N-dimethyl aniline 2a. No obvious electronic effect was
observed with 1 bearing an aromatic ring. However, the
desired methylene-bridged bis-1,3-dicarbonyl products were
obtained in low yields (ca.10-30%) when pentane-2,4-dione
and ethyl 3-oxobutanoate were used. We postulated that a
stabilized intermediates introduced by aromatic substituent
improves the efficiency of the present transformation.14 Two
diastereomers were obtained in ratios between 0.7 and 1.15
Pyrazoles are an important class of heteroaromatic ring
systems and exist in nature products, medical molecules, and
metallic ligands.16 With the methylene-bridged bis-1,3-
(8) Iron-catalyzed oxidation of N-methyl amines, see: Volla, C. M. R.;
Vogel, P. Org. Lett. 2009, 11, 1701.
(9) Other metal-catalyzed reactions, see: [Ru]: (a) Murahashi, S.-I.;
Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005. (b)
Murahashi, S.-I.; Komiya, N.; Terai, H. Angew. Chem., Int. Ed. 2005, 44,
6931. (c) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem.
Soc. 2003, 125, 15312[Cu]: (d) Huang, L.; Zhang, X.; Zhang, Y. Org. Lett.
2009, 11, 3730. (e) Chu, L.; Zhang, X.; Qing, F.-L. Org. Lett. 2009, 11,
2197. (f) Xu, X.; Li, X. Org. Lett. 2009, 11, 1027. (g) Shen, Y.; Li, M.;
Wang, S.; Zhan, T.; Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 953. (h)
Basle, O.; Li, C.-J. Green Chem. 2007, 9, 1047. (i) Zhang, Y.; Fu, H.;
Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813. (j) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2004, 126, 11810[Rh]: (k) Catino, A. J.; Nichols, J. M.; Nettles,
B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648.
(10) (a) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497.
(b) Li, Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.; Pan, S. Org. Lett. 2008,
10, 803.
(11) (a) Karvembu, R.; Natarajan, K. Polyhedron 2002, 21, 219. (b)
Martin, D. F.; Shamma, M.; Fernelius, W. C. J. Am. Chem. Soc. 1958, 80,
5851.
(12) The oxidative coupling product 9 was obtained as the major product
in 53% yield and bis-1,3-dicarbonyl compound 4a was only isolated in
trace amount at 80 °C; see ref 10.
(13) (a) References 8 and 9. (b) Baciocchi, E.; Lanzalunga, O.; Lapi,
A.; Manduchi, L. J. Am. Chem. Soc. 1998, 120, 5783.
Org. Lett., Vol. 11, No. 18, 2009
4177

acetate 7. The applications of the bis-1,3-dicarbonyl com-
pounds 1 and their derivatives in coordination chemistry and
synthetic chemistry are under investigated in this lab.
Interestingly, the oxidative coupling product 9 was ob-
tained in 47% yield together with 37% yield of 3a in the
presence of 10 equiv of 2a (eq 1). Subsequently, 9 was
subjected to the standard reaction conditions and 3a was
obtained with 91% yield (eq 2). The results suggested that
the oxidative-coupling product 9 is most likely a possible
intermediate for the present transformation. It was further
confirmed by the formation of the crossed product 3m under
the standard reaction conditions (eq 3).
Scheme 2. Some Representative Results
Based on these results, a plausible scenario of the
formation of the methylene-bridged bis-1,3-dicarbonyl prod-
uct 3 is illustrated in Scheme 4. The reaction of 1 and 2
dicarbonyl compounds in hands, bipyrazoles were synthe-
sized efficiently by the reported method (Scheme 3).17 In
Scheme 4. Possible Pathways for the Formation of 3
Scheme 3. Representative Drivatization of 3
affords the oxidative coupling product 9. 3 is formed by
either nucleophilic substitution reaction or the tandem
reaction of Cope elimination and Michael addition via a
intermediate 10 in the presence of iron catalyst and oxidant.
However, the reaction of 1,3-dicarbonyl compounds 1 with
formaldehyde, which was generated in situ via iron-catalyzed
(14) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46, 6505.
(15) The ratios of diastereomers were given in the Supporting Informa-
tion.
(16) (a) Elguero, J. ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol.
5. (b) Steel, P. J. Coord. Chem. ReV. 1990, 106, 227.
(17) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675.
addition, the substituted 1,4-dihydropyridine 8 was obtained
in moderate yield by the reaction of 3a and ammonium
4178
Org. Lett., Vol. 11, No. 18, 2009

oxidative N-demethylation,18 would also afford the methyl-
ene-bridged bis-1,3-dicarbonyl product 3.19 Therefore, this
alternative pathway could not be fully excluded at this stage.
In summary, we demonstrated a novel and efficient method
of synthesizing methylene-bridged bis-1,3-dicarbonyl deriva-
tives via iron-catalyzed oxidation of N-methyl amines.
Bipyrazoles and substituted 1,4-dihydropyridine were ob-
tained by the reaction of methylene-bridged bis-1,3-dicar-
bonyl compounds with hydrazines and ammonium acetate.
The mild reaction conditions and the high efficiency of the
oxidative functionalization make the present transformation
attractive for future applications.
Acknowledgment. We thank the program for New
Century Excellent Talents in University and the NSFC
(20602038 and 20832002) for the financial support. We are
indebted to Prof. Zhenfeng Xi, Peking University.
Supporting Information Available: Representative ex-
perimental procedure, characterization of all new compounds,
Nash test and 1H NMR and 13C NMR data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) The formation of formaldehyde in the present transformation was
proven by Nash test; the detailed experiments of Nash test were given in
the Supporting Information.
(19) (a) Nakanishi, M.; Bolm, C. AdV. Synth. Catal. 2007, 349, 861.
(b) Lecomte, V.; Bolm, C. AdV. Synth. Catal. 2005, 347, 1666. (c) Wilson,
B. D. J. Org. Chem. 1963, 28, 314.
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