Metal-free synthesis of methylene-bridged bis-1,3-dicarbonyl compounds via oxidative C-C bond cleavage of tertiary aliphatic amines

Article abstract of DOI:10.1039/c4ra04419c

A metal-free Bu₄NI mediated oxidative reaction utilizing tertiary aliphatic amines and 1,3-dicarbonyl compounds for the synthesis of methylene-bridged bis-1,3-dicarbonyl compounds has been developed. This reaction involved an unexpected C-C bond cleavage of tertiary aliphatic amines. With this approach, the completely regioselective functionalization of β-carbon on tertiary amines was realized. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra04419c

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Metal-free synthesis of methylene-bridged bis-1,3-
dicarbonyl compounds via oxidative C–C bond
cleavage of tertiary aliphatic amines†
Cite this: RSC Adv., 2014, 4, 26783
Received 12th May 2014
Accepted 5th June 2014
Li-Juan Xing, Xi-Mei Wang, Hong-Ying Li, Wen Zhou, Ning Kang, Peng Wang
*
and Bin Wang
DOI: 10.1039/c4ra04419c
www.rsc.org/advances
A metal-free Bu4NI mediated oxidative reaction utilizing tertiary reactions with complete regioselectivity and environmental
aliphatic amines and 1,3-dicarbonyl compounds for the synthesis of benign oxidants would be highly desirable.
methylene-bridged bis-1,3-dicarbonyl compounds has been devel-
In continuation of our work on the development of green
oped. This reaction involved an unexpected C–C bond cleavage of and efficient synthetic methods for the oxidative coupling
tertiary aliphatic amines. With this approach, the completely regiose- reactions,5 we have recently reported quaternary ammonium
lective functionalization of b-carbon on tertiary amines was realized.
iodides mediated C3-selective formylation of indoles using N-
methyl anilines as the carbonyl source.5b,c In this study, we
demonstrate a Bu4NI-catalyzed oxidative coupling of tertiary
aliphatic amines with 1,3-dicarbonyl compounds. This metal-
free transformation, involving unprecedented C–C bond
cleavage of trialkylamines, provides an efficient access to
methylene-bridged bis-1,3-dicarbonyl compounds, which are
valuable precursors for heterocycles and materials synthesis3c,6
(Fig. 1b).
Our initial studies focused on Bu4NI-catalyzed oxidative-
coupling of 1,3-diphenyl-1,3-propanedione 1a with a variety of
different tertiary amines in the presence of aqueous tert-butyl
hydroperoxide (TBHP).7 All reactions was carried out in
Oxidative functionalization of a-carbon in tertiary amines with
subsequent formation of C–C or C–heteroatom bonds is an
attractive transformation in organic synthesis.1 This approach,
termed cross-dehydrogenative coupling (CDC) reaction, allows
use of less functionalized reagents and oen reduces the
number of steps to the target molecule.2 In most cases, N,N-
dialkylanilines or tetrahydroisoquinolines are used as coupling
partners (Fig. 1a), which have proved to be very efficient for the
generation of electrophilic iminium ions in the presence of
metal catalysts and terminal oxidants.1,2 These highly reactive
iminium ion intermediates can be readily trapped by a variety of
nucleophiles (step a). In some cases, the coupling product A was
subsequently converted to a methylene-bridged compound B
through a sequential CDC reaction and C–N bond cleavage (step
b).3
While a variety of synthetic methods are available for
oxidative coupling of N-methyl tertiary aromatic amines and the
reactions occur regioselectively at a-carbon (Fig. 1a), there are
relatively few general and practical approaches for the oxidative
functionalization of tertiary aliphatic amines, particularly the
selective functionalization of b-carbon in non-N-methyl-
substituted trialkylamines.4 Moreover, the current oxidative
coupling reactions of tertiary amine require metal catalysts,
regardless of whether the reaction occurs at a-carbon or b-
carbon. The development of metal-free oxidative coupling
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai
University, Tianjin, 300071, China. E-mail: wangbin@nankai.edu.cn; Fax: +86-22-
2350-7760; Tel: +86-22-2350-6290
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra04419c
Fig. 1 Oxidative functionalization of tertiary amines.
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1,4-dioxane at 25 ꢀC for 24 h or 60 ꢀC for 5 h, and the results were subjected to the present oxidative conditions, the corresponding
shown in Table 1. The oxidative coupling reaction of 1a with N,N- product 3a was not detected at all, regardless of changes in the
dimethylaniline 2a as the carbon source afforded methylene- reaction temperature or time (Table 1, entries 7 and 8). Very
bridged product 3a in 25% yield at 25 ꢀC, while higher tempera- interestingly, tertiary amines with long alkyl chain such as tri-
ture led to complex reaction mixtures and compound 3a was not propylamine 2i and tributylamine 2j could also afford the meth-
detected (Table 1, entry 1). The reaction produced 3a in a ylene-bridged product 3a, albeit in very low yields (Table 1, entries
moderate yield (48%) at 25 ꢀC when 4-methyl-N,N-dimethylaniline 9 and 10). In light of the success with DIPEA, we envisioned that
2b was used as the amine component, but it also proved to be bulky amines could be benecial to the reaction. Two sterically
unsuccessful at 60 ꢀC (Table 1, entry 2). Both N,N-diethylaniline 2c hindered tertiary amines 2k and 2l were then investigated
and N,N-dimethylbenzylamine 2d were ineffective for this trans- respectively. In the case of N-cyclohexyl-N-methylcyclohexanamine
formation at 25 ꢀC and 60 ꢀC (Table 1, entries 3 and 4). We then 2k, the desirable product 3a was formed only when the reaction
investigated tertiary aliphatic amines in this oxidative system. To was performed at 25 ꢀC (Table 1, entry 11). In contrast, another N-
our delight, the reaction of 1a with triethylamine 2e generated the ethyl substituted amine 2l afforded 3a in moderated yields under
product 3a in 38% and 16% yields, respectively (Table 1, entry 5). different conditions (Table 1, entry 12). It is noted that secondary
It is noted that ethyl bis-adduct 4e, described by Li and coworkers amines are ineffective for the formation of 3a.9
in their iron-catalyzed oxidative reactions (Fig. 2),8 was not
detected in the reaction mixture. Further investigation revealed
that N,N-diisopropylethylamine 2f (DIPEA) reacted smoothly with
Table 2 Some representative resultsa
substrate 1a to give the product 3a in good yields under different
conditions (Table 1, entry 6). In sharp contrast, when N,N-diiso-
propylmethylamine 2g or N,N-diethylmethylamine 2h was
Table 1 Reactions of 1a with different aminesa
Entry
Amine
Yieldb
Yieldc
1
2
3
4
5
6
7
8
PhNMe2 2a
TolNMe2 2b
PhNEt2 2c
BnNMe2 2d
Et3N 2e
(i-Pr)2NEt 2f
(i-Pr)2NMe 2g
Et2NMe 2h
(n-Pr)3N 2i
(n-Bu)3N 2j
Cy2NMe 2k
Cy2NEt 2l
25%
48%
0
0
0
0
0
0
38%
72%
0
16%
73%
0
0
0
9
3%
Trace
26%
38%
9%
10%
0
10
11
12
59%
a
Reaction conditions: 1,3-diketone 1a (0.5 mmol), amine(1.5 mmol),
tert-butyl hydrogenperoxide (TBHP, 2.0 mmol, 70% aqueous solution),
tetrabutylammonium iodide (Bu4NI, 0.1 mmol, 36.9 mg) in 1,4-
b
dioxane (1 mL). Isolated yield based on compound 1a at 25 ꢀC, 24 h.
c
Isolated yield based on compound 1a at 60 ꢀC, 5 h.
a
Reaction conditions: 1,3-dicarbonyl compound 1 (0.5 mmol), amine
(1.5 mmol), TBHP (2.0 mmol, 70% aqueous solution), Bu4NI
(0.1 mmol, 36.9 mg) in 1,4-dioxane (1 mL), 60 ꢀC, 5 h, isolated yield
based on compound 1.
Fig. 2 Possible ethyl bis-adduct 4e.
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On the basis of the results achieved with DIPEA, a range of
1,3-dicarbonyl compounds 1 was next examined under optimal
conditions. In addition to 1,3-diphenyl-1,3-propanedione 1a,
dissymmetrical 1,3-diketones such as 1b and 1c were also
successfully applied in this transformation (Table 2, 3b and 3c).
The present oxidative reaction catalyzed by Bu4NI was easily
extended to b-ketoesters substrates (Table 2, 3d–o). Aromatic
b-ketoesters bearing electron-donating (3e–f, 3j–l) or electron-
withdrawing groups (3g–i) reacted with DIPEA smoothly,
affording the corresponding products in 30–86% yields.
However, substrates bearing electron-withdrawing groups gave
lower yields.
(1)
(2)
Scheme 1 Proposed reaction mechanism.
radical.11 This radical could undergo b-scission to give a
carbonyl compound and another alkyl iodide.12 In the present
reaction, amides were detected through 13C NMR experiments
during the course of the reaction (Fig. 1S†). On the basis of
earlier studies and results obtained above, we propose a plau-
sible reaction mechanism (Scheme 1). First, DIPEA reacts with
the oxidant via two single electron transfers (SET) to give imi-
nium ion A,7b which can isomerize to enamine B. At the same
time, TBHP efficiently oxidizes iodide (IÀ) to hypoiodous acid or
molecular iodine.7b,13 Then, the reaction of iodine species with
enamine B yields iodonium ion C,14 which is subsequently
opened at the sterically less hindered carbon by compound 1a
to give compound D. Oxidation of alkyl iodide D with TBHP
affords iodoso-compound E, which readily rearranges to the
hypoiodite F.10 The homolytic cleavage of O–I bond takes place
to afford the alkoxy radical G,11 followed by rearrangement
through C–C bond scission to provide amide H and alkyl iodide
I.12 Finally, the resulting alkyl iodide I reacts with 1a by either a
nucleophilic substitution or a tandem elimination/addition to
afford the product 3a. In addition, it cannot be excluded that the
reaction proceeds via a 1,2-dioxetane intermediate, which can
be generated from enamine and oxidant.15 The active 1,2-diox-
etane then undergoes C–C bond cleavage to produce formal-
dehyde and amide. The Knoevenagel condensation of
formaldehyde with 1a gives an a,b-unsaturated dicarbonyl
compound, which subsequently undergoes Michael addition
with remaining excess 1a to produce the nal bis adduct 3a.
However, due to the change in color in the reaction, the Nash
test16 is not applicable for detecting formaldehyde.
(3)
It is noteworthy that heterocyclic 1,3-dicarbonyl compounds,
such as thiophene and furan, can be transformed into their
corresponding methylene-bridged products in good yields
(Table 2, 3b–c and 3n–o).
The origin of methylene carbon in product 3a was the major
concern in our mechanistic study. Treatment of 1a with H2O2/I2
gave 3a in 21% yield in the presence of DIPEA (eqn (1)). In
contrast, a similar reaction without DIPEA did not take place at
all (eqn (2)). Obviously, DIPEA was the methylene donor in the
reaction, and the possibility of generating methylene carbon
from TBHP and Bu4NI could be excluded. To further investigate
the information of methylene group in 3a, 1–13C-labeled DIPEA
was subjected to the reaction conditions. To our surprise, only
1.8% incorporation at methylene carbon was observed (eqn (3)).
The results unambiguously established that the carbon atom of
methylene group was originated from b-carbon of DIPEA, rather
than a-carbon. Clearly, the Ca–Cb bond of DIPEA was cleaved,
resulting in the formation of methylene-bridged bis-1,3-dicar-
bonyl compound 3. Further mechanistic investigation indicated
that the formation of product 3a was suppressed in the presence
of radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO). To our knowledge, alkyl hypoiodite can be generated
from alkyl iodide by oxidation and rearrangement.10 The
homolytic cleavage of O–I bond can provide an alkoxyl free
Conclusions
In conclusion, we have developed a metal-free oxidative
coupling reaction mediated by Bu4NI that allows for the
synthesis of methylene-bridged bis-1,3-dicarbonyl compounds
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from tertiary aliphatic amines and 1,3-dicarbonyl compounds.
The b-carbon of DIPEA was converted to the methylene carbon
through an oxidative C–C bond cleavage. We believe this C–C
bond cleavage of tertiary aliphatic amine holds promise to
develop other novel transformations. The methodology is
currently under active investigation to explore its detailed
mechanism and is also extended to the synthesis of other
methylene-bridged bis adducts.
F. A. A. Paz, A. M. S. Silva, A. C. Tome and
J. A. S. Cavaleiro, Chem. Commun., 2012, 48, 6142–6144; (d)
´
A. Gogoll, C. Johansson, A. Axen and H. Grennberg, Chem.–
Eur. J., 2001, 7, 396–403; (e) D. Mousset, I. Gillaizeau,
´
A. Sabatie, P. Bouyssou and G. Coudert, J. Org. Chem.,
2006, 71, 5993–5999; (f) D. F. Martin, M. Shamma and
W. C. Fernelius, J. Am. Chem. Soc., 1958, 80, 5851–5856; (g)
R. Karvembu and K. Natarajan, Polyhedron, 2002, 21, 1721–
1727.
7 (a) M. Uyanik and K. Ishihara, ChemCatChem, 2012, 4, 177–
185; (b) P. Finkbeiner and B. J. Nachtsheim, Synthesis,
2013, 45, 979–999.
8 W. Liu, J. Liu, D. Ogawa, Y. Nishihara, X. Guo and Z. Li, Org.
Lett., 2011, 13, 6272–6275.
Acknowledgements
Financial support by the National Science Foundation of China
(no. 21172120, 20902050) and National University Student
Innovation Program (BX111359, 20130055020). We thank Prof.
Renhua Fan in Fudan University for helpful discussions.
9 X. B. Zhang, M. Wang, Y. C. Zhang and L. Wang, RSC Adv.,
2013, 3, 1311–1316.
10 (a) H. J. Reich and S. L. Peake, J. Am. Chem. Soc., 1978, 100,
4888–4889; (b) R. C. Cambie, D. Chambers, B. G. Lindsay,
P. S. Rutledge and P. D. Woodgate, J. Chem. Soc., Perkin
Trans. 1, 1980, 822–827; (c) T. L. Macdonald,
N. Narasimhan and L. T. Burka, J. Am. Chem. Soc., 1980,
102, 7760–7765.
Notes and references
1 (a) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069–1084; (b)
M. Klussmann and D. Sureshkumar, Synthesis, 2011, 353–
369.
2 (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335–344; (b) C. Liu,
H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780–
1824; (c) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,
111, 1215–1292.
3 (a) H. Li, Z. He, X. Guo, W. Li, X. Zhao and Z. Li, Org. Lett.,
2009, 11, 4176–4179; (b) W.-J. Yoo, A. Tanoue and
S. Kobayashi, Chem.–Asian J., 2012, 7, 2764–2767; (c)
L. Zhang, C. Peng, D. Zhao, Y. Wang, H.-J. Fu, Q. Shen and
J.-X. Li, Chem. Commun., 2012, 48, 5928–5930.
11 J. Janjatovic and Z. Majerski, J. Org. Chem., 1980, 45, 4892–
4898.
12 (a) P. Gray and A. Williams, Chem. Rev., 1959, 59, 239–328; (b)
C. Walling and A. Padwa, J. Am. Chem. Soc., 1963, 85, 1593–
1597; (c) D. E. O'Dell, J. T. Loper and T. L. Macdonald, J. Org.
Chem., 1988, 53, 5225–5229; (d) C. S. Aureliano Antunes,
M. Bietti, O. Lanzalunga and M. Salamone, J. Org. Chem.,
2004, 69, 5281–5289.
4 (a) X.-F. Xia, X.-Z. Shu, K.-G. Ji, Y.-F. Yang, A. Shaukat,
X.-Y. Liu and Y.-M. Liang, J. Org. Chem., 2010, 75, 2893–
2902; (b) B. Sundararaju, M. Achard, G. V. M. Sharma and
C. Bruneau, J. Am. Chem. Soc., 2011, 133, 10340–10343; (c)
K. Yuan, F. Jiang, Z. Sahli, M. Achard, T. Roisnel and
C. Bruneau, Angew. Chem., Int. Ed., 2012, 51, 8876–8880; (d)
N. Takasu, K. Oisaki and M. Kanai, Org. Lett., 2013, 15,
1918–1921.
5 (a) J. Huang, L.-T. Li, H.-Y. Li, E. Husan, P. Wang and
B. Wang, Chem. Commun., 2012, 48, 10204–10206; (b)
L.-T. Li, J. Huang, H.-Y. Li, L.-J. Wen, P. Wang and
B. Wang, Chem. Commun., 2012, 48, 5187–5189; (c) L.-T. Li,
H.-Y. Li, L.-J. Xing, L.-J. Wen, P. Wang and B. Wang, Org.
Biomol. Chem., 2012, 10, 9519–9522.
13 I. Matsuzaki, T. Nakajima and H. A. Liebhafsky, Chem. Lett.,
1974, 3, 1463–1466.
14 (a) A. Yoshimura, K. R. Middleton, C. Zhu, V. N. Nemykin
and V. V. Zhdankin, Angew. Chem., Int. Ed., 2012, 51, 8059–
8062; (b) J.-S. Tian, K. W. J. Ng, J.-R. Wong and T.-P. Loh,
Angew. Chem., Int. Ed., 2012, 51, 9105–9109.
15 (a) N. A. Milas and B. Plesnicar, J. Am. Chem. Soc., 1968, 90,
4450–4453; (b) W. Ando, T. Saiki and T. Migita, J. Am.
Chem. Soc., 1975, 97, 5028–5029; (c) H. H. Wasserman
and J. L. Ives, J. Am. Chem. Soc., 1976, 98, 7868–7869; (d)
J. E. Huber, Tetrahedron Lett., 1968, 9, 3271–3272; (e)
R. Lin, F. Chen and N. Jiao, Org. Lett., 2012, 14, 4158–
4161; (f) J. Basran, I. Emov, N. Chauhan, S. J. Thackray,
J. L. Krupa, G. Eaton, G. A. Griffith, C. G. Mowat,
S. Handa and E. L. Raven, J. Am. Chem. Soc., 2011, 133,
16251–16257.
¨
6 (a) J. Guin, R. Frohlich and A. Studer, Angew. Chem., Int. Ed.,
2008, 47, 779–782; (b) A. Cuadro, J. Elguero and P. Navarro,
Chem. Pharm. Bull., 1985, 33, 2535–2540; (c)
N. M. M. Moura, M. A. F. Faustino, M. G. P. M. S. Neves,
16 T. Nash, Biochem. J., 1953, 55, 416–421.
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