Reductive amination of tertiary anilines and aldehydes

Article abstract of DOI:10.1039/c3cc45084h

An unprecedented oxidant-mediated reductive amination of tertiary anilines and aldehydes without external reducing agents was developed via the nucleophilic attack of the oxygen atom of the carbonyl group to in situ generated iminium ions, in which tertiary anilines were used as both nitrogen source and reducing agent for the first time. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45084h

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Reductive amination of tertiary anilines and
aldehydes†
Cite this: DOI: 10.1039/c3cc45084h
Yunhe Lv, Yiying Zheng, Yan Li,* Tao Xiong, Jingping Zhang, Qun Liu and
Qian Zhang*
Received 6th July 2013,
Accepted 1st August 2013
DOI: 10.1039/c3cc45084h
www.rsc.org/chemcomm
An unprecedented oxidant-mediated reductive amination of tertiary
anilines and aldehydes without external reducing agents was devel-
oped via the nucleophilic attack of the oxygen atom of the carbonyl
group to in situ generated iminium ions, in which tertiary anilines were
used as both nitrogen source and reducing agent for the first time.
Scheme 1 Selectfluor-mediated reductive amination of tertiary anilines and
aldehydes.
In the context of the synthesis of natural products,1 bioactive com-
pounds2 or materials,3 the development of novel C–N bond formation
methodologies is a very important research field.4 The reductive
amination of amines and aldehydes or ketones constitutes one of
the most efficient and direct routes to construct C–N bonds.5 Primary
or secondary amines have been successfully installed into the corre-
sponding substrates via condensation and subsequent reduction,5
whereas tertiary amines as nitrogen sources have rarely been studied
in this area.6 Harsh conditions were required for the additional C–N
bond cleavage even in the presence of a transition-metal. For example,
in 2002, Cho’s group6a described ruthenium-catalyzed reductive
amination of aldehydes with tertiary amines under a 10 atm CO
atmosphere at 180 1C. In addition to nitrogen sources, reducing
agents are also important factors in reductive amination. Over the
past few decades, significant progress has been achieved,5,7–9 in which
internal reducing agents7–9 are highly attractive because they make
this procedure much more economical and environmentally friendly.
Recently, Seidel’s group7,8 and Tunge’s group9 independently reported
reductive amination of primary or secondary amines and aldehydes or
ketones by employing tertiary amines (contained in substrates or
in situ generated) to reduce carbonyl groups. Therefore, we envisaged
continuing effort towards the development of methodologies to
construct C–N bonds,11 we attempted amination of aldehydes and
tertiary anilines.12 Initially, we tested the reaction between N,N,4-
trimetylanilide (1a, 0.4 mmol) and ethyl glyoxylate (2a, 0.8 mmol,
2.0 equiv.) in the presence of Cu(OTf)2 (10%) and Selectfluor
(0.8 mmol, 2.0 equiv.) in dichloroethane (DCE) under an air atmo-
sphere eqn (1). After the reaction was performed at 90 1C for 14 hours,
the N-methyl amino acid (NMA) derivative 3aa was obtained in 40%
yield along with 14% N-methyl-N-p-tolylformamide (4). Interestingly,
when the reaction was performed under the same conditions but
without employing the copper catalyst, similar results were obtained.
(1)
Encouraged by the successful synthesis of NMA derivatives widely
that directly utilizing tertiary amines as both nitrogen source6 and existing in natural products and proteins,13 we pursued our investiga-
reducing agent7–9 will provide a new method for reductive amination. tion with the metal-free reductive amination reaction condition screen-
Herein, Selectfluor-mediated, the first metal-free reductive amination ing (Table 1). Gratifyingly, under nitrogen atmosphere in anhydrous
of tertiary anilines and aldehydes was presented (Scheme 1).
DCE, the desired product 3aa was obtained in 72% yield and no
Recently, we have developed various metal catalyzed C–N bond oxidation product 4 was detected (Table 1, entry 1). In the absence of
formation reactions directly from C–H bonds.10 As part of our Selectfluor, no reaction occurred (Table 1, entry 2). With other F+
reagents, such as N-fluoro-2,4,6-trimethylpyridinium tetrafluorobrate,
N-fluoropyridinium tetrafluorobrate and N-fluoro-2,4,6-trimethyl-
pyridinium triflate, 3aa was obtained in 21%, 41% and 16% yields,
respectively (Table 1, entries 3–5). When N-fluorobenzenesulfon-
Department of Chemistry, Northeast Normal University, Changchun, 130024,
China. E-mail: liy078@nenu.edu.cn, zhangq651@nenu.edu.cn;
Fax: +86-431-5099759
imide (NFSI) was used as the oxidant, no desired 3aa was obtained
(Table 1, entry 6). Using other oxidants, such as tert-butyl hydroperoxide
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc45084h
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Table 1 Optimization of reaction conditionsa
Table 2 The scope of reductive amination reactiona,b
Entry
Oxidant
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
Selectfluor
None
DCE
DCE
DCE
DCE
DCE
DCE
13
18
12
12
12
4
72
0
21
41
16
F+ c
F+ d
F+ e
NFSI
0
7
8
9
10
11
12
13
14f
TBHP
O2
DCE
DCE
DCE
THF
DMF
Toluene
Acetonitrile
DCE
4
18
4
9
9
9
9
9
0
0
PhI(OAc)2
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Trace
32
Trace
Trace
0
79
a
Reactions were carried out with 1a (0.4 mmol), 2a (0.8 mmol,
2.0 equiv.), and oxidant (0.8 mmol, 2.0 equiv.) in 4 mL anhydrous
solvent under nitrogen atmosphere at 90 1C unless specially mentioned.
b
c
Yield of the isolated product. N-Fluoro-2,4,6-trimethylpyridinium
d
tetrafluorobrate was used. N-Fluoropyridinium tetrafluorobrate was
used. N-Fluoro-2,4,6-trimethylpyridinium triflate was used. 1.6 mmol
(4.0 equiv.) 2a was used.
e
f
(TBHP) and O2, the reaction could not occur (Table 1, entries 7 and 8).
Changing the oxidant to PhI(OAc)2, a trace amount of 3aa was observed
(Table 1, entry 9). With tetrahydrofuran (THF) as the solvent, 3aa was
obtained in 32% yield (Table 1, entry 10). Other solvents, for example,
toluene and N,N-dimethylmethanamide (DMF), only gave a trace
amount of 3aa (Table 1, entries 11 and 12). Acetonitrile was not
effective and no reaction occurred (Table 1, entry 13). Satisfactorily,
upon increasing the feedstock of 2a to 4.0 equiv. (1.6 mmol), the yield
of 3aa was increased to 79% (Table 1, entry 14).
a
Reactions were carried out with 1 (0.4 mmol), 2 (1.6 mmol, 4.0 equiv.),
and Selectfluor (0.8 mmol, 2.0 equiv.) in 4 mL anhydrous DCE under a
nitrogen atmosphere at 90 1C. Yield of the isolated product. Recov-
ery of 1. 0.8 mmol (2.0 equiv.) aldehyde 2 was used. Reactions were
performed at 110 1C.
b
c
d
e
low (19–42%). Additionally, the reaction of 4-bromo-N,N-diethylaniline
(1l) with 2a afforded 3la in 26% yield. Starting from 4-bromo-N-ethyl-
N-methylaniline (1n), both reductive amination products 3ia (16%)
and 3la (26%) were obtained after 12 h under optimal conditions.
To understand the reaction, both 13C- and D-labelling experi-
ments were performed. Firstly, [13C2]-1h and 2b were subjected to
the standard reaction conditions eqn (2). After 12 hours, the
reductive amination product [13C1]-3hb was obtained in 52%
yield. This result showed that the a-carbon atom of the ester
group of [13C1]-3hb originated from aldehydes 2b. It is worth
noting that reduction of the carbonyl group could be efficiently
realized in the presence of the oxidant Selectfluor. Then, the
reaction of [D6]-1a and 2a was carried out and gave [D4]-3aa in
50% yield eqn (3). This outcome clearly revealed that the
tertiary anilines 1 served as a reducing agent. The two isotope
labelling experiments demonstrated that tertiary anilines
played a dual role in this unprecedented oxidant-mediated,
metal-free reductive amination reaction.
With the optimized conditions in hand (Table 1, entry 14), the
scope of the reductive amination was then examined and the results
are summarized in Table 2. The reaction of ethyl glyoxylate (2a) with
a variety of p-substituted N,N-dimethylaniline14 1a–1i having an
electron-donating group or an electron-withdrawing group could
afford the corresponding NMA derivatives 3aa–3ia in 50–86% yields.
Notably, Cl and Br substituents on the phenyl ring were well tolerated,
which offers an opportunity for further functionalization. With
triethylamine as the substrate, no desired reductive amination product
was obtained. Next, the scope of this reaction was investigated with
respect to aldehydes 2. Pleasingly, the reactions of 2-oxo-2-phenyl-
acetaldehyde (2b) with tertiary anilines 1 could proceed smoothly and
provided a-amino ketone derivatives constituting an important class
of biologically active compounds.15,16 Starting from tertiary anilines
1d–1h, 1j, 1k and 1m, a-amino ketones derivatives 3db–3hb, 3jb, 3kb
and 3mb were obtained in 50–76% yields. No reaction occurred when
2-oxoacetic acid, 2-oxopropanal or 1-phenylpropane-1,2-dione was
used as the substrate. It should be noteworthy that this reductive
amination reaction provided an alternative efficient approach to
obtain NMA17 and a-amino ketone18 derivatives. Furthermore, the
new reductive amination protocol was applied to aromatic aldehydes,
such as 4-nitrobenzaldehyde (2c), 4-formylbenzonitrile (2d), 3-nitro-
benzaldehyde (2e) and 4-chloro-3-nitrobenzaldehyde (2f). The desired
products 3ac–3af could be obtained although the yields were relatively
(2)
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Scheme 2 Possible mechanism for the synthesis of N-methyl amino acid 3aa.
7 C. Zhang, S. Murarka and D. Seidel, J. Org. Chem., 2009, 74, 419.
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(3)
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Although the mechanistic details of this transformation are not
very clear at the moment, based on the experimental results, the
probable mechanism of the reductive amination is depicted in
Scheme 2.19 Firstly, N,N,4-trimethylaniline (1a) reacted with Selectfluor
to form the iminium ion intermediate A.20–22 In the next step, a key
nucleophilic attack of the oxygen atom on the carbonyl group of 2a
to A takes place, providing a four-membered ammonium ylide B.23
This step was supported by our theoretical calculation results.19
Subsequent to 1,3-proton transfer, a new ammonium C was formed.
Finally, the desired reductive amination product 3aa was furnished
along with the loss of carbon monoxide and hydrogen fluoride via
thermal decomposition. It should be pointed out that the nucleo-
philic addition of the carbonyl group to iminium species as
described in Scheme 2 has never been reported, although iminium
intermediates generated by two-electron oxidation of amines have
been extensively studied on their transformations by the addition of
various nucleophiles.24 Moreover, the metal-free reductive amination
reaction between tertiary anilines and aldehydes is completely
distinguished from the common reductive amination procedure.5
In summary, a novel oxidant-mediated direct reductive amina-
tion of tertiary anilines and aldehydes was developed, in which
simple N,N-dialkylanilides acted as both nitrogen sources and
reducing agents. The nucleophilic addition of carbonyl group to
the in situ generated iminium ion intermediate was realized for the
first time, which initiated the next intramolecular sequential
amination and reduction. This protocol might open a new window
for the construction of C–N bonds through reductive amination.
Further studies on applying the dual role of tertiary amines to
perform other aminative reactions are underway in our lab.
12 For
a review on the a-functionalization of amines, see:
K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069.
13 (a) J. Chatterjee, F. Rechenmacher and H. Kessler, Angew. Chem., Int.
Ed., 2013, 52, 254; (b) S. J. Wen and Z. J. Yao, Org. Lett., 2004, 6, 2721;
(c) M. B. Andrus, W. Li and R. F. Keyes, J. Org. Chem., 1997, 62, 5542.
14 When para non-substituted aniline 5 was used as the substrate,
no desired reductive amination product was observed and the
Friedel–Crafts acylation product 6 was obtained in 58% yield, also
see: M. Soueidan, J. Collin and R. Gil, Tetrahedron Lett., 2006,
47, 5467.
15 D. M. Perrine, J. T. Ross, S. J. Nervi and R. H. Zimmerman, J. Chem.
Educ., 2000, 77, 1479 and references therein.
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17 For a review, see: R. Aurelio, R. T. C. Brown lee and A. B. Hughes,
Chem. Rev., 2004, 104, 5823.
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M. Murakami, J. Am. Chem. Soc., 2012, 134, 194; (b) A. Villar,
¨
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C. H. Hovelmann, M. Nieger and K. Muniz, Chem. Commun., 2005,
3304; (c) G.-Q. Li, L.-X. Dai and S.-L. You, Chem. Commun., 2007, 852.
19 To rationalize the proposed reaction mechanism, the preliminarily
DFT calculation for the formation of 3aa was performed on the
B3LYP/6-31G(d) theoretical level and the detailed see ESI†.
20 T. Furuya, J. E. M. N. Klein and T. Ritter, Synthesis, 2010, 1804.
21 H. Mayr, A. R. Ofial, E.-U. Wulrthwein and N. C. Aust, J. Am. Chem.
Soc., 1997, 119, 12727.
Financial support for this research by the SRFDP
(20110043110002), the NNSFC (21172033, 21202014, 21203021),
and the Fundamental Research Funds for the Central Universities
(11GJHZ001, 11QNJJ015) NENU-10SSXT139 is greatly acknowledged.
22 In ref. 20, the authors mentioned that the reaction of tertiary
anilines and Selectfluor could form iminium intermediate and
ref. 21 provided the NMR spectroscopic evidence of iminium
species. Accordingly, we tried to obtain any signals of the iminium
intermediate A with NMR tech, but we failed.
23 For a selected review, see: J. A. Vanecko, H. Wan and F. G. West,
Tetrahedron, 2006, 62, 1043.
Notes and references
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M. H. G. Munro and M. R. Prinsep, Nat. Prod. Rep., 2012, 24 Selected reviews, see: (a) C. J. Li, Acc. Chem. Res., 2009, 42, 335;
29, 144. (b) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.