Iron-catalyzed oxidative amidation of tertiary amines with aldehydes

Article abstract of DOI:10.1002/chem.201203824

Unconventional couple: A new oxidative coupling protocol for amide bond formation has been developed (see scheme). The method provides an efficient and practical route for the synthesis of tertiary amides from readily available tertiary amines and aldehydes in the presence of a simple FeCl₂ catalyst. Mechanistic studies indicated that a peroxide and an iminium ion act as the reactive intermediates in this oxidative amidation.

Full text of DOI:10.1002/chem.201203824

COMMUNICATION
DOI: 10.1002/chem.201203824
Iron-Catalyzed Oxidative Amidation of Tertiary Amines with Aldehydes
Yuanming Li,[a] Fan Jia,[a] and Zhiping Li*[a, b]
Amide bond formation is one of the most often used reac-
tions in the synthesis of natural products, pharmaceuticals,
and fine chemicals.[1] The most common routes toward
amides are the reactions of amines with the carboxylic acids
(or their derivatives), modified Staudinger reaction,[2] and
rearrangement reactions.[3] The transition-metal-catalyzed
conversion of aryl halides,[4] nitriles[5] and alkynes,[6] which
avoids the use of labile functional groups, also provides effi-
cient access to amide formation. Recently, direct oxidative
amidation of amines with aldehydes[7] (or alcohols)[8] has
Scheme 1. Oxidative transformation of tertiary amines.
been extensively studied and affords an attractive alterna-
tive approach in amide bond formation from simple sub-
strates. Mechanistically, the condensation of primary or sec-
ondary amines with aldehydes and the oxidation of the gen-
erated carbinoamine intermediates are key steps in oxida-
tive amidation for the following reasons: 1) The condensa-
tion step is reversible and thermodynamically uphill and
2) the undesirable oxidation of primary or secondary amines
are always accompanied; thus, investigating how to push the
equilibrium to carbinoamine formation without the use of
an activated leaving group and to expand the scope of oxi-
dative amidation are still the most challenging goals in this
research area.
envisioned that if the secondary amines generated by oxida-
tive dealkylation of tertiary amines in situ might react with
aldehydes, amide formation is expected. Given that tertiary
amines are widely found in nature products and more easily
available than secondary amines in the labs, the synthesis of
amides from tertiary amines offers new opportunities for
amide bond formation. To our best knowledge, efforts on
this hypothesis have never been reported. Herein, we wish
to report a new amide formation by iron-catalyzed oxidative
amidation of tertiary amines with aldehydes (Type IV).
The oxidative amidation of 1a with 2a was chosen as a
model to establish the reaction conditions (Table 1). FeCl2
The oxidation of tertiary amines has attracted much inter-
est in both biochemistry[9] and chemistry.[10] Imines or imini-
À
um ions, generated by oxidation of the C H bond adjacent
to a nitrogen atom, are key intermediates toward various
Table 1. Optimization of the reaction conditions.[a]
types of transformation (Scheme 1).[11] Synthetically, deal
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(Type II)[13] have been developed as efficient methods
toward valuable products. Recently, we demonstrated anoth-
er type of the oxidative transformation in which the sub-
stituents of tertiary amines are transformed into methylene-
bridged bis-1,3-dicarbonyl compounds[14] and b-substituted
aldehydes (Type III).[15] Based on these developments, we
Entry
Cat.
[O]
Conv.
3a
1a [%][b]
[%][b]
1
2
3
4
5
6
7
8
FeCl2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
90
35
24
70
78
67
73
74
18
39
91
83
62
<5
<5
61
62
50
45
60
8
Fe
N
FeSO4·7H2O
FeCl3
FeCl3·6H2O
CoCl2
CuCl
FeCl2
FeCl2
FeCl2
FeCl2
[a] Y. Li, F. Jia, Prof. Dr. Z. Li
Department of Chemistry
Renmin University of China
Beijing 100872 (P.R. China)
Fax : (+86)10-6251-6444
TBHP
T-HYDRO[c]
9
ACHTUNGERTN(NUNG tBuO)2
10
11[d]
12
mCPBA
TBHP
TBHP
–
90
<5
E-mail: zhipingli@ruc.edu.cn
–
[b] Prof. Dr. Z. Li
State Key Laboratory of Heavy Oil Processing
China University of Petroleum
Beijing 102249 (P.R. China)
[a] Conditions: 1a (0.5 mmol), 2a (2.5 mmol), Cat. (0.0125 mmol), oxi-
dant (1.0 mmol), and MeCN (3 mL) under nitrogen; unless otherwise
noted. [b] Detected by 1H NMR spectroscopy and based on 1a.
[c] TBHP in water (70 wt%) [d] FeCl2 (0.05 mmol) and TBHP
(1.5 mmol).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203824.
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Table 2. Amidation of aliphatic aldehydes.[a,b]
and tert-butyl hydroperoxide (TBHP) were found to be the
best catalyst (entries 1–7) and oxidant (entries 8–10), respec-
tively. An excellent yield of 3a was achieved in the presence
of 3 equiv of TBHP by using 10% FeCl2 as catalyst (Table 1,
entry 11). FeCl2 is essential to this reaction (entry 12). It is
worth noting that the reaction of 4 (which was supposed to
be firstly generated by oxidation of 1a for the reaction 1a
with 2a), with 2a led to 3a in only 26% yield due to the un-
desired oxidation of 4 under the present reaction conditions
[Eq. (1)].[16]
Entry
1
3
Yield
[%]
1
2
3
1b
1c
1d
3b
3c
3d
82 (73)
60 (59)
37 (32)
4
5
1e
1 f
3e
3 f
98 (95)
67 (52)
With the optimized reaction conditions in hand, the scope
and generality of this transformation with various aldehydes
and amines were investigated (Table 2). The efficiency of
this transformation was affected by the electronic effect of
anilines (Table 2, entries 1–3). To our delight, 2,6-diisoprop-
yl-N,N-dimethylaniline 1e was transformed efficiently into
the desired hindered amide 3e, which is difficult to prepare
by conventional methods (Table 2, entry 4).[17] We hypothe-
size that the minimization of the undesired amine oxidation
attributes to the high efficiency of the amidation. Tropinone
1 f could also be used for the oxidative amidation (Table 2,
entry 5). In addition, not only methyl group but also other
alkyl groups can react smoothly with 2a to give the corre-
sponding tertiary amides in good yields (Table 2, entries 6–
9). Other aliphatic aldehydes such as valeraldehyde 2b and
cyclopropanecarboxaldehyde 2c proceeded well under the
optimized reaction conditions (Table 2, entries 10 and 11).
Further investigation showed that aromatic aldehydes
were the more reactive substrates for the present transfor-
mation (2.5 mol% FeCl2 and 2 equiv TBHP), compared
with aliphatic aldehydes. The representative results are sum-
marized in Table 3. Aromatic aldehydes reacted smoothly
with various tertiary amines to give the corresponding
amides in good to excellent yields (Table 3, entries 1–8), in
which tropinone 1 f (Table 3, entry 7) and 4-bromo-benzal-
dehyde 2 f (Table 3, entry 8) showed slight lower reactivities
in the present amide formation. To our satisfaction, hetero-
aromatic aldehydes, for example, thiophene-2-carbaldehyde
2g and cinnamaldehyde 2h, were also compatible, providing
the desired amides efficiently (Table 3, entries 9 and 10).
The chemoselectivity of iron-catalyzed oxidative amida-
tion of unsymmetrical tertiary amines is shown in Figure 1.
6
7
1g
1h
3g
3h
65 (55)
63 (55)
8
9
1i
1j
3i
3j
60 (32)
86 (75)
10
11
1a
1a
3k
3l
87 (87)
73 (73)
[a] Conditions: 1 (0.5 mmol), 2 (2.5 mmol), FeCl2 (0.05 mmol), TBHP
(1.5 mmol), and MeCN (3 mL) under nitrogen; unless otherwise noted.
[b] Reported yields are based on 1 and determined by H NMR spec
AHCTUNGTRENNUNG
1
tros-
oxidation, the chemoselectivity of the present oxidative ami-
dation depends on the structures of tertiary amines.
À
The less sterically hindered a-C H bonds of amines were
To clarify the possible reaction pathway, we investigated
the potential intermediates. When 1a was treated with 2a
(1.0 equiv), the peroxide product 5 was formed as the major
product together with a 21% yield of 3a [Eq. (2)]. Subse-
quently, the transformation of 5 to 3a was studied [Eq. (3)].
The results indicated that 1) the peroxide product 5 is one
of possible intermediates in the present oxidative amidation;
2) the iron catalyst and TBHP are necessary for the amida-
preferentially oxidized to give the corresponding amide. The
results are consistent with the known chemoselectivity of hy-
drogen abstraction by tBuO from amines.[18] A combination
À
of the steric effect and the a-C H bond dissociation energy
(BDE) effect diminish the reactivities of the different sub-
stituents of amines (1n=1o=1p).[19] Assuming that C H
À
bond cleavage is generally a rate-determining step of amine
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Iron-Catalyzed Oxidative Amidation
Table 3. Amidation of other aldehydes.[a,b]
COMMUNICATION
tion step; 3) tBuOOÀ or tBuOOH is generated from 5, be-
cause 3a was obtained in 32% yield even without the addi-
tion of TBHP. To gain a further understanding of the reac-
tion progress, the conversion of 5 and 1a as well as the for-
mation of 3a were detected by 1H NMR spectroscopy at
408C ([Eq. (4)] and Figure 2). The outcomes of the oxidative
Entry
2
3
Yield
[%]
1
2
2d
3m
3n
75 (69)
87 (80)
2d
2d
3
3o
73(73)
4
5
2d
2d
3p
3q
85 (63)
79(75)
Figure 2. Reaction progress (reaction conditions given in Equation (4)).
6
2e
3r
3s
3t
90 (81)
62 (52)
71 (69)
amidation consistent with the mechanistic studies of oxida-
tive coupling reactions by Todd[20] and Klussmann[13a,21] con-
firmed that the oxidized amine and iminium cation act as
the reactive intermediates in the catalytic cycle. To probe
how 5 is generated, methanesulfonic acid (5 mol%) and 2,6-
di-tert-butyl-4-methylphenol (BHT; 3 equiv) were subjected
respectively to the reaction conditions. The results support-
ed that 5 is formed via radical intermediates (see details in
the Supporting Information). Importantly, the secondary
amine 4 could not be detected in the course of these reac-
tions, further indicating that the “slow”-releasing 4 ensures
its “fast” reaction with a relatively large excess of aldehyde,
and as a result, efficiently pushes the equilibrium of the con-
densation to the carbinoamine formation. In addition, the
dealkylation of tertiary amines to aldehyde was confirmed
by the reaction of 1n and 2e [Eq. (5)]. Moreover, because
7[c]
2e
8
2 f
9
2g
2h
3u
3v
70 (70)
90 (90)
10
[a] Compound 1 (0.5 mmol), 2 (2.5 mmol), FeCl2 (0.0125 mmol), TBHP
(1.0 mmol), and MeCN (3 mL) under nitrogen; unless otherwise noted.
[b] Reported yields are based on 1 and determined by H NMR spec
G
1
A
1
methyl ethers or esters were not observed by H NMR anal-
ysis when the reactions finished, the sequence of quaterniza-
tion of tertiary amines followed by demethylation could also
be excluded in the present amide bond formation.[22]
The coupling of acyl and aminyl radicals to amides is
demonstrated by Wan and co-workers.[23] Because the acyl
radical is also possibly generated by H-abstraction of alde-
hyde under our reaction conditions, anhydrides and acyl
chloride 6–8 were used to investigate the amide formation
Figure 1. Chemoselectivity of tertiary amines.
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Z. Li et al.
Scheme 2. A tentative mechanism for oxidative amidation with tertiary
amine.
amino radical A is generated by hydrogen abstraction or
one-electron oxidation of nitrogen followed by successive
loss of a proton. The radical coupling of A with tert-butyl-
peroxy radical generated from TBHP by an iron catalyst
leads to the peroxide 5. Then, peroxide 5 eliminates
tBuOOÀ to give an iminium intermediate B with assistance
of an iron catalyst. The secondary amine 4 is generated by
hydrolysis of B through C. As mentioned above, the in situ-
generated 4 immediately reacts with a relatively large excess
of aldehyde to push the equilibrium to a carbinoamine inter-
mediate D, which is oxidized to the final amide 3.
In conclusion, we have demonstrated a new and efficient
protocol for amide formation by an unconventional oxida-
tive amidation between tertiary amine and aldehyde in the
presence of a simple iron catalyst.[25] A variety of tertiary
amines and aldehydes were used to afford the corresponding
amides in moderate to excellent yields. Further investiga-
tions into the scope, mechanism, and synthetic application
of this reaction are now in progress.
(Table 4).[24] The desired amides were smoothly obtained, in-
dicating that an ionic coupling of amine with aldehyde is
most likely involved in this reaction. Furthermore, to assess
the nature of charge development in the transition state of
the reaction, a Hammett study was conducted by the rela-
tive reactivity of substituted substrates. A 1 value of À1.40
indicates the development of positive charge at the rate-lim-
iting step (for details see the Supporting Information).
Accordingly, a tentative reaction mechanism for this oxi-
dative amide bond formation is proposed (Scheme 2). An a-
Experimental Section
Table 4. Amidation of anhydrides and acyl chloride.[a,b]
General procedure: To a dry Schlenk tube equipped with a magnetic stir
bar, amine 1 (0.5 mmol) and aldehyde 2 (2.5 mmol) were added to a mix-
ture of FeCl2 (6.4 mg, 0.05 mmol) and acetonitrile (3.0 mL) under nitro-
gen at room temperature. Then tert-butyl hydroperoxide (TBHP,
1.5 mmol, 5–6m in decane) was dropped into the mixture. The resulting
mixture was stirred under 858C for 1 h. The temperature of the reaction
was cooled to room temperature. The resulting reaction solution was con-
centrated in vacuo. The resulting residue was purified by flash column
chromatography on silica gel with ethyl acetate/petroleum ether (1:10) as
an eluent to afford the amide product 3.
Entry
1
6–8
3
Yield
[%]
1
2
1a
1a
Ac2O (6)
3x
85 (85)
61 (52)
PhCOCl (7)
3m
Acknowledgements
3[c]
1 f
(Boc)2O (8)
3y
81 (69)
Financial support by the National Science Foundation of China
(20832002, 21072223, 21272267), State Key Laboratory of Heavy Oil
Processing (2012–1–06), the Fundamental Research Funds for the Cen-
tral Universities, and the Research Funds of Renmin University of China
(10XNL017).
[a] Compound 1 (0.5 mmol), 6–8 (1.0 mmol), FeCl2 (0.0125 mmol), TBHP
(1.0 mmol), and MeCN (3 mL). [b] Reported yields are based on 1 and
determined by 1H NMR spectroscopy using an internal standard; yields
of the isolated product are given in parentheses. [c] FeCl2 (0.05 mmol),
TBHP (1.5 mmol).
Keywords: aldehydes · amidation · amines · iron · oxidation
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Iron-Catalyzed Oxidative Amidation
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Received: October 25, 2012
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These are not the final page numbers!