TBN-Catalyzed Dehydrative N-Alkylation of Anilines with 4-Hydroxybutan-2-one

Article abstract of DOI:10.1002/ejoc.201901472

Until now, the substitution of alcohols by N-nucleophiles via TBN-catalyzed dehydrogenation was not known. Herein, we reported a TBN catalyzed dehydrative N-alkylation of anilines with 4-hydroxybutan-2-one in the presence of TEMPO, which was different from the TEMPO/TBN catalyzed oxidation reactions. A range of anilines reacted successfully with 4-hydroxybutan-2-one to generate the N-monoalkylation products in good yields. Mechanistic studies revealed that this reaction most possibly proceeded through aza-Michael addition. Water was the only by-product, making it more environmentally friendly. The gram-scale reactions verified the synthetic practicality of this protocol.

Full text of DOI:10.1002/ejoc.201901472

A Journal of
Accepted Article
Title: TBN-Catalyzed Dehydrative N-Alkylation of Anilines with 4-
Hydroxybutan-2-one
Authors: Wenchen Cheng, Shue Deng, Liya Jiang, Lanhui Ren,
Zicheng Wang, Jian Zhang, and Weiguo Song
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901472
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901472
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10.1002/ejoc.201901472
European Journal of Organic Chemistry
COMMUNICATION
TBN-Catalyzed Dehydrative N-Alkylation of Anilines with 4-
Hydroxybutan-2-one
Wenchen Cheng,[a] Shue Deng,[a] Liya Jiang,[a] Lanhui Ren,*[a] Zicheng Wang,[a] Jian Zhang,[a] and
Weiguo Song*[a]
Wenchen Cheng and Shue Deng contributed equally to this work
Abstract: Substitution of alcohols by N-nucleophiles via TBN-
catalyzed dehydrogenation was unknown. Herein, we reported a TBN
catalyzed dehydrative N-alkylation of anilines with 4-hydroxybutan-2-
one in the presence of TEMPO which was different from the
TEMPO/TBN catalyzed oxidation reactions. A range of anilines
reacted successfully with 4-hydroxybutan-2-one to generate the N-
monoalkylation products in good yields. Mechanistic studies revealed
that this reaction most possibly proceeded α, β-unsaturated ketones
and aza-Michael addition. Water was the only by-product, making it
more environmentally friendly. The gram-scale reactions verified the
synthetic practicality of this protocol.
Mn16 and Ni17), bimetallic catalysts18 and non-metal catalysts19 etc
(Scheme 1a). Most of these catalyst systems needed high
temperatures and strong alkalis to work.
β-Aminoketones are important structures found in many
bioactive molecules and pharmaceutical agents, and are very
useful intermediates in the synthesis of β-aminoacids, β-
aminoalcohols, 1,3-alkamines, lactams, nikkomycins and
neopolyoxines which also find wide applications in fine chemicals
and pharmaceuticals.20 We had developed a dehydrative N-
alkylation of anilines with 4-hydroxybutan-2-one forming β-
aminoketones and benzo[h]quinolones.19b During our ongoing
studies, we found that TBN (tert-butyl nitrite) could catalyze the
dehydrative N-alkylation of anilines with 4-hydroxybutan-2-one to
yield β-aminoketones in the presence of TEMPO (2,2,6,6-
As one of the most useful transformations in organic synthesis,
the construction of C-N bonds has long been pursued by synthetic
chemists. Amines have wide applications in academic
laboratories, chemical and pharmaceutical industries, and they
can also be used for the synthesis of various biologically active
materials.1 Many methods have been employed to form C-N
bonds, for example, substitution, addition, cycloaddition, and
cross-coupling reactions, etc.2 The direct substitution of hydroxy
groups in alcohols by N-nucleophiles offers straightforward
access to C-N bonds formation which has advantages of easy
accessible raw materials, the sole by-product (H2O), high
increased efficiency and atom economy over the alternative
stoichiometric activation and displacement protocol. However, the
hydroxy group is not a good leaving group owing to the intrinsic
thermodynamic and kinetic barriers. The alcohols have to be deri-
vatized as potentially genotoxic alkyl halides, tosylates, triflates,
and sulfonates, etc.3 Direct substitution of alcohols was selected
as one of the top 10 key green chemistry research areas by the
ACS Green Chemistry Institute®Pharmaceutical Roundtable
(GCIPR).4
tetramethyl-1-piperidinyloxy)
which
differed
from
the
TEMPO/TBN-catalyzed oxidation reactions (Scheme 1b). A broad
range of anilines were alkylated with 4-hydroxybutan-2-one.
Preliminary mechanistic investigation suggested that this reaction
most possibly experienced α, β-unsaturated ketones and followed
by aza-Michael addition.
In 1981, Grigg5 and Watanabe6 reported the first examples of
alcohol substitution by N-nucleophiles in the presence of rhodium,
iridium, and ruthenium compounds. Since then, many efficient
catalytic methods for the N-alkylation of amines as well as the
related reactions by activating alcohols were developed using
metal catalysts (Ag,7 Au,8 Ir,9 Pd,10 Re,11 Ru,12 Co,13 Cu,14 Fe,15
Scheme 1. N-alkylation of amines with alcohols.
We began our investigations using commercially available
aniline (1a) as amine source and 4-hydroxybutan-2-one (1b) as
alcohol substrate with 10 mol% TEMPO and 10 mol% TBN in
DMSO at room temperature for 12 h as shown in Table S1 (see
the ESI). The 4-(phenylamino)butan-2-one (1c) was obtained in
37% isolated yield (Table S1, entry 1). A change of TBN to NaNO2
and HCl contributed to the decline of the product yield (Table S1,
entry 2). The reactions might involve NO• radical. In the absence
of TEMPO or TBN, we did not detect 4-(phenylamino)butan-2-one
(1c) (Table S1, entries 3 and 4). When this N-alkylation reaction
was carried out in nitrogen atmosphere, 4-(phenylamino)butan-2-
one (1c) was obtained in 73% isolated yield (Table 1, entry 1)
which showed that O2 had an impact on this N-alkylation reaction.
Various conditions were tested in nitrogen atmosphere for the
[a]
Wenchen Cheng, Shue Deng, Liya Jiang, Dr. Lanhui Ren,* Zicheng
Wang, Dr. Jian Zhang, and Prof. Weiguo Song*
College of Pharmacy
Weifang Medical University
Weifang 261053, P. R. China
E-mail: Ren_lanhui@163.com
http://yxxy.wfmc.edu.cn/2017/1127/c1953a43176/page.htm
williamsong@doyepharma.com
http://yxxy.wfmc.edu.cn/2018/0927/c1956a51177/page.htm
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901472
European Journal of Organic Chemistry
COMMUNICATION
optimization of reaction parameters including TEMPO, TBN,
solvents and reaction time to identify the optimal reactions
conditions. First, brief screening of other solvent systems such as
N, N-dimethylformamide (DMF), MeCN, MeOH, EtOH, toluene,
THF, ethyl acetate (EA) and solvent-free system yielded 4-
(phenylamino)butan-2-one (1c) in 7-65% isolated yields (Table 1,
entries 2-9). This N-alkylation reaction did not occur in CH2Cl2,
1,2-dichloroethane (DCE) and H2O (Table 1, entries 10-12). TBN
was broken down by H2O resulting in no N-alkylation reaction
occur. Therefore, DMSO was the best choice for the next
optimization study. Next, the influences of the TEMPO derivatives
were investigated which revealed that TEMPO promoted this
process more efficient than other derivatives (Table 1, entries 13-
15). Subsequently, brief screening of the dosage of TEMPO
provided a satisfactory alkylation product yield using 20 mol%
TEMPO (Table 1, entries 16-19). The increase in the amount of
TBN did not improve the product formation, and decrease in the
amount of TBN led to the decrease of the product yield (Table 1,
entries 20 and 21). It was worth noting that acceptable reaction
yield was obtained when the reaction time was cut down to 9 h
(Table 1, entries 22-25). Thus, further experiments were
conducted with 20 mol% TEMPO and 10 mol% TBN at room
temperature in DMSO for 9 h under nitrogen atmosphere.
18
TEMPO (15)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
DMSO
78
89
62
88
53
72
76
83
19
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
20[b]
21[c]
22[d]
23[e]
24[f]
25[g]
[a] Isolated yield, n. r. = no reaction. [b] The dosage of TBN was 5 mol%. [c] The
dosage of TBN was 15 mol%. [d] Reaction time was 6 h. [e] Reaction time was
7 h. [f] Reaction time was 8 h. [g] Reaction time was 9 h.
Table 1. Optimization of Reaction Conditions.
entry
1
TEMPO (mol%)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
HO-TEMPO (10)
H2NCO-TEMPO (10)
H2N-TEMPO (10)
TEMPO (5)
solvent
DMSO
DMF
yield[a] (%)
73
2
63
3
MeCN
MeOH
EtOH
Toluene
THF
7
4
56
5
57
6
65
7
42
8
EA
25
Scheme 2. Scope of Substrates (isolated yield).
9
-
42
With the optimal conditions established, a wide range of
structurally diverse anilines were subjected to the TBN-catalyzed
dehydrative N-alkylation reaction (Scheme 2). Both electron-rich
and electron-deficient anilines could be employed efficiently in
this catalytic platform (1c-28c, 39-89%). Bromine and chlorine
substituents had slight influences on our process (Scheme 2, 2c-
7c). By comparison, fluorine substituent had obvious effects
(Scheme 2, 8c-10c). It might be due to the strong electronegativity
of fluorine. The halogen substituents with different positions on
the phenyl groups had different influences on the reactivity. The
effects of ortho- and para-substituents were greater than that of
meta-substituents (Scheme 2, 2c-10c). Substrates bearing
methyl substituent at ortho-, meta-, and para-positions of anilines
10
11
12
13
14
15
16
17
CH2Cl2
DCE
n. r.
n. r.
n. r.
47
H2O
DMSO
DMSO
DMSO
DMSO
DMSO
57
45
64
TEMPO (8)
65
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10.1002/ejoc.201901472
European Journal of Organic Chemistry
COMMUNICATION
afforded the N-monoalkylated anilines in 81%, 81% and 82%
yields, respectively (Scheme 2, 11c-13c). tert-Butyl and methoxy
substitutes followed a similar trend with reasonably good yields
(Scheme 2, 14c and 15c). Phenyl and cyano substitutes had
obvious impacts on this dehydrative N-alkylation reaction, and
were unfavorable for it. The yields of the products were 56%, 61%
and 66%, respectively (Scheme 2, 16c, 22c and 23c). The
substrates with strong electron-withdrawing groups in the
aromatic rings, such as -NO2 (Scheme 2, 17c and 18c), -SO2CH3
(Scheme 2, 19c) and -CF3 (Scheme 2, 20c and 21c), were
tolerated in this dehydrative N-alkylation reaction in moderate
yields (40%, 45%, 51%, 39% and 40% yields, respectively).
Surprisingly, electron-deficient aniline substituted with a para-
ester group was converted into 24c in 84% yield (Scheme 2, 24c).
Anilines bearing two substituents afforded the corresponding N-
monoalkylated anilines in good yields (Scheme 2, 25c, 26c, 27c
and 28c).
hydroxybutan-2-one. t-BuO• radicals could react with TEMPOH
forming TEMPO. Other stabilizers such as hydroquinone and 2,6-
di-tert-butyl-4-methylphenol (BHT) were studied. The yield of 4-
(phenylamino)butan-2-one (1c) were 36% and 44% respectively
(Scheme 4, eq 6 and 7). Increase the dosage of TEMPO to 1
mmol led to the decline in yield of 4-(phenylamino)butan-2-one
(32%). It was probably because a large amount of TEMPO
destroyed the key radicals of this dehydrative N-alkylation
reaction.
Figure 1. 1H NMR spectra of 4-hydroxybutan-2-one and TBN.
Scheme 3. Gram Scale Reactions (isolated yield).
To highlight the synthetic practicality of the present protocol,
gram-scale (10 mmol) reactions with anilines and 4-
hydroxybutan-2-one were performed until complete consumption
of starting materials as monitored by TLC or 72 h. The desired
products were obtained in good isolated yields (Scheme 3),
indicating that this protocol was a practical process for the
preparation of β-aminoketone.
1
The H NMR was used to study the structural changes of 4-
hydroxybutan-2-one (1b) in the presence of TBN (Figure 1). The
resonance characteristics of olefins were displayed, which
suggested that transformation of 4-hydroxybutan-2-one (1b) to
methyl vinyl ketone took place in the reaction.
Encouraged by the above outcomes, further studies of this
dehydrative N-alkylation reaction were carried out by various
control experiments (Scheme 4). When only TEMPO or TEMPOH
was used in nitrogen atmosphere, we did not detect 4-
(phenylamino)butan-2-one (1c) (Scheme 4, eq 1 and 2) which
liked the result of experiment in air atmosphere (Table S1, entry
3). 4-(phenylamino)butan-2-one (1c) was obtained in 19% yield
when only TBN was used in nitrogen atmosphere (Scheme 4, eq
3) which was different from the result of experiment in air
atmosphere (Table S1, entry 4). TBN appeared to be the real
catalyst of the reaction. When TEMPOH or TEMPO was used
together with TBN, 4-(phenylamino)butan-2-one (1c) was
obtained in 83% and 45% yields, respectively (Scheme 4, eq 4
and 5). TEMPO might act as a stabilizing agent to prevent the
polymerization of methyl vinyl ketone in-situ generated from 4-
Scheme 4. Control Experiments.
We speculated this dehydrative N-alkylation reaction involved
•OH radical. We conducted quenching tests to recognize OH
using isopropanol (Table 2). Low yields of 4-(phenylamino)butan-
2-one (1c) were obtained in the cases of isopropanol, and the
more isopropanol dosage, the lower product yield. These results
•
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10.1002/ejoc.201901472
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•
revealed the involvement of OH radical in this dehydrative N-
alkylation reaction.
National Natural Science Foundation of China (No. 81803368) for
support of this research.
Table 2. Quenching experiments (isolated yield).
Keywords: TEMPO • TBN • N-Alkylation • Substitution • Alcohol
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Scheme 5. Possible Reaction Pathway.
In summary, an efficient protocol for the dehydrative N-
alkylation of anilines with 4-hydroxybutan-2-one using TBN as
catalyst had been developed. A range of anilines reacted
successfully with 4-hydroxybutan-2-one to generate the β-
aminoketones products in good yields. A possible catalytic
mechanism was proposed. Water was the only by-product, and
this reaction could be scaled up. Further studies will be aimed at
extending the substrate scope and investigating the reaction
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Acknowledgements
We gratefully acknowledge the Research Foundation of Weifang
Medical University, the Innovative Drug Research and
Development Center of Weifang Medical University and the
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10.1002/ejoc.201901472
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Catalytic N-Alkylation
Wenchen Cheng,[a] Shue Deng,[a] Liya
jiang,[a] Lanhui Ren,*[a] Zicheng Wang,[a]
Jian Zhang,[a] and Weiguo Song*[a]
Page 1. – Page 6.
An efficient protocol for the dehydrative N-alkylation of anilines with 4-hydroxybutan-
2-one using TBN as catalyst in the presence of TEMPO has been developed. Various
anilines could be transformed into the N-monoalkylation products in good yields. α,
β-Unsaturated ketone generated in situ from 4-hydroxybutan-2-one and aza-Michael
addition were involved. Water was the only by-product.
TBN-Catalyzed Dehydrative N-
Alkylation of Anilines with 4-
Hydroxybutan-2-one
This article is protected by copyright. All rights reserved.