Efficient oxidative N-dealkylative addition of trialkylamines to dimethyl acetylenedicarboxylate using BrCCl3 as the terminal oxidant

Article abstract of DOI:10.1016/j.tetlet.2017.05.073

Herein we present a continuous improvement of visible-light mediated N-dealkylative addition of tertiary amines to dimethyl acetylenedicarboxylates (DMAD) using alkyl halogenides as external oxidants together with base additives. This method is highlighted by excellent tolerance with various tertiary amines and good to excellent yields in short reaction time under mild conditions.

Full text of DOI:10.1016/j.tetlet.2017.05.073

Accepted Manuscript
Efficient Oxidative N-Dealkylative Addition of Trialkylamines to Dimethyl
Acetylenedicarboxylate using BrCCl3 as the Terminal Oxidant
Fangnan Liu, Zhiguo Zhang, Zongbi Bao, Huabin Xing, Yiwen Yang, Qilong
Ren
PII:
S0040-4039(17)30664-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.073
TETL 48966
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
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19 April 2017
18 May 2017
19 May 2017
Please cite this article as: Liu, F., Zhang, Z., Bao, Z., Xing, H., Yang, Y., Ren, Q., Efficient Oxidative N-Dealkylative
Addition of Trialkylamines to Dimethyl Acetylenedicarboxylate using BrCCl3 as the Terminal Oxidant, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.073
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Tetrahedron Letters
Efficient Oxidative N-Dealkylative Addition of Trialkylamines to Dimethyl
Acetylenedicarboxylate using BrCCl3 as the Terminal Oxidant
Fangnan Liu, Zhiguo Zhang, Zongbi Bao, Huabin Xing, Yiwen Yang and Qilong Ren
Key Laboratory of Biomass Chemical Engineering of Ministry of Education
College of Chemical and Biological Engineering
Zhejiang University, Hangzhou 310027, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we present a continuous improvement of visible-light mediated N-dealkylative addition
of tertiary amines to dimethyl acetylenedicarboxylates (DMAD) using alkyl halogenides as
external oxidants together with base additives. This method is highlighted by excellent tolerance
with various tertiary amines and good to excellent yields in short reaction time under mild
conditions.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
N-dealkylative addition
Photoredox catalysis
Trialkylamines
Organocatalysis
The N-dealkylation of tertiary amines is one of the most challenging research subjects in modern organic synthesis.1 In general, owing
to the high C-N bond dissociation energy2 and inert reactivity, C-N cleavage reactions are usually catalyzed by transition metal
catalysts.1a, 3 Nevertheless, these methods were often encountered with some disadvantages such as harsh reaction conditions, limited
substrate scope, etc. Thus, from a practical point of view, there is still a need to explore new methods enabling efficient dealkylation of
tertiary amines at ambient conditions. In this regard, photoredox catalysis has recently received much attention and grown rapidly into
an alternative pathway for this transformation. Rueping and co-workers reported an efficient dealkylation of various tertiary amines to
secondary amines using an iridium-based photoredox catalyst.4 We recently showed that eosin Y (EY) was a suitable organocatalyst for
visible-light-driven N-dealkylative addition of tertiary amines to dimethyl acetylenedicarboxylates (DMAD) using O2 as an external
oxidant5 (Scheme 1). Although our protocol was able to furnish the corresponding product, the yield and substrate scope are still
unsatisfactory. In line with previous reports, we presumed that the inferior results with our title reaction might be resulted from the
peroxy radical6 during the reaction pathway, which could gave rise to some side products. On the other hand, some strategies on the
improvement of photocatalytic reaction outcomes have been directed toward tuning external oxidants7 as well as base additives.8 As
showed from our previous experimental results, we have proposed that the generation of an iminium intermediate is a key for the
dealkylation of tertiary amines and subsequent interception with DMAD (Scheme 1). Taking all these considerations together, we
wonder that the replacement of O2 with other suitable oxidants that enable efficient formation of the iminium intermediate might be
beneficial for this transformation in terms of yields and substrate scope. Herein, we present a continuous improvement of Eosin Y
catalyzed N-dealkylative addition reaction by using BrCCl3 as the external oxidant and Cs2CO3 as a base additive.
Scheme 1. Eosin Y catalyzed N-dealkylative addition to DMAD.
With this idea in mind, we initiated our studies by examining the influence of several conventional oxidants on this reaction in the
presence of 3 mol % of eosin Y as photoredox catalyst. Ceric ammonium nitrate (CAN), K2S2O8, and Na2S2O8 tested are less effective
than O2, giving the addition product in poor yields (12–15%) after 20 h (Table 1, entries 1–3). Gratifyingly, when N-Bromosuccinimide
(NBS) was used as the oxidant, the reaction furnished a comparable yield with that with O2 (Table 1, entries 4), suggesting that
———

2
Tetrahedron
halogenated organic oxidant is superior to inorganic ones. Encouraged by this result, we further tested the reaction with CBr4 and
BrCCl3 and were pleased to find that the yield of the reaction can be dramatically improved to 86% and 88% in much less reaction time
(5 h), respectively (Table 1, entries 5–6). After BrCCl3 was established to be the best oxidant, we also investigated solvent effects on the
reaction outcomes. Among all the solvents tested, DCM proved to be optimal, affording the product in 88% yield (Table 1, entry 6). In
line with our previous work, the addition of 1 equiv of H2O can further increase the yield to 93% yield (Table 1, entry 12). Furthermore,
only trace amount of product was observed after 20 h in the absence of the photocatalyst or visible light (Table 1, entry 13–14).
Table 1. Optimization of Reaction Conditionsa
Entry
1
2
3
4
5
6
7
Oxidant (equiv.) Solvent
Time (h)
Yieldb (%)
12
15
12
56
86
88
60
CAN (3)
DCM
DCM
DCM
DCM
DCM
DCM
toluene
MeCN
DMF
THF
20
20
20
20
5
5
5
5
5
18
5
3
20
20
K2S2O8 (3)
Na2S2O8 (3)
NBS (3)
CBr4 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
BrCCl3 (3)
8
9
59
58
15
45
10
11
12d
13d, f
14d, g
DMSO
DCM
DCM
DCM
93 (93)c
Trace
Trace
aReaction conditions: DMAD (0.2 mmol), TEA (0.4 mmol), photocatalyst (3.0
mol%), solvent (2.0 mL), room temperature, using Green LEDs as the visible
light source bYield determined by crude 1H NMR analysis. cIsolated yield. d1.0
equiv H2O was used. eUnder nitrogen atmosphere fWithout catalyst gPerformed
in the dark.
With the optimal conditions in hand, we next investigated the generalities of the N-dealkylative addition reaction by employing a large
variety of tertiary amines 1 as the substrate (Table 2). Generally, all linear trialkyl substituted amines 1a-e were tolerated with this
protocol, giving the corresponding product in good to excellent yield (Table 2, entries 1–5). According to recent study on the reactivity
of N-dealkylation,4 ethyl substituted amine has relatively poor reactivity compared with methyl group, which in line with our
observation that the yield of long chain substituted tertiary amines decrease progressively. In addition, when N-n-Octyldimethylamine
1e was used, alongside 66% yield of 3e, a 28% de-octyl product 3e’ was observed, which indicates that C-N cleavage prefers short alkyl
chain. However, when branched alkyl-substituted tertiary amines 1f were tested with this protocol, a considerable decrease in yields
was observed, presumably due to steric hindrance of these substrates. In light that basic additives are helpful in improvement of product
yield,9 we added 2 equiv. of CsCO3 into the reaction mixture. To our delight, the yields for those branched amines can be enhanced up
to 95% (Table 2, entries 6–8), which are much higher than the yields with O2. In addition, the yields for tertiary amines bearing allyl
(Table 2, entry 9) or carbonyl groups (Table 2, entry 10) were also improved (54%, 40% versus 35%, 29%). When cyclohexyl
substituted tertiary amines 1k-m were employed as the substrate, the reaction affords the respective product with a yield of 83%, 70%,
and 60%, which seems likely that the efficiency of N-deakylative addition was reversely proportional to the bulky size of the
substituents at tertiary amines. Notably, the dealkylative addition of tribenzylamine to DMAD also proceeded smoothly, giving the
product in 82% yield, which was in stark contrast to the reaction using O2 as the oxidant (no reaction). Notably, when N, N-
dimethylbenzylamine 1o was used as the substrate, an excellent chemoselectivity was achieved under this protocol, giving N-
debenzylation product 3o as the sole product (Table 2, entry 15).
Table 2. Substrate screen of different tertiary aminesa
Entry Trialkylamines
Product
Yieldb (%)

NEt3
1a
1
2
3
4
5
6
93c
3a
NPr3
92c
91c
1b
3b
3c
NBu3
1c
N[(CH2)5CH3]3
1d
87c
3d
3e
Me2N(CH2)7CH3
1e
94 (2.4 : 1)c, d
DIPEA
1f
62
3f
N[(CH2)CH(CH3)2]
1g
7
8
75
95
3g
3h
N[(CH2)2CH(CH3)2]
1h
N(CH2CH=CH2)3
1i
9
54
40
3i
3j
Et2NCH2CO2Me
1j
10
Me2NCy
1k
11
12
83
70
3k
Et2NCy
1l
3l
MeNCy2
1m
13
14
15
60
82e
90
3m
3n
3o
NBn3
1n
Me2NBn
1o
aReaction conditions: trialkylamine 1 (0.4 mmol), dimethyl
acetylenedicarboxylate 2 (0.2 mmol), eosin Y 3 mol%, H2O (1.0 equiv),
BrCCl3 (0.6 mmol), Cs2CO3 (0.4 mmol), DCM (2.0 mL), Green LEDs, 3 h.
bYield of the isolated product after column chromatography. cWithout
Cs2CO3. dRatio of demethyl product 3e with deoctyl product 3e’ in

4
Tetrahedron
parenthesis. e16 hours.
To elucidate the mechanism, a control experiment without
DMAD was performed, gratifyingly, a signal of diethyl amine
was observed by means of ESI-MS spectra, suggesting that this
secondary amine was possibly generated via hydrolysis of
iminium under visible light irradiation (see SI). Based on our
experimental results and literature reported4,
a plausible
mechanism for the photocatalytic dealkylative addition is
depicted in Scheme 2. Initial irradiation of EY under visible light
gives rise to excited state EY* which then oxidizes tertiary
amine 1 via single electron transfer (SET) to furnish the
corresponding radical cation 4. The resulting anion radical of EY
reduces BrCCl3 to trichloromethyl radical and bromide ion.
Then, hydrogen atom transfer (HAT) from 4 to trichloromethyl
radical occurs to form iminium ion 5, which is subsequently
hydrolyzed by H2O to form secondary amine 6. Finally,
secondary amine 6 was captured by DMAD to afford the desired
product.
Scheme 2. Proposed mechanism
In summary, we have developed an efficient protocol for dealkylative addition of tertiary amine with DMAD at room temperature using
BrCCl3 as an external oxidant and CsCO3 as a base additive. The present protocol extends the scope to a large variety of tertiary alkyl
amine through visible light catalysis using eosin Y, leading the corresponding products in much better yields than those with molecular
oxygen as the oxidant (40-95% versus 29-61%) in a much shorter reaction time (3 h versus 20 h). Further studies will be focused on
exploring the scope of this reaction to aromatic substituted tertiary amines.
Experimental Section
The 10-mL round-bottom flask was equipped with a magnetic stirrer bar. Afterwards Triamine 1 (0.4 mmol), DMAD 2 (0.2 mmol),
Eosin Y (0.006 mmol), BrCCl3 (0.6 mmol), Cs2CO3 (0.4 mmol), H2O (0.2 mmol) and DCM (2 mL) were added. Then the reaction
mixture was sealed with stopper and placed in room temperature. A 3w green LED was placed at a distance of about 5 cm from the
reaction vessel. After the reaction was complete (as judged by TLC plate). The solvent was removed under reduced pressure directly.
The crude product was purified by flash chromatography on silica gel to afford the desired product 3.
Acknowledgements
We are grateful for financial support from the MOST (2016YFA0202900), the National Natural Science Foundation of China
(21376212, 21436010), the Fundamental Research Funds for the Central Universities (2016FZA4019) and the Natural Science
Foundation of Zhejiang Province, China (LY13B060001).
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6
Tetrahedron
Highlights
1. An improved protocol for N-dealkylative addition of trialkylamines with DMAD.
2. High efficiency under mild oxygen-free conditions.
3. Good to excellent yield and better substrate tolerance.