Transition-metal-free nucleophilic allylic substitutions of Morita–Baylis–Hillman bromides with aliphatic and aromatic amines

Article abstract of DOI:10.1080/00397911.2016.1228109

A simple protocol for the preparation of functionalized allylic amines under mild, transition-metal-free conditions from the reaction of Morita–Baylis–Hillman (MBH) bromides with amines is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et₃N in aqueous acetone solution and at room temperature affords the corresponding functionalized allyl amines in moderate to good yields (45–87%). The reaction is rapid and carried out at room temperature.

Full text of DOI:10.1080/00397911.2016.1228109

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Transition-Metal-Free Nucleophilic Allylic
Substitutions of Morita-Baylis-Hillman Bromides
with Aliphatic and Aromatic Amines
Narjes Baioui, Haitham Elleuch & Farhat Rezgui
To cite this article: Narjes Baioui, Haitham Elleuch & Farhat Rezgui (2016): Transition-Metal-
Free Nucleophilic Allylic Substitutions of Morita-Baylis-Hillman Bromides with Aliphatic and
Aromatic Amines, Synthetic Communications, DOI: 10.1080/00397911.2016.1228109
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1228109
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Date: 05 September 2016, At: 05:05

Transition-Metal-Free Nucleophilic Allylic Substitutions of Morita-Baylis-Hillman
Bromides with Aliphatic and Aromatic Amines
Narjes Baioui1, Haitham Elleuch1, Farhat Rezgui1
1University of Tunis El Manar Faculty of Sciences of Tunis, Laboratory of Structural
Organic Chemistry and Macromolecular LR99ES14, Tunis, Tunisia
Corresponding author Farhat Rezgui E-mail: rez_far@yahoo.fr
Abstract
Under mild, transition-metal-free conditions, a simple protocol for the preparation of
functionalized allylic amines from the reaction of Morita-Baylis–Hillman (MBH)
bromides with amines, is described herein. The treatment of the MBH bromides with
various amines in the presence of NaI and Et3N in aqueous acetone solution and at room
temperature, affords the corresponding functionalized allyl amines in moderate to good
yields (45-87%). The reaction is rapid and carried out at room temperature.
Graphical Abstract
KEYWORDS: Morita Baylis-Hillman Bromide; Allylic substitution; Allylic amines
INTRODUCTION
In recent years, nucleophilic substitution reactions of allyl compounds have been
developed very well [1]. Among them, the allylic amination has attracted considerable
1

attention [1,2] as it provides an efficient synthetic approach for biologically active
compounds with an allylamino moiety that represents an important structural motif
frequently found in natural products, pharmaceuticals, as well as versatile building blocks
for the synthesis of molecules of higher complexity [3]. These reports revealed that the
direct nucleophilic displacements on allyl substrates could be performed under metal-free
catalytic conditions as well as under catalytic conditions in order to expand the scope of
the allylic substitutions.
The literature reported a large number of synthetic methods, allowing access to allyl
amines. Over the last decades, their preparation using the MBH adducts through
nucleophilic substitution reactions, has become a method of choice, generally simple and
efficient [4]. In 2002, Rajesh and co-workers [5] reported a palladium-catalyzed allylic
amination of the MBH acetates, with moderate regioselectivity. Moreover, in 2007,
Nemeto and co-workers [6] studied the asymmetric allylic amination reactions of the
MBH adducts, in which they described a highly enantioselective allylic amination of
MBH carbonates using Pd catalyst systems. Recently, Wang and co-workers [7] reported a
palladium-catalyzed α-regioselective allylic amination of MBH acetates with aromatic
amines.
The α-(N,N-dialkylaminomethyl)cyclic enones are of great interest in organic synthesis
[8]. Tamura and co-workers have reported a successful method for their preparation by
denitro-amination and desulfonyl-amination of the corresponding allylic derivatives [9].
Moreover, Liu and co-workers [10] have described a highly α-regioselective In(OTf)3-
2

catalyzed N-nucleophilic substitution of cyclic MBH adducts with aromatic amines,
providing an efficient route to aromatic allylic amines bearing cyclic unsaturated ketone
unit.
The syntheses of allyl amines, under mild conditions, still an important industrial and
synthetic goal. The development of efficient and highly selective methods for their
preparation merits a thorough investigation [11]. To the best of our knowledge, the N-
allylation of amines with cyclic MBH bromides 3a-c has not been extensively studied
under Pd-free conditions. Hence, we wish to report in this paper an efficient method for
the synthesis of various functionalized allyl amines, in aqueous acetone and at room
temperature, from the cyclic MBH bromides.
RESULTS AND DISCUSSION
Allylic alcohols 2a-c were first prepared through the MBH reaction involving the cyclic
enones 1a-b [12,13,14], followed by their direct conversion into the corresponding allylic
bromides 3a-c using aqueous 48% hydrobromic acid (Scheme 1) [15]
.
It is noted that these allyl bromides 3a-c are of limited stability, particularly when neat.
Therefore, they were prepared from the MBH alcohols 2a-c and then directly used
without further purification.
With the desired allylic bromides 3a-c in hand, our first challenge was the development
of a general and efficient route for a range of allyl amines. In our preliminary attempts,
3

the reaction of morpholine and the MBH bromide 3a in THF was carried out for 1 hour,
at room temperature, without any additive. In this case, we have observed that the allyl
amine 4a was obtained but with a low 30% yield. Therefore, we thought that a more
efficient route would work in a homogeneous and basic medium, so we investigated the
behavior of the allyl bromide 3a with morpholine in the presence of Et3N in THF as
solvent. Under these conditions, we have actually noticed an increase in the yield of the
reaction from 30 % to 50 %. In order to more improve this modest yield, morpholine was
reacted, this time, with the allylic bromide 3a, but in the presence of sodium iodide and
Et3N as additives in an acetone-water (1:1 v/v) mixture, as solvents mixture. The allyl
amine 4a was selectively obtained and the yield was significantly improved from 50 to 80
% (Entry 1, Table 1). Encouraged by these results, we attempted to extend this simple
synthetic methodology to a series of amines (Scheme 2).
Under the above optimized reaction conditions, we have observed that the six-membered
allylic bromide 3a rapidly reacted with relatively hard secondary amines (Entries 1-4,
Table 1 ) as well as the relatively soft aniline derivatives (Entries 5-8, Table 1), affording,
within 5 min, in 60-87% yields, the allyl amines 4a-d and 4e-h, respectively. This
allylation reaction of amines also worked with the six-membered bromide 2b but the
latter is less reactive than its homologous compound 2a, presumably as it is slightly
hindered at the -allyl bromide carbon atom bearing a methyl group. The corresponding
amines 4i-k were obtained within 60 min and in 45-55% moderate yields (Entries 9-11,
Table 1).
4

Next, we have explored the effect of the substrate ring size 3 on the steric course of the
amination reaction. For this purpose, we have selected the five-membered allylic bromide
3c. Successfully, the corresponding allyl amines 4l-n were obtained within 5 min and in
70-85% high yields (Entries 12-14, Table 1).
We note that the spectroscopic data of allyl amines 4a-n are in agreement with those of
literature [4,9]
.
Furthermore, the acceleration of the amination reaction can be explained by the in situ
formation of the iodinated intermediate I that subsequently undergoes a relatively rapid
SN2-type reaction in the presence of amines, affording the allyl amines 4a-n (Scheme 3).
Indeed, the iodine is more polarizable than bromine and the iodide ion is a better leaving
group than the bromide ion in a SN2-type reaction. We note that the role of triethylamine
in this reaction is to trap the hydrogen bromide formed in the reaction medium.
We believe that, in the present study, the various amines, first react in a 1,4-addition-
elimination of the iodide ion, to give the SN2’ intermediate I2 (i and ii), which then
undergo a second β’-1,4-addition-elimination of the amine, affording the SN2’ products 4
(Scheme 4).
EXPERIMENTAL SECTION
Typical Procedure For The Preparation Of Allyl Bromides (3a-C)
5

An aqueous 48% hydrobromic acid (4 mL, 4 mmol) was added to the corresponding
MBH alcohols 2a-c (4 mmol) and the reaction mixture was stirred at room temperature
until TLC indicated complete consumption of the starting material. It is noted that the
reaction was carried out for 1 hour in the case of the MBH alcohols 2a and 2c and it took
3h in the case of the alcohol 2b. Then the reaction was quenched with water (4 mL) and
the aqueous phase was extracted with methylene chloride (3×10 mL). The organic phase
was washed with a saturateted solution of NaHCO3, with brine, dried over MgSO4 and
concentrated in vacuo. The resulting residue was then used without further purification.
Typical Procedure For The Preparation Of Allyl Amine (4a)
To a solution of the allyl bromides 3a (4 mmol) in 5 mL of acetone-water (1:1 v/v)
mixture, was added Et3N (6 mmol) and NaI (6 mmol). The reaction mixture was stirred
for 10 min then the hard-soft amine was added (6 mmol).
The mixture was stirred at room temperature until TLC indicated complete consumption
of the starting material. The reaction was then quenched with water and extracted with
CH2Cl2 (3×10 mL). The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting residue was purified by a column
chromatography on silica gel (ether/petroleum ether).
CONCLUSION
In summary, a concise and practical approach for the synthesis of a series of
functionalized allyl amines 4a-n has been disclosed using the allyl bromides 3a-c,
6

directly obtained from the corresponding MBH alcohols 2a-c. This strategy is considered
attractive as it involves commonly available inexpensive reagents and does not require
any elaborate reaction conditions.
SUPPORTING INFORMATION
Supporting Information: Full experimental detail, IR,1H and 13C NMR spectra and GC-
MS /HRMS. This material can be found via the “Supplementary Content” section of this
article’s webpage.
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8

Table 1. Synthesis of allyl amines 4a-n from the MBH bromides 3a-c
Entry R
Hard-soft amine
Allyl amine 4
Reaction
time/min
5
Yield 4
(%)
1
2
3
4
5
6
H
80
(3a)
4a
4b
4c
4d
4e
H
5
5
5
5
5
60
85
75
87
70
(3a)
H
(3a)
H
(3a)
H
(3a)
H
(3a)
4f
9

7
8
H
5
5
75
65
(3a)
4g
H
(3a)
4h
9
CH3
60
60
60
45
55
45
(3b)
4i
10
11
CH3
(3b)
4j
4k
CH3
(3b)
12
13
H (3c)
H (3c)
5
5
70
85
4l
10

4m
4n
14
H (3c)
5
84
11

Scheme 1. Synthesis of the MBH bromides 3a-c
12

Scheme 2. Synthesis of allyl amines 4a-n from the MBH bromides 3a-c
13

Scheme 3. Formation of allyl amines 4a-n in a two-step sequence
14

Scheme 4. Proposed mechanism for the synthesis of allyl amines 4a-n from the
intermediate I
15