"On-water" conjugate additions of anilines

Article abstract of DOI:10.1039/c0cc02502j

The conjugate addition of anilines onto unsaturated ketones, esters and N-acylpyrroles was investigated. Based on a recently proposed explanation for the phenomenon of on-water catalysis, operationally simple and mild reaction conditions for effecting these addition reactions have been developed. The success of these additions provides further support for the acid-catalysed nature of on-water chemistry.

Full text of DOI:10.1039/c0cc02502j

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
‘‘On-water’’ conjugate additions of anilinesw
Christopher B. W. Phippen, James K. Beattie and Christopher S. P. McErlean*
Received 12th July 2010, Accepted 8th September 2010
DOI: 10.1039/c0cc02502j
The conjugate addition of anilines onto unsaturated ketones,
esters and N-acylpyrroles was investigated. Based on a recently
proposed explanation for the phenomenon of on-water catalysis,
operationally simple and mild reaction conditions for effecting
these addition reactions have been developed. The success of
these additions provides further support for the acid-catalysed
nature of on-water chemistry.
Given the ubiquity of amines and nitrogen heterocycles in the
natural and built environments, it is unsurprising that methods
Scheme 1 Conjugate addition of aniline to methyl acrylate.
to construct the C–N bond have been intensively studied.
One general method that has been widely adopted is the
Michael addition of amines onto a,b-unsaturated carbonyl
compounds. Whilst it is known that the rate of addition of
aliphatic amines can be increased by acid or base catalysis in
organic solvents,1–8 several reports have been disclosed that
utilise water as the solvent where no catalyst is required.9–11 In
contrast to those aliphatic cases, the Michael addition of
substituted anilines onto enones and enoates has traditionally
been a difficult transformation to effect, with only highly
activated Michael acceptors participating in the non-catalysed
reaction.12 This is somewhat surprising given that the
nucleophilicity (in contrast to the basicity) of aniline has been
measured experimentally to be similar to that of other primary
amines.13 The use of Lewis acids,3,14,15 metal promoters,16,17
surfactants18–21 and other additives2,22 have all been proffered
as a means to overcoming this inherent lack of reactivity. For
example, Chen et al.23 and Surendra et al.24 reported the
conjugate addition of aniline onto methyl acrylate at room
temperature in water catalysed by tungstophosphoric acid and
b-cyclodextrin respectively. Even under those catalyst-
promoted conditions the reactions were sluggish, requiring
up to 40 h to reach completion.
generated in good yield at a slightly lower temperature
(54 1C). Rather than being uncatalysed, the conjugate addition
of anilines in those instances appears to be acid catalysed.
We recently proposed a mechanism that explains the pheno-
menon of on-water catalysis.25 Protonation of organic
substrates at the oil–water interface is driven by the strong
adsorption of hydroxide ions to the interface.26,27 The
protonated species is available to undergo acid-catalysed
reactions while the hydroxide ion is sequestered in a deep
thermodynamic well. This mechanism is consistent with the
observed on-water rate enhancements for the conjugate
addition of nitromethane to enones.28–30 Based on this new
understanding of acid catalysis on neutral water, we
anticipated that the rate of conjugate addition of aniline to
methyl acrylate could be accelerated by conducting the
reaction as a heterogeneous suspension of organic droplets
in water (the reaction conditions described by Sharpless et al.
as ‘‘on-water’’).31 This would provide a straightforward and
economical route for effecting the acid catalysed additions. As
detailed below, this supposition proved correct.
We began our investigations by vigorously stirring a 1 : 1.1
mixture of aniline and methyl acrylate on-water for 24 h at
ambient temperature. To our delight the desired adduct 3 was
collected in 21% isolated yield after chromatography
(see Table 1). In agreement with previous work,16 employing
the more nucleophilic p-methoxyaniline in the conjugate addition
lead to an increased yield (entry 2), whilst the less nucleophilic
p-bromoaniline disfavoured the coupling reaction (entry 5).
The modest yields can be improved by altering the reaction
stoichiometry, but when coupling more complex anilines and
acrylates, an excess of either reactant may be undesirable. We
therefore repeated the on-water reactions at 50 1C. As shown
in Table 1 there was a corresponding increase in the yield of
the desired adducts. The yields obtained using this simple
protocol were in general superior to the yields obtained using a
threefold excess of acrylate at high temperatures in previous
work.16 Even the halogenated aniline (entry 5) which had
proven immune to coupling in previous work, provided the
1,4-adduct, albeit in low yield.
Recently, Legros, Crousse and co-workers reported the
uncatalysed addition of aniline (1) onto methyl acrylate (2)
using hot water (80 1C) as the solvent (Scheme 1).16 When a
1 : 1 ratio of aniline : methyl acrylate was employed the
desired reaction proceeded to only 15% conversion. When a
threefold excess of methyl acrylate was employed the Michael
adduct 3 was produced in 34% yield. Revealingly, the use of
the more acidic trifluoroethanol (pKa 12.5) as a co-solvent at
80 1C, gave the product 3 in 85% yield. Increasing the acidity
of the solvent still further by employing hexafluoroisopropanol
(pKa 9.3) allowed the bis-alkylated compound 4 to be
School of Chemistry, The University of Sydney, NSW, 2006,
Australia. E-mail: christopher.mcerlean@sydney.edu.au;
Fax: +61 2 9351 3329; Tel: +61 2 9351 3970
w Electronic supplementary information (ESI) available: General
experimental procedures and spectroscopic data for all synthesized
compounds. See DOI: 10.1039/c0cc02502j
c
8234 Chem. Commun., 2010, 46, 8234–8236
This journal is The Royal Society of Chemistry 2010

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Table 1 On-water conjugate addition of anilines
Table 2 On-water conjugate addition of anilines to an N-acylpyrrole
Methyl acrylatea (%)
Yield at
rta (%)
Yield at
50 1Ca (%)
MVKb (%)
Entry
Nucleophile
Method A Method B Method A
Entry Nucleophile
1
2
3
4
5
6
7
8
9
10
Aniline
96
—
—
—
1
2
3
4
5
6
7
8
9
10
Aniline
21
46
18
6
35
94
45
8
10
NR
55 (25)c
—
100
p-Methoxyaniline
p-Methylaniline
2,4-Dimethylaniline
p-Bromoaniline
2,4,5-Trichloroaniline
p-Aminophenol
Thiophenol
100
100
70b
20
p-Methoxyaniline
p-Methylaniline
2,4-Dimethylaniline
p-Bromoaniline
2,4,5-Trichloroaniline NR
p-Aminophenol
Thiophenol
70 (30)c
80 (10)c
100
100c
100c
65c
—
30c
75 (25)
95
NR
85
14d
16
46
38
45
70 (25)c
95
92
—
—
—
p-Methylthiophenol
p-Bromothiophenol
94
96
p-Methylthiophenol
p-Bromothiophenol
—
—
95
a
Yield of isolated product after chromatography, reaction time
a
b
4 h. Reaction time 16 h. Reaction time 24 h.
c
Yield of isolated product after chromatography, reaction time
b
24 h. Reaction time 1 h. Yield of dialkylated product in parentheses.
d
c
Reaction time 2 h. Method A: 1.1 equiv. at rt; Method B: 1.1 equiv.
at 50 1C.
As shown in Table 2, unsubstituted aniline and electron-rich
anilines underwent conjugate addition onto N-acryloyl-2,5-
dimethylpyrrole (5) at room temperature in as little as 4 h to
give the desired products in preparatively useful yields.
The use of the more electrophilic and hydrophobic pyrrolic
amide removed the need for heating or excess reagents.
Electron-poor anilines required longer reaction times to
generate useful yields (entries 4 and 6), but even 2,4,5-trichloro-
aniline participated in the reaction under ambient conditions.
Increasing the reaction temperature to 50 1C facilitated the
conjugate addition of electron poor and sterically hindered
anilines in excellent yields (entries 4–6). The double alkylation
product was only observed for the reaction involving
p-aminophenol.z Again, thiophenols proved to be exceptional
coupling partners in the conjugate addition to N-acryloyl-2,5-
dimethylpyrrole (entries 8–10).
The increased yields at lower temperatures that arise from
the formation of an oil-in-water emulsion are consistent
with the hypothesis of interfacial acid-catalysis to explain the
on-water effect.25
Legros, Crousse and co-workers reported that substituted
anilines participated in uncatalysed conjugate additions onto
the highly electrophilic methyl vinyl ketone (MVK) at room
temperature under aqueous conditions.16 We anticipated that
performing the same reactions on-water (i.e. using a hetero-
geneous aqueous suspension) would lead to increased yields
via acid-catalysis. As shown in Table 1 the on-water Michael
addition of both electron-rich and electron-poor anilines onto
MVK proceeded in excellent yield after short reaction times.
Even the deactivated and sterically hindered 2,4,5-trichloro-
aniline participated in the conjugate addition (entry 6). Only in
the case of the electron-rich anilines was double alkylation
observed (entries 2, 3 and 7). Legros, Crousse and co-workers
demonstrated a clear relationship between the acidity of the
solvent and the amount of bis-alkylation.16 Therefore this
result provides yet more evidence that these addition reactions
are accelerated by acid-catalysis at the oil–water interface.
Unsurprisingly, thiophenols proved to be excellent coupling
partners (entries 8–10).
To unambiguously demonstrate that each of the conjugate
additions detailed in this communication was subject to
on-water catalysis rather than hydrophobic-driven concentration
effects, we compared the product yield of the reactions
between aniline and the Michael acceptors after a fixed
reaction time. As shown in Table 3, each of the reactions
was substantially faster on-water than neat, demonstrating
that formation of the oil-in-emulsion catalysed the reaction.
In summary, we have used our mechanistic understanding
of the phenomenon of on-water catalysis to uncover a
general and efficient method for effecting the conjugate
addition of anilines (and thiophenols) onto methyl acrylate
and N-acryloyl-2,5-dimethylpyrrole. The success of this
strategy provides evidence in favour of acid-catalysis at the
interface being responsible for the ‘‘on-water’’ effect. The use
of this new protocol in synthetic settings is underway in our
laboratories and will be reported in due course.
We next turned our attention to designing a system that
incorporated the salient synthetic features of both previous
conjugate addition reactions. That is, a reaction that was as
efficient as the on-water Michael additions using MVK,
but that gave products with the same synthetic utility as the
on-water Michael additions using methyl acrylate. We
anticipated that employing N-acryloyl-2,5-dimethylpyrrole
(5) (Fig. 1) as the electrophilic partner would achieve this
goal. Unsaturated N-acylpyrroles are known to be more
electrophilic than the corresponding esters, and the pyrrole
unit serves as a masked ester, acid or amide.32,33
Table 3 Comparative rates of reaction
Neata (%)
‘‘On-water’’a (%)
Methyl acrylateb
0
66
51
21
100
70
Methyl vinyl ketonec
N-Acryloyl-2,5 dimethylpyrroled
a
b
Yield of isolated product after chromatography. Reaction time of
c
24 h. Reaction time of 11 h. Reaction time of 15 min.
d
Fig. 1 N-Acryloyl-2,5-dimethylpyrrole.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8234–8236 8235

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16 K. De, J. Legros, B. Crousse and D. Bonnet-Delpon, J. Org.
Chem., 2009, 74, 6260–6265.
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initial mono-alkylated compound was observed to convert into the
bisalkylated compound on standing.
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