Uncatalysed intermolecular aza-Michael reactions

Article abstract of DOI:10.1016/j.crci.2012.11.001

The catalyst-free reactions of activated alkenes with primary and secondary amines were investigated leading to various mono- and di-hydroamination products, the latter being rare and original. These reactions were shown to depend first on the strength of the nucleophile. Temperature and steric hindrance of the reagents were the other key factors controlling the selectivity of these aza-Michael reactions. In spite of their poor nucleophilicities, some N-heterocyclic amines could react with different activated alkenes affording valuable intermediates. Such results tended to demonstrate the hydrogen-bonding interactions between activated alkenes and poly-nitrogen aromatic cycles may control these concerted or fully conjugate aza-Michael additions.

Full text of DOI:10.1016/j.crci.2012.11.001

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´
Full paper/Memoire
Uncatalysed intermolecular aza-Michael reactions
Florian Medina a,b,c, Nathalie Duhal a,d, Christophe Michon a,b,c,
,
*
Francine Agbossou-Niedercorn a,b,c,
*
a Universite´ Lille nord de France, 59000 Lille, France
b CNRS, UCCS UMR 8181, 59655 Villeneuve d’Ascq, France
c ENSCL, CCCF, (Chimie-C7), BP CS 90108, 59652 Villeneuve d’Ascq cedex, France
d
´
Service commun de physico-chimie CUMA, faculte de pharmacie, BP 83, 3, rue du Professeur-Laguesse, 59006 Lille cedex, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The catalyst-free reactions of activated alkenes with primary and secondary amines were
investigated leading to various mono- and di-hydroamination products, the latter being
rare and original. These reactions were shown to depend first on the strength of the
nucleophile. Temperature and steric hindrance of the reagents were the other key factors
controlling the selectivity of these aza-Michael reactions. In spite of their poor
nucleophilicities, some N-heterocyclic amines could react with different activated alkenes
affording valuable intermediates. Such results tended to demonstrate the hydrogen-
bonding interactions between activated alkenes and poly-nitrogen aromatic cycles may
control these concerted or fully conjugate aza-Michael additions.
Received 25 August 2012
Accepted after revision 12 November 2012
Available online xxx
Keywords:
aza-Michael
Hydroamination
Alkenes
Amines
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Catalyst-free reactions
N-heterocycles
1. Introduction
on advantages and limits of uncatalysed aza-Michael
reactions. The reactivity scope will be exposed leading to
Highly selective and atom-economic reactions can be
reached using catalysis but challenges remain for some
reactions like the synthesis of amines through hydro-
amination reactions [1]. The aza-Michael reaction involv-
ing the reaction of activated alkenes and amines can be
considered as a hydroamination reaction. It was largely
applied in organic synthesis with the use of various metal
or organic catalysts [2]. Surprisingly, the uncatalysed
‘‘background’’ aza-Michael reaction has only been scarcely
reported [3,4] and, to the best of our knowledge, no
comprehensive study has been carried out so far. Such data
could be of interest for highly selective aza-Michael
original mono- and di-hydroamination products.
2. Results and discussion
As a start, several weak amine nucleophiles were
allowed to react with 10 equivalents of methylvinylketone
1 (Table 1). The use of an excess of alkene to react with an
amine is known to increase drastically the conversions;
indeed, such
a reactivity enhancement was already
observed for several catalysed hydroamination reactions
of unactivated alkenes [1c,d,g].
In order to check the reactivity issues at a sufficient
level of activation, reactions were performed at 100 8C in
polar or apolar solvents, respectively tetrachloroethane
(TCE) or toluene. Reaction of 1 proceeded with imine 2e to
lead to product 3e most likely because of higher amine
nucleophilicity (entry 5). The use of toluene instead of TCE
proved to increase drastically the yield of 3e, acid traces in
TCE decomposing imine 2e. By comparing reactivity and
reactions through
a rational choice of reagents and
experimental conditions. Herein, we would like to report
* Corresponding authors.
E-mail addresses: christophe.michon@ensc-lille.fr (C. Michon),
francine.agbossou@ensc-lille.fr (F. Agbossou-Niedercorn).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.11.001
Please cite this article in press as: Medina F, et al. Uncatalysed intermolecular aza-Michael reactions. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.11.001

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Table 1
nucleophile addition afforded an enol intermediate and
Amine reactivity towards methylvinylketone 1.
later the final addition product after a retro-enolization.
Hence, as a general trend, the catalyst-free reactions of
amines with activated alkenes appeared to depend on the
strength of the nucleophile. Nevertheless, in spite their
poor pKas, N-heterocyclic amines could react with differ-
ent activated alkenes affording valuable intermediates.
Such results tended to demonstrate the hydrogen-bonding
interactions between activated alkenes and such poly-
nitrogen aromatic cycles may control these concerted or
fully conjugate aza-Michael additions.
Entry
1
Equivalents
Amine
Conversion
(%)a
of alkene 1
10
0
Next, we studied the reactivity of acrylate derivatives
4a,b with primary and secondary amines 2f-s at 100 8C and
30 8C in toluene. The last was preferred to TCE as far as
basic amines proved to be more sensitive to acidic residues
of chlorinated solvents (Table 2).
2
10
0
With the exception of amine 2f which afforded poor
yields of compounds 5fa1, 5fa2 and 5fb1 (entries 1–2), the
reactions proceeded quite well for secondary amines 2i-k
at 100 8C affording mono-hydroamination products 5ia,
5ib, 5ja and 5ka in good yields (entries 3–6). For these last
products, yields were quite low at 30 8C except for reaction
with N-methylbenzylamine 2k (entry 6). Regarding N-
methylaniline 2l and diisopropylamine 2m (entries 7,8), no
conversion was obtained. On the whole, these results
confirmed that the less the nitrogen atom was hindered,
the more the hydroamination reaction was enabled. The
reactivity of primary amines 2n-t with acrylates 4a,b was
then investigated in detail. At 100 8C, mono-hydroamina-
tion 5(n-t)a and di-hydroamination 6(n-t)a products were
obtained with average to good yields (entries 9–16). It was
worth noting methyl crotonate 4b afforded only mono-
hydroamination product 5pb (entry 12) and aniline 2q did
not react (entry 13). Strikingly, cyclohexylamine 2o,
tertiobutylamine 2s led selectively to mono-hydroamina-
tion products 5oa and 5sa (entries 10, 15) whereas
butylamine 2r and methylamine 2t afforded only di-
hydroamination products 6ra and 6ta (entries 14, 16).
Hence, we could state a sterically bulky primary amine
reagent would privilege a mono-hydroamination product
whereas a less hindered amine would mainly lead to a di-
3
4
10
10
0
0
5
10
77b
6
7
8
10
2
100 (79 + 21)c
76 (60 + 16)c
71 (64 + 7)c
1
Conversions measured by 1H NMR.
a
b
c
Performed in toluene at 100 8C for 40 h.
Yields of compounds 3f1 (branched) + 3f2 (linear).
pKa values in DMSO of the involved amine reagents, imine
2e (pKa 31.0) was found to be the strongest nucleophile of
that series as compared to benzamide 2a (pKa 23.3),
oxazolidone 2b (pKa 20.8) or the amines 2c-d,f. By
allowing a 71% yield of products 3f1 and 3f2, benzotriazole
2f (pKa 11.9) first appeared to be an exception regarding
the poor nucleophilicity of 2f (Table 1, entry 8 and
Scheme 1). It was worth noting the reaction was
quantitative as respect to the amine by using 10
equivalents of alkene 1 (entry 6). Moreover, the observed
rearrangement of branched product 3f1 into linear product
3f2 was already reported in other syntheses [5].
hydroamination product. However, g-substituted activat-
ed alkenes would offer exclusively mono-hydroamination
products. Moreover, lowering the temperature to 30 8C
induced the selective formation of mono-hydroamination
compounds 5na, 5oa, 5pa and 5ra but in low yields (entries
9–11, 14). The use of a large excess of alkene 4a proved to
be crucial in order to reach average to good yields of mono-
hydroamination product 5pa and di-hydroamination
product 6pa (entries 11, 17–19). To the best of our
knowledge, such results are rare examples of controlled di-
hydroamination reactions [6].
However, Wang et al. recently described catalyst-free
aza-Michael reactions of azoles with
b,g–unsaturated-a-
keto esters [3e]. The hydrogen bonding between the
carbonyl oxygen of the activated alkene and the NH moiety
of the N-heterocyclic nucleophile was proposed to form the
key reaction intermediate. Then, the fully conjugate
Scheme 1.
Please cite this article in press as: Medina F, et al. Uncatalysed intermolecular aza-Michael reactions. C. R. Chimie
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3
Table 2
Primary and secondary amine reactivity towards acrylate derivatives 4a,b.
Entry
Amine
Alkene (eq.)
Yield (%)
Yield (%)
Yield (%)
5(f-t)(a-b)
at 100 8Ca
6(n-t)(a-b)
at 100 8Ca
5(f-t)(a-b)
at 30 8Ca,b
1c
2
4a (10 eq.)
4b (10 eq.)
15 (6 + 9)f
0
0
< 5 (5fa)g
(5fa1 + 5fa2)
< 5 (5fb1)g
0
3c,d
4
4a (10 eq.)
4b (10 eq.)
70 (5ia)
77 (5ib)
0
0
< 5 (5ia)g
–
5e
6
2j (nBu)2NH
2k MeBnNH
2l MePhNH
2m (iPr)2NH
2n iPrNH2
2o CyNH2
2p BnNH2
2p BnNH2
2q PhNH2
2r nBuNH2
2s tBuNH2
2t MeNH2
2p BnNH2
2p BnNH2
2p BnNH2
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4b (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (10 eq.)
4a (5 eq.)
90 (5ja)
96 (5ka)
0
0
15 (5ja)
0
55 (5ka)
7
0
0
8
0
0
0
9
37 (5na)h
100 (5oa)
58 (5pa)
95 (5pb)
0
38 (6na)
8 (5na)
10
11
12
13
14
15
16
17
18
19
0
23 (5oa)
42 (6pa)
38 (5pa)
0
–
0
–
0
90 (6ra)
0
42 (6ta)i
12 (6pa)
11 (6pa)
0
44 (5ra)
32 (5sa)
0
0
0
84 (5pa)
83 (5pa)
99 (5pa)
25 (5pa)g
4a (2 eq.)
–
–
4a (1 eq.)
a
Isolated yield; all reactions performed with 0.5 mmol of amine.
b
c
d
e
f
20 h reactions.
TCE as solvent.
23 h reaction.
26 h reaction.
Compounds 5fa1 (branched) and 5fa2 (linear).
Measured by 1H NMR.
40 h reactions.
g
h
i
Same result at 30 8C.
Table 3
Solvent and additive effects on the reaction of butylacrylate 4a and benzylamine 2p.
Entry
Solvent
Additive
Yield (%)a 5pa
Yield (%)a 6pa
1
2
3
4
5
6
7
8
9
10
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
THF
–
38
59
65
90
87
37
31
43
62
85
0
Undistilled alkene
0
H2O (2 eq.)
0
hydroquinone (10 mol%)
10
Silica (10 mol%)
Traces
–
–
–
–
–
0
0
0
0
9
Et2O
DCM
None
a
Alkene and solvent were distilled. Amine was not distilled.
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Table 4
Benzotriazole reactivity towards activated alkenes.
Entry
1
Alkene 7a-f
Time (h)
20
Yield (%) at 100 8Ca
86c (69 + 17) (8a1, 8a2)
Conversion (%) at 30 8Cb
100c (84 + 26) (8a1, 8a2)
2
20
82 (8b1)
94 (8b1)
3
4
20
20
97c (84 + 13) (8c1, 8c2)
69c (46 + 23) (8d1, 8d2)
86 (8c1)
< 5 (8d1)
5
6
65
65
51 (8e1)
11d (8e1)
100c (83 + 17) (8f1, 8f2)
–
a
Isolated yield.
b
c
Performed in CH2Cl2 for 30 h, conversions by 1H NMR.
Products 5fa1, 8a1,c1,d1,f1 from addition and 5fa2, 8a2,c2,d2,f2 from rearrangement.
d
20 h reaction.
Finally, the reaction of compounds 4a and 2p using
products 8a1-f1 in good yields (Table 4, entries 1–6).
Moreover, alkenes 7a, 7c, 7d, 7f afforded rearranged
products 8a2, 8c2, 8d2, 8f2 in low yields (entries 1, 3, 4, 6)
[5]. At 30 8C in dichloromethane, the uncatalysed reactions
using alkenes 7a-c were almost quantitative and there was
no evidence for any polymerisation of the alkene reagents
at such a reaction temperature according NMR spectra of
the corresponding crude mixtures (Table 4, entries 1–3).
However, at 30 8C, reactions of benzotriazole 2f with
alkenes 7d-f offered lower conversions or none (Table 4,
entries 4–6). Finally, no reactivity was observed for
ethylcrotonate, acrylonitrile, 2-butenitrile, 3-penten-2-
one, ethylcinnamate and phenyltrans-styryl sulphone,
independently of the reaction conditions used.
10 mol% of mono-hydroamination compound 5pa as
catalyst afforded 5pa in a 17% yield which was lower
than the 38% yield of the reaction run without catalyst at
30 8C (Table 2, entry 11). Hence, product 5pa could not
perform any autocatalysis for the reaction of reagents 4a
and 2p [7]. Moreover, reactions of amine 2p with alkene 4a
proved to be sensitive to the nature of the solvent used,
neat reaction running also very well (Table 3, entries 1, 6–
10). It is worth noting the yields of 5pa were drastically
increased by the addition of water to the reaction medium
(entries 2, 3). The use of protic additives like hydroquinone
and silica did also enhance the yields of 5pa and small
amounts of 6pa could be isolated (entries 4, 5) [8]. Such
rate enhancement in aza-Michael reactions, though known
but rarely quoted, can be described as an external proton
transfer activation by protic media [6d,8a].
3. Conclusion
In order to clarify the scope of these catalyst-free aza-
Michael reactions, we next studied reactions of different
activated alkenes with an amine. Considering the raising
interest on conjugate addition reactions of nitrogen-
centered heterocyclic nucleophiles to electron-deficient
olefins [3e,9], we choose benzotriazole 2f which is also a
useful synthetic auxiliary (Table 4) [10]. At 100 8C in TCE,
reactions of 2f with alkenes 7a-f afforded addition
The studied aza-Michael reactions were shown to be
performed without the use of any catalyst depending on a
combination of different factors. The strength of the
nucleophile appeared to be the key parameter to control
the reactivity, temperature and steric hindrance of the
reagents being the other factors mastering the selectivity
of these mono- and di-hydroamination reactions. The last
were shown to proceed only when heat and large excesses
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of activated alkenes were used. This allowed the synthesis
of rare products resulting from a double-addition of an
amine on two equivalents of an activated alkene.
Moreover, the catalyst-free conjugate addition reaction
of various electron-deficient olefins and poor nucleophiles
like N-heterocyclic amines was demonstrated and afforded
valuable intermediates for organic synthesis. Such results
tended to demonstrate the hydrogen-bonding interactions
between activated alkenes and poly-nitrogen aromatic
cycles may control these concerted or fully conjugate aza-
Michael additions. Finally, when a catalysed aza-Michael
reaction is performed, it may be asked whether a strict
catalysed reaction is involved or if any competitive
background reaction is taking place.
4.2.2. General procedure for amine substrate screening
Amine substrate (0.5 mmol) (if solid) was added in a
Schlenk flask and dried during 30 minutes under vacuum.
Then, dry toluene (1 mL), butylacrylate (5.0 mmol, 0.7 mL),
and freshly distilled amine substrate (0.5 mmol) (if liquid)
were added under a nitrogen atmosphere. After stirring at
100 8C for the corresponding time, the mixture was
concentrated under vacuum, and the resulting product
was isolated by flash chromatography.
4.2.3. General procedure for activated alkene screening
Benzotriazole (0.5 mmol, 59.6 mg) and activated alkene
(5.0 mmol) (if solid) were added in a Schlenk flask and
dried during 30 min under vacuum. Then, dry 1,1’,2,2’-
tetrachloroethane (1 mL), and activated alkene (5.0 mmol)
(if liquid) were added under a nitrogen atmosphere. After
stirring at 100 8C at the corresponding time, the mixture
was concentrated under vacuum, and the corresponding
product was isolated by flash chromatography.
4. Experimental
4.1. General remarks
All solvents were dried using standard methods.
Alkenes were distilled under vacuum over CaH2 and
4.3. Physical and spectra data for 5ja, 5ka, 6na, 6pa, 6ra, 6ta,
8e1, 8f1, 8f2
˚
stored over molecular sieves (4 A). Amine substrates were
placed under vacuum during one hour before use, or
distilled over CaH2 if they were liquid. All reactions were
carried out under a dry nitrogen atmosphere. Analytical
thin layer chromatography (TLC) was performed on Merck
pre-coated 0.20 mm silica gel Alugram Sil 60 G/UV254
plates. Flash chromatography was carried out with
Macherey silica gel 60 M. 1H (300 MHz or 400 MHz), 13C
(75 MHz) and 31P (121 MHz) NMR spectra were acquired
on Bruker Avance spectrometers. Chemical shifts are
reported downfield of Me4Si and coupling constants are
expressed in Hz. 1,3,5-trimethoxybenzene and 1,2,4,5-
tetrachlorobenzene were used as internal standards when
needed. Gas chromatography analyses were done on GC
Varian 3900 and 430 using Alltech EconoCap EC-5TM
4.3.1. Butyl-3-(dibutylamino)propanoate 5ja
Isolated after flash chromatography with petroleum
ether/NEt3 (9:1), as
0.45 mmol-116 mg, 90% yield). 1H NMR (CDCl3, 300 MHz):
= 0.85–0.95 (q*, 9H), 1.20–1.45 (m, 10H), 1.58 (quin,
a colourless oil (from 0.5 mmol,
d
J(H,H) = 7.2 Hz, 2H), 2.30–2.45 (m, 6H), 2.75 (t,
J(H,H) = 7.5 Hz, 2H), 4.05 (t, J(H,H) = 6.7 Hz, 2H). 13C NMR
(CDCl3, 75 MHz):
d = 13.7 (CH3), 14.1 (2 CH3), 19.1 (CH2),
20.6 (2 CH2), 29.3 (2 CH2), 30.7 (CH2), 32.4 (CH2), 49.4 (CH2),
53.6 (2 CH2), 64.2 (CH2), 173.1 (C). IR (KBr): nꢀ = 2959, 2933,
2873, 1717,1202 cmÀ1. HMRS(ESI)m/zcalcdforC15H32NO2:
258.2428 [MH+], found: 258.2423.
4.3.2. Butyl-3-(benzyl(methyl)amino)propanoate 5ka
Isolated after flash chromatography with petroleum
ether/ethylacetate/NEt3 (9:1:1) (Rf = 0.75) as a colourless oil
(from 0.5 mmol, 0.48 mmol-120 mg, 96% yield). 1H NMR
column (30 m, 0.25 mm, 0.25 mm) with program (5 8C/min,
100–230 8C, 36 min) and with tetradecane as internal
standard. GC-MS analyses were performed on a Shimadzu
QP2010 + using Supelco column SLBTM-5ms (30 m,
(CDCl3, 300 MHz): d = 0.95 (t, J(H,H) = 7.4 Hz, 3H), 1.39 (sex,
0.25 mm, 0.25
m
m). Infrared spectra were recorded on a
J(H,H) = 7.4 Hz, 2H), 1.63 (quin, J(H,H) = 7.1 Hz, 2H), 2.22 (s,
3H), 2.54 (t, J(H,H) = 7.2 Hz, 2H), 2.77 (t, J(H,H) = 7.2 Hz, 2H),
3.53 (s, 2H), 4.10 (t, J(H,H) = 6.7 Hz, 2H), 7.20–7.40 (m, 5H).
ThermoScientific-Nicolet 6700 spectrometer; the samples
being prepared with KBr powder. HRMS-ESI analyses were
performed at CUMA-University Lille Nord de France.
Elemental analyses were performed on a Elementar Vario
Micro Cube apparatus at UCCS, University Lille Nord de
France. See supporting information for other details.
13C NMR (CDCl3, 75 MHz):
d = 13.8 (CH3), 19.2 (CH2), 30.7
(CH2), 33.0 (CH2), 41.8 (CH3), 52.9 (CH2), 62.1 (CH2), 64.3
(CH2), 127.0(CH), 128.2 (2CH), 129.0 (2CH), 138.9 (C), 172.7
(C). IR (KBr): nꢀ = 2954, 2841, 2791, 1734, 1124 cmÀ1. HMRS
(ESI) m/z calcd for C15H24NO2: 250.1802 [MH+], found:
250.1798.
4.2. General procedures
4.2.1. General procedure for amine reactivity screening with
methylvinylketone
4.3.3. Dibutyl-3,3’-(isopropylazanediyl)dipropanoate 6na
Isolated after flash chromatography with petroleum
ether/NEt3 (9:1) as a colourless oil (from 0.50 mmol,
0.19 mmol-60 mg, 38% yield). 1H NMR (CDCl3, 300 MHz):
Amine substrate (0.5 mmol) (if solid) was added in a
Schlenk flask and dried under vacuum for 30 minutes.
Next, dry 1,1’,2,2’-tetrachloroethane or toluene (1 mL),
methylvinylketone (5.0 mmol, 0.4 mL), and amine sub-
strate (0.5 mmol) (if liquid) were added. After stirring at
100 8C for the corresponding time, the mixture was
concentrated under vacuum, and the resulting product
was isolated by flash chromatography.
d
= 0.85–1.00 (m, 12H), 1.34 (sex, J(H,H) = 7.5 Hz, 4H), 1.57
(quin, J(H,H) = 6.9 Hz, 4H), 2.38 (t, J(H,H) = 7.2 Hz, 4H), 2.68
(t, J(H,H) = 7.2 Hz, 4H), 2.85 (sep, J(H,H) = 6.6 Hz, 1H), 4.03
(t, J(H,H) = 6.6 Hz, 4H). 13C NMR (CDCl3, 75 MHz):
d = 13.8
(2 CH3), 18.4 (2 CH3), 19.2 (2 CH2), 30.8 (2 CH2), 34.8 (2
CH2), 45.8 (2 CH2), 50.7 (CH), 64.2 (2 CH2), 173.0 (2 C). IR
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(KBr): nꢀ = 2979, 1733, 1137 cmÀ1. HMRS (ESI) m/z calcd
0.50 mmol, 0.42 mmol-114 mg, 83% yield). M.p. = 123–
125 8C. 1H NMR (CDCl3, 300 MHz):
= 1.70 (d,
for C17H34NO4: 316.24824 [MH+], found: 316.24873.
d
J(H,H) = 6.9 Hz, 3H), 3.47 (dd, J(H,H) = 4.6 Hz and
J(H,H) = 18.2 Hz, 1H), 3.70-3.95 (m, 2H), 4.08 (dd,
J(H,H) = 9.0 Hz and J(H,H) = 18.2 Hz, 1H), 4.30 (sex,
J(H,H) = 8.4 Hz, 2H), 5.35–5.50 (m, 1H), 7.31 (t,
J(H,H) = 7.5 Hz, 1H), 7.45 (t, J(H,H) = 7.5 Hz, 1H), 7.62 (d,
J(H,H) = 8.4 Hz, 1H), 7.98 (d, J(H,H) = 8.4 Hz, 1H). 13C NMR
4.3.4. Dibutyl-3,3’-(benzylazanediyl)dipropanoate 6pa
Isolated after flash chromatography with petroleum
ether/ethylacetate/NEt3 (8:2:1), Rf = 0.7, as a colourless oil
(from 0.50 mmol, 0.21 mmol-76 mg, 42% yield). 1H NMR
(CDCl3, 300 MHz): d = 0.85 (t, J(H,H) = 7.3 Hz, 6H), 1.28 (sex,
J(H,H) = 7.3 Hz, 4H), 1.49 (quin, J(H,H) = 6.9 Hz, 4H), 2.38 (t,
J(H,H) = 7.2 Hz, 4H), 2.73 (t, J(H,H) = 7.2 Hz, 4H), 3.52 (s, 2H),
3.98 (t, J(H,H) = 6.7 Hz, 4H), 7.15–7.25 (m, 5H). 13C NMR
(CDCl3, 75 MHz): d = 21.2 (CH3), 41.4 (CH2), 42.3 (CH2), 50.6
(CH), 62.3 (CH2), 109.9 (CH), 119.8 (CH), 124.0 (CH), 127.2
(CH), 132.7 (C), 145.9 (C), 153.5 (C), 169.8 (C). IR (KBr):
nꢀ = 2985, 2928, 1777, 1698, 1221, 1120 cmÀ1. HMRS (ESI)
m/z calcd for C13H15N4O3: 275.11387 [MH+], found:
275.1139.
(CDCl3, 75 MHz): d = 13.7 (2 CH3), 19.1 (2 CH2), 30.6 (2 CH2),
32.7 (2 CH2), 49.2 (2 CH2), 58.2 (CH2), 64.3 (2 CH2), 127.0
(CH), 128.2 (2 CH), 128.7 (2 CH), 139.1 (C), 172.7 (2 C). IR
(KBr): nꢀ = 2959, 2873, 1734, 1176 cmÀ1. HMRS (ESI) m/z
calcd for C21H34NO4: 364.2482 [MH+], found: 364.2475.
4.3.9. 3-(3-(2H-benzo[d][1,2,3]triazol-2-
yl)butanoyl)oxazolidin-2-one 8f2
4.3.5. Dibutyl-3,3’-(butylazanediyl)dipropanoate 6ra
Isolated after flash chromatography with petroleum
ether: NEt3 (9:1) as a colourless oil (from 0.5 mmol,
0.45 mmol-148 mg, 90% yield). 1H NMR (CDCl3, 300 MHz):
Isolated after flash chromatography with petroleum
ether/ethylacetate (8:2), Rf = 0.5, as a white solid (from
0.500 mmol, 0.085 mmol-23 mg, 17% yield). M.p. = 82–
84 8C. 1H NMR (CDCl3, 300 MHz):
d = 1.75 (d, J = 6.8 Hz,
d
= 0.80–0.95 (m, 9H), 1.15–1.40 (m, 8H), 1.55 (quin,
3H), 3.52 (dd, J = 4.7 Hz and J(H,H) = 18 Hz, 1H), 3.85–4.00
(m, 2H), 4.04 (dd, J(H,H) = 8.8 Hz and J(H,H) = 18 Hz, 1H),
4.30–4.45 (m, 2H), 5.50–5.65 (m, 1H), 7.34 (dd,
J(H,H) = 3.0 Hz and J(H,H) = 6.5 Hz, 2H), 7.83 (dd,
J(H,H) = 3.0 Hz and J(H,H) = 6.5 Hz, 2H). 13C NMR (CDCl3,
J(H,H) = 7.5 Hz, 4H), 2.35 (q, J(H,H) = 7.5 Hz, 6H), 2.71 (t,
J(H,H) = 7.3 Hz, 4H), 4.01 (t, J(H,H) = 6.7 Hz, 4H). 13C NMR
(CDCl3, 75 MHz): d = 13.7 (2 CH3), 14.0 (CH3), 19.1 (2 CH2),
20.4 (CH2), 29.3 (CH2), 30.6 (2 CH2), 32.6 (2 CH2), 49.2 (2
CH2), 53.4 (CH2), 64.2 (2 CH2), 172.8 (2 C). IR (KBr):
nꢀ = 2960, 2934, 2873, 1734, 1189 cmÀ1. HMRS (ESI) m/z
calcd for C18H36NO4: 330.2639 [MH+], found: 330.2632.
75 MHz):
d = 21.6 (CH3), 41.5 (CH2), 42.3 (CH2), 58.6 (CH),
62.3 (CH2), 118.1 (2 CH), 126.2 (2 CH), 144.0 (2 C), 153.5
(C), 169.7 (C). IR (KBr): nꢀ = 2958, 2927, 1780, 1703, 1275,
1116 cmÀ1
. HMRS (ESI) m/z calcd for C13H15N4O3:
4.3.6. Dibutyl-3,3’-(methylazanediyl)dipropanoate 6ta
275.11387 [MH+], found: 275.1135.
Isolated after flash chromatography with petroleum
ether/NEt3 (9:1) as
0.2 mmol-60 mg, 42% yield). 1H NMR (CDCl3, 300 MHz):
= 0.88 (t, J(H,H) = 7.2 Hz, 6H), 1.34 (hex, J(H,H) = 7.2 Hz,
a colourless oil (from 0.5 mmol,
Acknowledgements
d
This work is first financed by the French National
Research Agency with project ANR-09-BLAN-0032-02
(with a PhD fellowship to F.M.). Support from CNRS is
warmly acknowledged. Partial funding from Region Nord-
Pas de Calais with ‘‘Projet Prim: Etat-Re´gion’’ and with
4H), 1.55 (quin, J(H,H) = 6.9 Hz, 4H), 2.20 (s, 3H), 2.42 (t,
J(H,H) = 7.2 Hz, 4H), 2.66 (t, J(H,H) = 7.2 Hz, 4H), 4.03 (t,
J(H,H) = 6.6 Hz, 4H). 13C NMR (CDCl3, 75 MHz):
d = 12.8 (2
´
CH3), 18.2 (2 CH2), 29.7 (2 CH2), 31.7 (2 CH2), 40.8 (CH3),
´
51.6 (CH2), 63.3 (2 CH2), 171.7 (CO). IR (KBr): nꢀ = 2960,
´
´
´
‘‘Fonds europeen de developpement regional (FEDER)’’ are
2930, 2850, 1738, 1180 cmÀ1
.
´
also appreciated. Mrs C. Meliet (UCCS) is thanked for
elemental analyses. Ms C. Delabre (UCCS) is thanked for
GC-MS analyses.
4.3.7. 1-(2-(phenylsulfonyl)ethyl)-1H-
benzo[d][1,2,3]triazole 8e1
Isolated after flash chromatography with petroleum
ether/ethylacetate (1:1), Rf = 0.3, as a white solid (from
0.50 mmol, 0.25 mmol-72 mg, 51% yield). M.p. = 97–99 8C.
Appendix A. Supplementary data
1H NMR (CDCl3, 300 MHz):
d = 3.89 (t, J(H,H) = 6.9 Hz, 2H),
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.crci.2012.11.001.
5.01 (t, J(H,H) = 6.9 Hz, 2H), 7.30–7.45 (m, 3H), 7.45–7.60
(m, 3H), 7.71 (d, J(H,H) = 7.8 Hz, 2H), 7.94 (d, J(H,H) = 8.3 Hz,
1H). 13C NMR (CDCl3, 75 MHz):
d = 41.5 (CH2), 54.9 (CH2),
109.13 (CH), 120.1 (CH), 124.3 (CH), 127.6 (2 CH), 127.9
(CH), 129.3 (2 CH), 132.9 (C), 134.1 (CH), 138.2 (C), 145.7
(C). IR (KBr): nꢀ = 2989, 1308, 1140 cmÀ1. HMRS (ESI) m/z
calcd for C14H14N3O2S: 288.08012 [MH+], found:
288.08004.
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(2013), http://dx.doi.org/10.1016/j.crci.2012.11.001