New selective synthesis of dimethyl 3-alkylamino itaconates

Article abstract of DOI:10.1080/00397910802213786

The ammonium 6 salt resulting from the reaction of the DABCO and the allyl bromide 2 was converted with good yields into a new family of dimethyl 3-amino itaconates 5. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802213786

Synthetic Communications1, 38: 3717–3725, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802213786
New Selective Synthesis of Dimethyl
3-Alkylamino Itaconates
´
A¨ıcha Arfaoui, Feten Beji, Ta¨ıcir Ben Ayed, and Hassen Amri
Laboratoire de Chimie Organique et Organometallique, Universite de
´
´
´
Tunis El Manar, Faculte des Sciences, Tunis, Tunisia
Abstract: The ammonium 6 salt resulting from the reaction of the DABCO and
the allyl bromide 2 was converted with good yields into a new family of dimethyl
3-amino itaconates 5.
Keywords: Allyl amines, DABCO, dimethyl a-(bromomethyl) fumarate, dimethyl
itaconates, regioselectivity
INTRODUCTION
The dimethyl a-(bromomethyl) fumarate 2[1–4] is a required compound
in organic synthesis. Indeed, it constitutes a key intermediary in the
synthesis and the development of molecules with biological properties.
Starting from commercially dimethyl itaconate 1, the addition of
bromine under reflux of carbon tetrachloride gives an intermediate
dibromide compound that can be easily converted into a regio- and
stereoselective[5] dehydrobromination process induced with triethyla-
mine to give the dimethyl a-(bromomethyl) fumarate 2 in 73% overall
yield (Scheme 1).
Previous reports have investigated factors that influence the reac-
tivity of allylic systems with amines.[6–14] In this report, we found that
Received April 23, 2008.
Address correspondence to Hassen Amri, Laboratoire de Chimie Organique et
´
Organometallique, Faculte des Sciences, Campus Universitaire 2092, Tunis,
Tunisia. E-mail: hassen.amri@fst.rnu.tn
´
3717

3718
A. Arfaoui et al.
Scheme 1.
the allyl bromide 2 revealed a high synthetic potentiality induced by
its easy conversion into different heterocyclic and aliphatic com-
pounds. In fact, it opposed an increased reactivity with primary amines
(2 eq.) in the bromobenzene at reflux, leading exclusively via two
successive allylic substitutions (2 ꢀ SN20) followed by an intermolecular
cyclization to produce a new functional pyrrolin-2-ones 3[15] with high
yields (Scheme 2).
On the other hand, the treatment of 2 with excess secondary amines
(2–4 molar equivalents) at 25 ꢁC leads to the corresponding allyl amino
substrates or SN20 type-products 4,[16–19] which deserve special attention
as a result of their physiological properties,[20] biological activities,[21,22]
and their presence in several natural products.[23,24] However, in less
bulky or bulky secondary amines the secondary amines, allyl bromide
2, can only be transformed into products 5 arising from two bimolecular
SN20 type-reactions (Scheme 3).
Scheme 2.
Scheme 3.

Dimethyl 3-Alkylamino Itaconates
RESULTS AND DISCUSSION
3719
In light of the results obtained, we propose a new strategy for the produc-
tion of functional allylic amines 4 in high yields regardless of the size
of the amine (primary, secondary, as well as tertiary amines) via the suc-
cessive reaction coupling of functional allyl bromide 2 with diaza-
bicyclo[2.2.2]octane (DABCO) for 3 h in tetrahydrofuran (THF) at 25 ꢁC
followed by the replacement of THF by methanol, then the addition of
amine (1 molar equivalent) at low temperature (0 ꢁC). As a bulky dia-
mine, the nucleophilic substitution on the allylic bromide 2 by DABCO
promotes first a SN20 type-reaction, in a second step, the amine proceeds
in a SN20 process providing the liberation of the DABCO. Highly pure
allyl amines 5 were obtained in good yields (Scheme 4). It should be noted
that this method can be extended to the primary amines and some slightly
bulky secondary amines.
Unexpectedly, an easy coupling between the formed salt 6 and some
bulky secondary and tertiary amines such as diethylamine, diisopropyla-
mine, diphenylamine, and triethylamine, led to only one functionalized
allyl ether 7 resulting from SN20 reaction of the methanol as solvent
and nucleophilic reagent (Scheme 5). Because of the important steric hin-
drance, the conjugate addition of these amines was not observed, but the
allylic ether formation was much faster in the presence of amine (1.8–3 h)
than when the methanol was used only (1 week). As mentioned in the
literature, conjugate reaction of nucleophilic reagent in protic solvent
to activated olefins was pseudo second order and kinetically much
faster.[25]
Scheme 4.
Scheme 5.

3720
A. Arfaoui et al.
In summary, we have developed an efficient and simple regio- and
stereoselective synthesis of functional allylamine via an effective coupling
of primary, secondary amines, and dimethyl a-(bromomethyl) fumarate 2.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography (TLC) on
silica-gel plates (Fluka Kieselgel 60 F254). For column chromatography,
Fluka Kieselgel (70–230) mesh was used. 1H and 13C NMR (fully
decoupled) and spectra were recorded on Bruker AMX 300 spectrometers
1
in CDCl3 as solvent and TMS as the internal. H and 13C NMR (fully
decoupled) were recorded on Bruker AMX 300 in CDCl3 as solvent
and TMS as the internal standard. Mass spectrometry was performed
on an Autospec 200, Micromass (Waters) instrument.
Synthesis of Dimethyl 3-Alkylamono Itaconates 5a–i: Typical Procedure
To 8.44 mmol (2 g) of dimethyl a-(bromomethyl) fumarate 2 in 30 ml of
THF, 1.13 g (10.13 mmol) of DABCO were added under magnetic stir-
ring during 3 h until the allyl bromide salt was formed. The solvent
was removed in vacuum and the obtained residue was dissolved in
20 ml of methanol. The amine (8.44 mmol) diluted in 5 mL of methanol
was added dropwise at 0 ꢁC. After the completion of the reaction indi-
cated by TLC analysis, the solvent was evaporated under reduced
pressure and the crude mixture was purified by silica-gel flash chro-
matography (hexane=EtOAc, 80=20) to give the corresponding dimethyl
3-alkylamino itaconate 5.
Table 1. Synthesis of dimethyl 3-alkylamino itaconates 5a–i
5
R1
R2
Time (h)
Yield (%)
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
Me
Ph-CH2
1
1
89
87
85
78
76
72
69
70
79
Ph-(CH3)-CH
p-FC6H4-CH2
p-MeOC6H4-CH2
p-ClC6H4-CH2
nBu
0.5
0.3
0.3
0.5
0.5
0.5
0.5
5g
5h
5i
iPr
cC6H11
cC6H11

Dimethyl 3-Alkylamino Itaconates
3721
Table 2. Synthesis of dimethyl 2-methoxy-3-itaconate 7
Ether
R1
R2
R3
Time (h)
Yield (%)
7
7
7
7
Et
iPr
Ph
Et
Et
iPr
Ph
Et
H
H
H
Et
1,8
2
3
83
85
72
70
3
Data
Dimethyl 3-Benzylamino Itaconate 5a
1H NMR (CDCl3, d ppm, J Hz): 7.27 (m, 5H); 6.34 (s, 1H), 5.79 (1 s, 1H),
4.17 (s, 1H), 3.79 (d, 2H, J ¼ 4.05), 3.75 (s, 3H), 3.70 (s, 3H), 2.35 (br s,
1H). 13C NMR (CDCl3, d ppm): 172.42 (C¼O), 166.11 (C¼O), 139.31
(¼C), 137.72 (aromatique C), 128.42 (aromatique CH), 128.24 (aroma-
tique CH), 127.74 (aromatique CH), 127.15 (¼CH2), 61.16 (CH), 52.33
(OCH3), 52.08 (OCH3), 51.42 (PhꢂCH2).
Dimethyl 3-(1-Phenylethylamino) Itaconate 5b
1H NMR (CDCl3, d ppm, J Hz): 7.28 (m, 5H); 6.25 (d, 1H, J ¼ 31.60),
5.62 (d, 1H, J ¼ 10.29), 3.96 (d, 1H, J ¼ 1.36), 3.94 (q, 1H, J ¼ 7.23),
3.72 (s, 3H), 3.67 (s, 3H), 2.33 (br s, 1H), 6.25 (d, 3H, J ¼ 6.60). 13C
NMR (CDCl3, d ppm): 173.13 (C¼O), 166.01 (C¼O), 144.47 (¼C),
138.75 (aromatic C), 128.33 (aromatic CH), 127.19 (aromatic CH),
127.02 (aromatic CH), 126.32 (¼CH2), 60.15 (O¼CꢂCH), 56.85
(H3CꢂCH), 52.17 (OCH3), 51.90 (OCH3), 24.42 (CH3). HRMS calcd.
for C15H19NO4: 277.1314; found: 277.1314.
Dimethyl 3-(4-Fluorobenzylamino) Itaconate 5c
1H NMR(CDCl3, d ppm, J Hz): 7.28 (dd, 2H, J ¼ 8.46, J ¼ 8.46), 6.99 (t,
2H, J ¼ 7.32), 6.34 (s, 1H), 5.79 (1 s, 1H), 4.15 (s, 1H), 3.75 (s, 2H), 3.75
(s, 3H), 3.70 (s, 3H),2.35(br s, 1H). 13C NMR (CDCl3, d ppm): 172.48
(C¼O), 166.18 (C¼O), 162.13 (d, aromatic CꢂF, J1 ¼ 144.75), 137.85
(¼C), 135.19 (aromatic CꢂCH2), 129.87, 129.97 (aromatic CH), 127.78
(¼CH2), 115.13, 115.41 (aromatic CH), 61.23 (CHꢂHN), 50.81, 52.43
(OCH3), 52.19 (CH2ꢂPh).

3722
A. Arfaoui et al.
Dimethyl 3-(4-Methoxybenzylamino) Itaconate 5d
1H NMR (CDCl3, d ppm, J Hz): 7.13 (d, 2H, J ¼ 4.09), 6.74 (d, 2H,
J ¼ 4.09), 6.24 (s, 1H), 5.69 (1 s, 1H), 4.06 (s, 1H), 3.66 (s, 3H), 3.65 (s,
3H), 3.62 (d, 2H, J ¼ 4.41), 3.60 (s, 3H), 2.19 (br s, 1H). 13C NMR
(CDCl3=TMS): 172.26 (C¼O), 165.93 (C¼O), 158.65 (aromatic
CꢂOMe), 137.65 (¼C), 131.23 (aromatic CH), 129.26 (aromatic C),
127.41 (¼CH2), 113.63 (aromatic CH), 60.82 (O¼CꢂCH), 55.01
(PhꢂOCH3), 52.07 (OCH3), 51.85 (OCH3), 50.64 (PhꢂCH2).
Dimethyl 3-(4-Chlorobenzylamino) Itaconate 5e
1H NMR (CDCl3, d ppm): 7.29 (s, 4H), 6.35 (s, 1H), 5.81 (s, 1H), 4.13
(s, 1H), 3.81 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 2.41 (br s, 1H). 13C
NMR (CDCl3, d ppm): 171.76 (C¼O), 166.26 (C¼O), 137.45 (¼C),
135.25 (aromatic CꢂCH2), 131.23 (aromatic C–Cl), 129.26 (aromatic
CH), 127.41 (aromatic CH), 121.63 (¼CH2), 61.62 (O¼CꢂCH), 52.29
(OCH3), 52.17 (OCH3), 51.84 (PhꢂCH2).
Dimethyl 3-Butylamino Itaconate 5f
1H NMR (CDCl3, d ppm, J Hz): 6.34 (s, 1H), 5.83 (s, 1H), 4.18 (s, 1H),
3.77 (s, 3H), 3.72 (s, 3H), 2.57 (m, 2H), 1.91 (br s, 1H), 1.43 (m, 2H), 1.37
(m, 2H), 0.90 (t, 3H, J ¼ 6.99). 13C NMR (CDCl3, d ppm): 172.25 (C¼O),
165.82 (C¼O), 137.70 (¼C), 127.01 (¼CH2), 61.90 (O¼CꢂCH), 51.92
(OCH3), 51.72 (OCH3), 47.33 (HNꢂCH2), 31.73 (H2CꢂCH2), 20.05
(H3CꢂCH2), 13.57 (CH3). HRMS calcd. for C11H19NO4: 229.1316;
found: 229.1314.
Dimethyl 3-Isopropylamino Itaconate 5g
1H NMR (CDCl3, d ppm, J Hz): 6.32 (s, 1H), 5.82 (s, 1H), 4.30 (s, 1H), 3.78
(d, 2H, J ¼ 4.09), 3.77 (s, 3H), 3.72 (s, 3H), 2.79 (st, 1H, J ¼ 6.24), 1.99 (br s,
1H), 1.06 (d, 6H, J¼ 6.24). 13C NMR (CDCl3, d ppm): 173.05 (C¼O),
166.18 (C¼O), 138.58 (¼C), 127.14 (¼CH2), 59.59 (O¼CꢂCH), 52.32
(OCH3), 52.08 (OCH3), 46.69 (H3CꢂHCꢂCH3), 22.78 (CH3).
Dimethyl 3-Cyclohexylamino Itaconate 5h
1H NMR (CDCl3, d ppm): 6.32 (s, 1H), 5.82 (s, 1H), 4.36 (s, 1H), 3.77 (s,
3H), 3.72 (s, 3H), 2.40 (qt, 1H, J ¼ 6.63), 2.40 (m, 1H), 1.94 (br s, 1H),

Dimethyl 3-Alkylamino Itaconates
3723
1.82 (m, 2H), 1.72 (m, 2H), 1.65 (m, 2H), 1.20 (m, 2H), 1.14 (m, 2H), 1.73
(m, 6H), 1.17 (m, 4H). 13 C NMR (CDCl3=TMS): 173.16 (C¼O), 166.22
(C¼O), 138.66 (¼C), 127.04 (¼CH2), 58.94 (O¼CꢂCH), 54.79
(HNꢂCH), 52.39 (OCH3), 54.32 (OCH3), 33.36 (CH2), 26.01 (CH),
24.83 (CH2).
Dimethyl 3-N,N-Cyclohexylmethylamino Itaconate 5i
1H NMR (CDCl3, d ppm): 6.38 (s, 1H), 5.95 (s, 1H), 4.55 (s, 1H), 3.75 (s,
3H), 3.69 (s, 3H), 2.57 (m, 1H), 2.32 (s, 3H), 1.70 (m, 6H), 1.30 (m, 4H).
13C NMR (CDCl3, d ppm): 171.91 (C¼O), 167.05 (C¼O), 137.66 (¼C),
126.68 (¼CH2), 63 (O¼CꢂCH), 61.61 (NꢂCH), 52.19 (OCH3), 51.94
(OCH3), 33.53 (NꢂCH3), 30.56 (CH2), 30.15 (CH2), 26.39 (CH). HRMS
calcd. for C14H23NO4: 269.1623; found: 269.1627.
Synthesis of Dimethyl 3-Methoxy Itaconate 7: Genral Procedure
To 4.22 mmol (1 g) of dimethyl a-(bromomethyl) fumarate 2 in 15 ml of
THF, 0.565 g (5.06 mmol) of DABCO was added under magnetic stirring
during 3 h until the allyl bromide salt was formed. After removing THF,
the obtained salt from the reaction coupling of the allyl bromide, and
DABCO, addition of 20 ml of methanol, secondary, or tertiary amine
(4.22 mmol) diluted in 2.5 mL of methanol was added dropwise at 0 ꢁC.
After the total formation of ether 7 (TLC analysis), the excess of the sol-
vent was evaporated under reduced pressure and the crude mixture was
purified by silica-gel flash chromatography (hexane=EtOAc, 80=20) to
give the corresponding dimethyl 3-methoxy itaconate 7.
1H NMR (CDCl3, d ppm): 6.49 (s, 1H), 6.01 (s, 1H), 4.71 (s, 1H),
3.82 (s, 3H), 3.78 (s, 3H), 3.46 (s, 3H). 13C NMR (CDCl3=TMS):
170.18 (C¼O), 165.57 (C¼O), 136.25 (¼C), 128.52 (¼CH2), 78.74
(O¼CꢂCH), 58.20 (HCꢂOCH3), 52.42 (OCH3), 52.24 (OCH3). HRMS
calcd. For C8H12O5: 188.0686; found: 188.0685.
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