High pressure promoted aza-Michael addition of primary and secondary amines to α-substituted acrylates

Article abstract of DOI:10.1039/c2gc16220b

The α-dialkoxymethyl α,β-unsaturated ester 1 can be easily converted, under high pressure and at ambient temperature, into the corresponding aza-Michael adducts 2 and/or push-pull α-aminomethyl-β- methoxy-α,β-unsaturated esters 3 by treatment with primary

Full text of DOI:10.1039/c2gc16220b

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PAPER
High pressure promoted aza-Michael addition of primary and secondary
amines to a-substituted acrylates
Alexander Yu. Rulev,*a Hiyoshizo Kotsukib and Jacques Maddaluno*c
Received 1st October 2011, Accepted 22nd November 2011
DOI: 10.1039/c2gc16220b
The a-dialkoxymethyl a,b-unsaturated ester 1 can be easily converted, under high pressure and at
ambient temperature, into the corresponding aza-Michael adducts 2 and/or push–pull
a-aminomethyl-b-methoxy-a,b-unsaturated esters 3 by treatment with primary or secondary
amines. The ratio between these two types of products is shown to depend on the nature of the
nitrogen nucleophile.
Introduction
According to recent standards, an ideal organic synthesis should
lead to the desired product in as few steps as possible, in
good overall yield, and by means of environmentally compat-
ible reagents.1 Generally, the attempts to improve yields and
selectivities focus on the reagents and/or catalysts, less often on
the activation method. Organic reactions rely most of the time
Scheme 1
on the two very general methods that are heat and catalysis.
The once called “extreme” conditions (mainly photochemistry,
ultrasounds, microwaves or high pressure) can sometime offer
a helpful alternative to these techniques. The latter (HP) is par-
ticularly well suited to cases where fragile and/or non-reactive
reagents/products are needed.2 This technique is also energy-
economical: the energy input is limited to the compression
step at the onset of the reaction, in sharp contrast with a
classical heating that triggers continuous energy consumption
until completion.
reaction rate and the pressure applied to the system has led to the
Evans–Polanyi5 equation that links the acceleration of a reaction
to its activation volume.
The integrated form of this equation, albeit mathematically
incorrect since DV‡ is pressure dependent, suggests that the
logarithm of the speed constant k varies linearly with the
pressure and that the slope is directly proportional to - DV‡:
‡
dLogk
dP
−DV ‡
RT
−DV
RT
⎛
⎜
⎜
⎞
⎛
⎜
⎜
⎞
⎟
⎟
⎟
⎟
⎟
⎟
⎠
=
→ Logk ≈
P
⎟
⎟
⎠
⎜
⎜
⎝
⎜
⎝
T
While DV‡ has the physical dimension of a volume, it probably
does not fit the over simplistic view of Scheme 1.6 Nevertheless,
and because of the practical importance of this parameter,7 an
extremely large body of DV‡ values has been collected through
the years and concerns most classes of reactions.8
If the effect of pressure on the aza-Michael addition,9 the
Diels–Alder cycloaddition,10 and more recently organocatalytic
reactions,11 has been extensively studied because of their very
large negative activation volume values, the importance of
HP techniques to general organic chemistry has also been
emphasized.12
Physico-chemical background
The kinetic effects induced by HP are directly related to the
negative activation volume DV‡ characterizing the reactions that
go through a compact transition state (Scheme 1).3
If pressure alters the kinetics by helping the system to reach its
transition state and therefore decreasing the activation barrier
in chemically mild conditions, it has of course no influence
on the overall thermodynamic characteristics of the reaction.4
The mathematical formalization of the relationship between the
aA. E. Favorsky Institute of Chemistry, Siberian Division of the Russian
academy of sciences, 1 Favorsky Str., Irkutsk, 664033, Russia.
E-mail: rulev@irioch.irk.ru; Fax: + 7 3952 419346
Challenges in the hyperbaric aza-Michael addition
bLaboratory of Natural Products Chemistry, Faculty of Science, Kochi
University, Akebono-cho, Kochi, 780-8520, Japan
The so-called aza-Michael addition corresponds to the regiose-
lective hydroamination of activated olefins. It provides b-amino
acids, which are important synthons playing a pivotal role in
the access to natural and synthetic products such as alkaloids
cIRCOF, CNRS UMR 6014 & FR 3038, Universite´ de Rouen et INSA de
Rouen, 76821, Mont St Aignan Cedex, France.
E-mail: jmaddalu@crihan.fr; Fax: (33) 02 35 52 29 71
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or antibiotics.13 Because it is convergent and atom-economical,
the conjugate addition of nitrogen nucleophiles (amines, amides,
azides, carbamates) to a,b-unsaturated carbonyl compounds is
probably the greenest path to b-amino carbonyl derivatives.9,14
However, the reported methods are sometimes unattractive
because of long reaction time, harsh conditions, and toxic
catalysts. Moreover, the reactions with primary amines are not
always selective and often afford a mixture of the mono- and
bis-adduct. In some cases, the primary addition products are
unstable and further react in domino transformations, resulting
in the formation of polyfunctional derivatives, including hete-
rocycles and analogs of natural products. It has, for instance,
been recently reported that the reaction of bromoalkenyl triflu-
oromethylketones with secondary amines proceeds via the initial
formation of the aza-Michael adduct, which easily converts into
functionally substituted 1-indenols.15 Tandem transformations
in which an hetero-Michael reaction is the key-step have been
systematically listed in recent reviews.9a,16 Of particular interest
is the generalisation of an eco-friendly method for the design of
b-amino carbonyl skeletons bearing the 1,3-aza-oxa motive.
We have been interested for a while in the high pressure
accelerated conjugate addition of nitrogen nucleophiles onto
a,b-unsaturated carbonyl compounds.17 We wish to disclose
here recent results showing that a-substituted acrylates, known
to be sluggish electrophiles in the hetero-Michael addition,18
react easily under 1.5 GPa (ª 15 kbar ª 15 000 atm). In-
stead of a classical methacrylate, we have selected methyl 2-
(dimethoxymethyl)acrylate19 as an attractive model substrate.
Actually, if the double bond of this compound is slightly
activated (as in methyl methacrylate), it can in principle undergo
either a simple aza-Michael addition, affording the expected b-
aminoester, or an addition–elimination process, leading to the
one-pot formation of the conjugated enol ether. The effect of
pressure on the addition of both primary and secondary amines
on this dual Michael-acceptor is described underneath.
manner to the amine addition.21 But some protic solvents,
methanol in particular, have their downsides in this reaction:
they can compete and add following an oxa-Michael process. For
instance, the treatment of methyl 2-bromo-2-(cycloalkylidene)
acetates with aniline in methanol under high pressure leads
to the selective addition of the solvent instead of the poorly
nucleophilic aromatic amine, affording the oxa-Michael adduct
in this case.17c Such a strong effect is not necessarily expected here
since 1 is an a-substituted, b-unsubstituted substrate exhibiting
a relatively accessible terminal sp2 carbon. This is expected to
facilitate the addition of the amine, even poorly nucelophilic
ones, in the absence of a proton donor.
Heterocyclic secondary amines, such as morpholine, piperi-
dine or pyrrolidine, successfully react with ester 1 in THF
at room temperature under 1.5 GPa, giving rise to the cor-
responding aza-Michael adducts 2c–e (Table 1, entries 3–5).
No catalyst is required in any cases. Both primary and cyclic
secondary aliphatic amines, whatever their basicity, afford the
target products in good to excellent yields.
Acyclic secondary amines were next tested under the same
reaction conditions. We found that treating ester 1 with di-
isopropylamine selectively affords the aza-Michael adduct 2f
in 66% yield (Table 1, entry 7). For comparison, we also
examined the same reaction at atmospheric pressure. In this
case no reaction occurs even after a long reflux in THF. So, this
bulky secondary amine adds well under high pressure while it
does not react at all in thermal conditions (Table 1, entries 7
and 8).
Dibenzyl- and benzyl(ethyl)amine as well as N-benzyl
ethanolamine successfully underwent aza-Michael addition to
ester 1 to give aminoesters 2g–i in good yield (Table 1, entries
9–12). The entry 11 shows that the same reaction takes place
at atmospheric pressure, although in this case the reaction does
not reach completion, even after 48 h at reflux of the reaction
mixture. In all these latter reactions, the addition–elimination
products 3 were also isolated. These densely functionalized
compounds have a structure similar to that of the aza-Baylis–
Hillman (ABH) products, a reaction focusing a considerable at-
tention lately.22 Note that accessing 3 by an ABH reaction would
Results and Discussion
On the basis of our previous experience in the field, we first
examined the conjugate addition of primary amines to ester 1
(Scheme 2). Choosing the structure of the amine was likely to
be of consequence since we,17 and others,20 have shown that
the success of the reaction is directly related to the amine
nucleophilicity, provided the reaction is run in a protic solvent
likely to protonate the a-carbon in a more or less synchronous
Table 1 Aza-Michael addition of amines onto ester 1 in THF
Yield, %a
Entry Amine
Experimental conditions
2
3
1
2
3
4
5
6
7
8
PhNH2
BnNH2
25 ◦C, 1.5 GPa 24 h
25 ◦C, 1.5 GPa, 48 h
25 ◦C, 1.5 GPa, 5 h
25 ◦C, 1.5 GPa, 5 h
25 ◦C, 1.5 GPa, 5 h
25 ◦C, 1.5 GPa, 24 h
25 ◦C, 1.5 GPa, 5 h
Rfx, 10-4 GPad, 24h
25 ◦C, 1.5 GPa, 5 h
25 ◦C, 1.5 GPa, 48 h
Rfx, 1.5 GPa, 48 h
34b
73c
91
86
73
0
66
0
32
73
55e
76
0
0
0
0
0
0
0
0
56
21
22
15
morpholine
pyrrolidine
piperidine
p-nitroaniline
(i-Pr)2NH
9
Bn2NH
Bn(Et)NH
10
11
12
BnNH(CH2)2OH 25 ◦C, 1.5 GPa, 5 h
a Isolated yield after silica gel column chromatography; b The starting
ester 1 (53%) was also isolated; c The corresponding amide (5%) was
also isolated; d 10-4 GPa = 1 atm e The starting ester 1 (18%) was also
isolated.
Scheme 2
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require using inconvenient methylenimines as electrophiles.
Conclusions
With dibenzylamine, the push–pull alkoxy ester 3a was even
In conclusion, we present an eco-friendly and high-yielding
procedure for the conjugate addition of nitrogen nucleophiles
to alkenes bearing a low-activated double bond, such as a-
dialkoxymethyl-a,b-unsaturated ester 1 under high pressure
at room temperature in non-catalytic conditions. This mild
and energy saving procedure leads to the simple aza-Michael
adduct 2 or to the addition-elimination product 3, a compound
featuring an interesting aza-Baylis–Hillman type structure. The
ratio between 2 and 3 depends on the structure of the amine,
probably on the acidity of the NH proton. Further studies about
the conjugate addition of other hetero-nucleophiles on various
families of electron deficient alkenes are now in progress. Results
will be reported in due time.
1
the major product. According to H and 13C NMR spectra,
compounds 3a–c are obtained as single isomers. Their (Z) con-
figuration was established from a 1H–1H NOESY homonuclear
experiment.
Examination of the reaction of ester 1 with benzyl(ethyl)amine
in different solvents revealed that the nature of the solvent has
little influence on the outcome of the reaction: the molar ratio
of esters 2h and 3b varied from 75 : 25 in THF or Et2O to
85 : 15 in hexane and 90 : 10 in MeCN. As to the mechanism
of formation of ester 3, we initially assumed that the conjugate
addition of amine onto ester 1 was followed by the elimination
of one equivalent of methanol from the primary aza-Michael
adduct 2. To check this hypothesis, that is the possibility of
transforming 1 → 2 → 3, we placed pure ester 2h under reaction
conditions favouring the formation of ester 3b (Bn(Et)NH (1
Experimental section
1
eq.), THF, reflux, 48 h). Analysis of the H NMR spectrum
of the crude reaction mixture showed no evidence for the 2
→ 3 transformation: the starting aminoester 2 was recovered
unaltered.
General remarks
1H and13C NMR spectra were recorded on a Bruker AVANCE
300 MHz spectrometer at 300 and 75 MHz, respectively, for
solution in CDCl3. Chemical shifts (d) in ppm are reported
This complementary information prompted us to prefer the
following mechanistic scheme. In aprotic media, such as those
considered here, hydrogen bonds probably play an important
role in organizing the reactants in solution.23 This phenomenon
probably tends to be reinforced under high pressure.24 In the
case of ester 1, the amine NH proton can bind either to the
carbonyl oxygen atom (route A) or to the methoxy one (route B,
Scheme 3). The relative rates of these two competing patterns of
pre-organization should determine the ratio of the two reaction
products. It seems that the poorly acidic proton of strongly basic
amines interacts selectively with the best Lewis base, that is the
carbonyl oxygen atom, favoring the formation of ester 2. As the
amine basicity decreases, and therefore the acidity of the NH
proton increases, the Lewis basicity of the ethereal oxygen atom
becomes sufficient to compete with that of the carbonyl oxygen
atom; thus, the parallel formation of esters 2 and 3 is observed.
Note that the more or less concerted character of route B can
explain the Z-selectivity associated to 3. On the other hand, the
fact that despite its relatively acidic NH protons, aniline yields
the b-aminoester 2a instead of the addition–elimination product
3 can seem inconsistent with the above hypothesis. However,
one should consider that the sp2 nitrogen atom of aniline is
also a poor nucleophile. The same observation applies to the
case of N-methyl-p-nitroaniline (entry 6) that does not react at
all.
using residual chloroform (7.25 for H and 77.20 for 13C) as
1
internal reference. The coupling constants (J) are given in
Hertz. The IR spectra were measured with a Perkin–Elmer 16
PC FT-IR instrument. The mass spectra were recorded on an
ATI-Unicam Automass spectrometer (EI, 70 eV), ammoniac
was used for chemical ionization (CI). High pressure reactions
were performed in a piston-cylinder type apparatus (Unipress,
Warsaw, Poland), designed for pressures up to 2.0 GPa. The
silica gel used for flash chromatography was 230–400 Mesh. All
reagents were of reagent grade and were used as such or distilled
prior to use. All the solvents were dried according to standard
procedures and freshly distilled prior to use. The ester 1 was
prepared as reported previously.
Methyl 2-(dimethoxymethyl)acrylate (1)
1H NMR (300 MHz, CDCl3): d 3.28 (s, 6H, OMe), 3.72 (s, 3H,
COOCH3), 5.14 (s, 1H, O–CH–O), 5.97 (d, J = 1.2 Hz, 1H,
CH ), 6.32 (d, J = 1.2 Hz, 1H, CH ) ppm. 13C NMR (75
MHz, CDCl3): d 52.03 (COOCH3), 53.61 (OCH3), 99.49 (O–
CH–O), 127.46 ( CH2), 136.84 (C ), 165.99 (C O) ppm. IR
n
max/cm-1: 1641 (C C), 1729 (C O). MS (EI): m/z (%) = 129
(M+- OMe, 13), 84 (43), 75 (100); (CI, NH3): m/z (%) = 161
Scheme 3
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(MH+, 14), 114 (100). C7H12O4: calcd. C 52.49, H 7.55; found C
52.35, H 7.68.
MHz, CDCl3): d 23.62 (CH2)2, 49.20 (CH), 51.90 (COOCH3),
52.42, 54.52 (OCH3), 54.32 (N(CH2)2), 54.71 (CH2N), 103.74
(O–CH–O), 173.06 (C O) ppm. IR nmax/cm-1: 1742 (C O)
cm-1. MS (EI): m/z (%) = 231 (M+, 6), 216 (8), 140 (4), 84 (100).
C11H21NO4: calcd. C 57.12, H 9.15, N 6.06; found C 57.02, H
9.23, N 6.59.
Typical procedure for the treatment of ester 1 with amines
A solution of the ester (1 mmol) and amine (1 mmol) in THF (1–
1.5 mL) 1.5 mL) was refluxed at atmospheric pressure or allowed
to stand under 1.5 GPa at rt. After reversion to atmospheric
pressure, the solvent was evaporated. The residue was chro-
matographed (CH2Cl2/MeOH 9 : 1) to yield the corresponding
products. The following compounds were all prepared according
to this procedure.
Methyl 3,3-dimethoxy-2-(1-piperidinomethyl)propanoate (2e)
1H NMR (300 MHz, CDCl3): d 1.25-1.50 (m, 6H, (CH2)3), 2.15–
2.25 (m, 2H, N(CH2)2), 2.35–2.45 (m, 2H, N(CH2)2), 2.46 (dd,
J 12.1, 4.2 Hz, 1H, NCH2), 2.65 (dd, J 12.1, 10.9 Hz, 1H,
NCH2), 2.99 (ddd, J 10.9, 7.9, 4.2 Hz, 1H, CH), 3.25 (s, 3H,
OCH3), 3.29 (s, 3H, OCH3), 3.65 (s, 3H, COOCH3), 4.44 (d, J
7.9 Hz, 1H, O–CH–O) ppm. 13C NMR (75 MHz, CDCl3): d
24.37, 26.14 (CH2)3, 47.51 (CH), 51.81 (COOCH3), 52.58, 54.46
(OCH3), 54.62 (N(CH2)2), 57.57 (CH2N), 103.93 (O–CH–O),
173.12 (C O) ppm. IR nmax/cm-1: 1743 (C O) cm-1. MS (EI):
m/z (%) = 245 (M+, 1), 230 (3), 155 (2), 98 (100). C12H23NO4:
calcd. C 58.75, H 9.45, N 5.71; found C 58.71, H 9.53, N 5.71.
Methyl 2-(anilinomethyl)-3,3-dimethoxypropanoate (2a)
1H NMR (300 MHz, CDCl3): d 3.05 (ddd, J 12.4, 7.6, 4.9 Hz,
1H, CH), 3.39 (s, 3H, OCH3), 3.40 (s, 3H, OCH3), 3.40–3.55
(m, 2H, NCH2), 3.71 (s, 3H, COOCH3), 4.03 (br.s., 1H, NH),
4.67 (d, J 7.6 Hz, 1H, O–CH–O), 6.50–6.75 (m, 3H, Ph), 7.10–
7.20 (m, 2H, Ph) ppm. 13C NMR (75 MHz, CDCl3): d 41.92
(CH2N), 48.65 (CH), 52.15 (COOCH3), 54.57, 54.89 (OCH3),
104.21 (O–CH–O), 113.09, 117.76, 129.38, 147.75 (CAr), 172.37
(C O) ppm. IR nmax/cm-1: 1735 (C O), 3405 (NH) cm-1. MS
(EI): m/z (%) = 253 (M+, 36), 135 (36); 106 (100). C13H19NO4:
calcd. C 61.64, H 7.56, N 5.53; found C 61.63, H 7.54, N 5.67.
Methyl 2-[(diisopropylamino)methyl)-3,3-dimethoxypropa-noate
(2f)
1H NMR (300 MHz, CDCl3): d 0.89 (d, J 6.4 Hz, 12H, CH3),
2.67 (dd, J 10.9, 5.2, 1H, NCH2), 2.67 (dd, J 10.9, 9.8 Hz, 1H,
NCH2), 2.85–2.90 (m, 2H, CH3CH), 2.95 (ddd, J 9.8, 8.3, 5.2 Hz,
1H, CH), 3.27 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.61 (s, 3H,
COOCH3), 4.48 (d, J 8.3 Hz, 1H, O–CH–O) ppm. 13C NMR (75
MHz, CDCl3): d19.16, 22.32 (CH3), 44.30 (CH2N), 47.48 (CH),
49.80 (CH–N), 51.45 (COOCH3), 52.45, 54.14 (OCH3), 103.92
(O–CH–O), 173.03 (C O) ppm. IR nmax/cm-1: 1742 (C O)
cm-1. MS (EI): m/z (%) = 261 (M+, 14), 246 (35), 114 (100).
C13H27NO4: calcd: C 59.74, H 10.41, N 5.36; found C 59.86, H
10.33, N 5.32.
Methyl 2-[(benzylamino)methyl]-3,3-dimethoxypropanoate (2b)
1H NMR (300 MHz, CDCl3): d 1.66 (br.s., 1H, NH), 2.70–2.95
(m, 3H, CH, NCH2), 3.25 (s, 3H, OCH3), 3.29 (s, 3H, OCH3),
3.64 (s, 3H, COOCH3), 3.68 (d, J 13.6 Hz, 1H, PhCH2), 3.73
(d, J 13.6 Hz, 1H, PhCH2), 4.52 (d, J 7.5 Hz, 1H, O–CH–O),
7.15–7.30 (m, 5H, Ph) ppm. 13C NMR (75 MHz, CDCl3): d
47.19 (CH2N), 49.60 (CH), 51.95 (COOCH3), 53.75 (Ph–CH2),
53.67, 54.66 (OCH3), 104.06 (O–CH–O), 127.00, 128.09, 128.42,
140.17 (CAr), 172.74 (C O) ppm. IR nmax/cm-1: 1738 (C O),
3338 (NH) cm-1. MS (EI): m/z (%) = 268 (M++1, 4), 252 (6),
120 (68); 106 (43), 91 (100). C14H21NO4: calcd. C 62.90, H 7.92,
N 5.24; found C 62.83, H 7.84, N 5.18.
Methyl 2-[(dibenzylamino)methyl]-3,3-dimethoxypropanoate
(2g)
1H NMR (300 MHz, CDCl3): d 2.46 (dd, J 12.4, 4.2 Hz, 1H,
NCH2), 2.81 (dd, J 12.4, 11.3 Hz, 1H, NCH2), 3.04 (ddd, J 11.3,
8.3, 4.2 Hz, 1H, CH), 3.13 (s, 3H, OCH3), 3.21 (s, 3H, OCH3),
3.22 (d, J 13.5, 2H, PhCH2), 3.60 (s, 3H, COOCH3), 3.71 (d,
J 13.5, 2H, PhCH2), 4.34 (d, J 8.3 Hz, 1H, O–CH–O), 7.10–
7.25 (m, 10H, Ph) ppm. 13C NMR (75 MHz, CDCl3): d 48.52
(CH), 51.81 (COOCH3), 52.63 (Ph–CH2), 52.29, 54.43 (OCH3),
58.58 (CH2N), 103.54 (O–CH–O), 127.11, 128.27, 129.10, 139.22
(CAr), 172.44 (C O) ppm. IR nmax/cm-1: 1742 (C O) cm-1. MS
(EI): m/z (%) = 357 (M+, 1), 266 (5), 210 (87), 91 (100).
Methyl 3,3-dimethoxy-2-(1-morpholinomethyl)propanoate (2c)
1H NMR (300 MHz, CDCl3): d 2.20–2.30 (m, 2H, N(CH2)2),
2.40 (dd, J 12.9, 4.4 Hz, 1H, NCH2), 2.45–2.55 (m, 2H,
N(CH2)2), 2.66 (dd, J 12.9, 12.1 Hz, 1H, NCH2), 2.98 (ddd,
J 12.1, 7.9, 4.4 Hz, 1H, CH), 3.26 (s, 3H, OCH3), 3.30 (s, 3H,
OCH3), 3.55–3.65 (m, 4H, O(CH2)2), 3.66 (s, 3H, COOCH3),
4.47 (d, J 7.9 Hz, 1H, O–CH–O) ppm. 13C NMR (75 MHz,
CDCl3): d 47.37 (CH), 51.88 (COOCH3), 52.78, 54.47 (OCH3),
53.70 (N(CH2)2), 57.23 (CH2N), 67.10 (O(CH2)2), 103.79 (O–
CH–O), 172.74 (C O) ppm. IR nmax/cm-1: 1741 (C O) cm-1.
MS (EI): m/z (%) = 247 (M+, 3), 232 (8), 100 (100). C11H21NO5:
calcd. C 53.43, H 8.56, N 5.66; found C 53.24, H 8.44, N 5.85.
Methyl 2-{[benzyl(ethyl)amino]methyl}-3,3-dimethoxypropa-
noate (2h)
1H NMR (300 MHz, CDCl3): d 0.90 (t, J 7.2 Hz, 3H, CH3CH2),
2.30 (m, 1H, CH3CH2), 2.47 (m, 1H, CH3CH2), 2.49 (dd, J 12.8,
4.3 Hz, 1H, NCH2), 2.79 (dd, J 12.8, 12.4 Hz, 1H, NCH2),
2.98 (ddd, J 12.4, 8.3, 4.3 Hz, 1H, CH), 3.04 (s, 3H, OCH3),
3.20 (s, 3H, OCH3), 3.28 (d, J 13.7 Hz, 1H, PhCH2), 3.63 (s,
3H, COOCH3), 3.67 (d, J 13.7 Hz, 1H, PhCH2), 4.41 (d, J 8.3
Hz, 1H, O–CH–O), 7.10–7.25 (m, 5H, Ph) ppm. 13C NMR (75
MHz, CDCl3): d 11.61 (CH3CH2), 47.42 (CH2N), 48.56 (CH),
Methyl 3,3-dimethoxy-2-(1-pyrrolidinylmethyl)propanoate (2d)
1H NMR (300 MHz, CDCl3): d 1.65–1.75 (m, 4H, (CH2)2), 2.46
(dd, J 10.9, 3.4 Hz, 1H, NCH2), 2.45–2.55 (m, 2H, N(CH2)2),
2.88 (dd, J 11.3, 10.9 Hz, 1H, NCH2), 2.98 (ddd, J 11.3, 7.9, 3.4
Hz, 1H, CH), 3.27 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 3.67 (s, 3H,
COOCH3), 4.46 (d, J 7.9 Hz, 1H, O–CH–O) ppm. 13C NMR (75
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51.69 (COOCH3), 52.28 (Ph–CH2), 52.41, 54.26 (OCH3), 58.41
(CH3CH2), 103.64 (O–CH–O), 126.86, 128.13, 128.82, 137.72
(CAr), 172.75 (C O) ppm. IR nmax/cm-1: 1743 (C O) cm-1.
MS (EI): m/z (%) = 295 (M+, 2), 280 (7), 148 (64); 91 (100).
C16H25NO4: calcd. C 65.06, H 8.53, N 4.74; found C 64.93, H
8.77, N 4.58.
(NCH2), 51.59 (COOCH3), 54.66 (NCH2), 58.71 (OCH2), 58.88
(PhCH2), 61.85 (OCH3), 108.20 ( C), 127.06, 128.29, 128.97,
139.58 (CAr), 161.60 (CH ), 168.84 (C O) ppm. IR nmax/cm-1:
1645 (C C), 1704 (C O), 3468 (OH) cm-1. MS (EI): m/z (%) =
280 (M++1, 1), 248 (81), 129 (57), 91 (69), 75 (100). C15H21NO4:
calcd. C 64.50, H 7.58, N 5.01; found C 64.35, H 7.62, N 4.92.
Methyl 2-{[benzyl(2-hydroxyethyl)amino]methyl}-3,3-dime-
Acknowledgements
thoxypropanoate (2i)
We are grateful to Dr Alexey B. Zaitsev (Akzo Nobel Polymer
Chemicals) for helpful discussions. We wish to thank the
CRUNCh program and the Re´gion Haute-Normandie for
grants related to the high pressure equipment employed in this
work. A.R. is indebted to the CNRS for a 2011 research associate
position. The collaboration between the Rouen and Kochi labo-
ratories took place within the frame of the Sakura cooperation
program between the Japan Society for the Promotion of Science
(JSPS) and CNRS (2008–2009).
1H NMR (300 MHz, CDCl3):
d
2.45–2.35 (m, 1H,
NCH2CH2OH), 2.55 (dd, J 12.8, 4.2 Hz, 1H, NCH2), 2.70–
2.60 (m, 1H, NCH2CH2OH), 2.70 (br.s., 1H, OH), 2.84 (dd, J
12.8, 12.1 Hz, 1H, NCH2), 3.02 (ddd, J 12.1, 8.3, 4.2 Hz, 1H,
CH), 3.20 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.34 (d, J 13.6 Hz,
1H, PhCH2), 3.35–3.45 (m, 1H, NCH2CH2OH), 3.50–3.60 (m,
1H, NCH2CH2OH), 3.61 (s, 3H, COOCH3), 3.71 (d, J 13.6 Hz,
1H, PhCH2), 4.42 (d, J 8.3 Hz, 1H, O–CH–O), 7.10–7.25 (m,
5H, Ph) ppm. 13C NMR (75 MHz, CDCl3): d 48.66 (CH), 51.95
(COOCH3), 52.72, 54.21 (OCH3), 52.62, 56.04 (CH2N), 59.12
(CH2OH), 103.38 (O–CH–O), 127.30, 128.38, 129.05, 138.49
(CAr), 172.87 (C O) ppm. IR nmax/cm-1: 1737 (C O), 3502
(OH) cm-1. MS (EI): m/z (%) = 280 (M+- OMe, 19), 164 (46);
91 (100). C16H25NO5: calcd. C 61.72, H 8.09, N 4.50; found C
61.59, H 7.89, N 4.46.
Notes and references
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Methyl 2-[(dibenzylamino)methyl]-3-methoxy-2-propenoate (3a)
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6 R. A. Firestone and M. A. Vitale, J. Org. Chem., 1981, 46, 2160.
7 G. Jenner, in High Pressure Molecular Science, ed. R. Winter and J.
Jonas, Kluwer Verlag, Amsterdam, 1999, pp. 291.
1H NMR (300 MHz, CDCl3): d 0.99 (t, J 6.8 Hz, 3H, CH2CH3),
2.41 (q, J 6.8 Hz, 2H, CH2CH3), 3.21 (s, 2H, NCH2), 3.43
(s, 4H, PhCH2), 3.57 (s, 3H, COOCH3), 3.65 (s, 3H, OMe),
7.05–7.30 (m, 10H, Ph), 7.27 (s, 1H, CH ) ppm. 13C NMR
(75 MHz, CDCl3): d 46.92 (NCH2), 51.21 (COOCH3), 58.01
(PhCH2), 61.46 (OCH3), 108.35 ( C), 126.68, 127.98, 128.84,
140.29 (CAr), 161.32 (CH ), 168.98 (C O) ppm. IR nmax/cm-1:
1644 (C C), 1713 (C O) cm-1. MS (EI): m/z (%) = 325 (M+,
1), 234 (42), 196 (23), 129 (25), 91 (100). C20H23NO3: calcd. C,
73.82, H, 7.12, N, 4.30; found C 73.89, H 7.24, N 4.26.
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Methyl 2-{[benzyl(ethyl)amino]methyl}-3-methoxy-2-
prope-noate (3b)
1H NMR (300 MHz, CDCl3): d 0.99 (t, J 6.8 Hz, 3H, CH2CH3),
2.41 (q, J 6.8 Hz, 2H, CH2CH3), 3.28 (s, 2H, NCH2), 3.51 (s, 2H,
PhCH2), 3.63 (s, 3H, COOCH3), 3.74 (s, 3H, OMe), 7.10–7.30
(m, 5H, Ph), 7.33 (s, 1H, CH ) ppm. 13C NMR (75 MHz,
CDCl3): d 11.50 (CH3CH2), 45.94, 46.87 (NCH2, CH3CH2),
51.27 (COOCH3), 57.76 (PhCH2), 61.51 (OCH3), 108.17 ( C),
126.67, 127.97, 129.00, 139.90 (CAr), 161.31 (CH ), 168.90
(C O) ppm. IR nmax/cm-1: 1643 (C C), 1710 (C O) cm-1.
MS (EI): m/z (%) = 263 (M+, 1), 172 (42), 134 (46), 129 (45), 91
(90), 75 (100). C15H21NO3: calcd. C 68.42, H 8.04, N 5.32; found
C 68.34, H 8.09, N 5.52.
Methyl 2-{[benzyl(2-hydroxyethyl)amino]methyl}-3-methoxy-2-
propenoate (3c)
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1H NMR (300 MHz, CDCl3): d 2.48 (m, 2H, NCH2CH2OH),
3.28 (s, 2H, NCH2), 3.45–3.55 (m, 4H, OCH2, PhCH2); 3.66
(s, 3H, COOCH3), 3.77 (s, 3H, OMe), 7.15–7.30 (m, 5H, Ph),
7.35 (s, 1H, CH ) ppm. 13C NMR (75 MHz, CDCl3): d 46.47
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508 | Green Chem., 2012, 14, 503–508
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