Microwave-assisted synthesis of α-ethoxycarbamates

Article abstract of DOI:10.1016/j.tet.2009.09.023

An efficient and reproducible synthesis of various α-ethoxycarbamates is described via a microwave heating mode. Compared to the thermal process, the microwave dielectric heating induces a dramatic reduction of the reaction time and the improvement of the

Full text of DOI:10.1016/j.tet.2009.09.023

Tetrahedron 65 (2009) 9180–9187
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted synthesis of a-ethoxycarbamates
Alexandre Lumbroso a, Floris Chevallier a, Isabelle Beaudet a, Jean-Paul Quintard a,
,
a,
*
Thierry Besson b , Erwan Le Grognec
*
a
´
´
`
´
Universite de Nantes, CNRS, Chimie et Interdisciplinarite: Synthese, Analyse, Modelisation (CEISAM), UMR CNRS 6230,
Faculte´ des Sciences et des Techniques, 2 rue de la Houssinie`re, BP 92208, 44322 Nantes Cedex 3, France
b Universite´ de Rouen, UMR CNRS 6014dC.O.B.R.A.dI.R.C.O.F., rue Tesnie`re, F-76130 Mont Saint-Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2009
Received in revised form 26 August 2009
Accepted 7 September 2009
Available online 11 September 2009
An efficient and reproducible synthesis of various
a-ethoxycarbamates is described via a microwave
heating mode. Compared to the thermal process, the microwave dielectric heating induces a dramatic
reduction of the reaction time and the improvement of the yields. The reaction is general since applicable
to aromatic and aliphatic aldehydes with various primary amines. Several examples involving chiral
aldehydes have also been considered.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
a
-Ethoxycarbamate
N-Acyliminium ion
Imine
Microwave-assisted synthesis
1. Introduction
X¼OEt or OMe). The preparation of
a-ethoxycarbamates involves
reaction of an imine with a dialkyl pyrocarbonate in ethanol through
an iminium ion, which is trapped by the solvent (ethanol or
methanol).3
N-Acyliminium ions are versatile electrophilic species with
many applications in the synthesis of nitrogen-containing com-
pounds and have received a significant amount of interest over the
past two decades.1 These reactive species can be generated starting
from alkyl chloroformate and an imine as described by Yamamoto.2
This preparation is however limited to imines displaying no eno-
lisable proton due to the presence of chloride. N-acyliminium ions
can also be obtained from the corresponding more stable
Among the nucleophiles considered for the addition to these in
situ generated electrophiles, several studies involving organometallic
reagents like allylsilane,4 allenylsilane and propargylsilane,5 allyltin,6
propargyltin,7 allenyltin,8 alkenylalane,9 allenylzinc,10 organozinc,11
organocopper,12 have been reported. As part of our ongoing research
on the synthesis of polyhydroxylated nitrogen-containing heterocy-
a
-substituted N-acylamines by treatment with a Lewis acid or
cles, we have been interested in the addition of
g
g-alkoxyallyltins and
a protic acid (Scheme 1).
-silyloxyallyltins to N-acyliminium ions.6e,f In the latter case, we
have shown that the reaction affords cleanly the syn adduct whatever
the configuration of the carbon–carbon double bond or the steric
hindrance of the a-substituent on the allyltins. Using this highly se-
lective allylstannation followed by a ring-closing metathesis, we have
developed a rapid synthesis of polyhydroxypiperidines and (ꢀ)-1-
deoxy-6,8a-di-epi-castanospermine.6e,f
O
Nu
R3
O
X
O
Nu
+
Lewis Acid
R1
N
R1
N
R3
R1
N
R3
R2
R2
R2
X = SO2Ph, Bt, OH, OMe, OEt, OTMS
Scheme 1.
However, in the course of the development of this program, we
encountered some difficulties to prepare efficiently N-ethoxy-
carbamates in a reproducible manner and in a short time. There-
fore, we decided to consider their preparation by using microwave
heating. The use of microwave-assisted reactions has increased
dramatically over the past decade13 and notably by improving
yields or by allowing significant rate enhancements of chemical
The preparation of N-acyliminium ions starting from the corre-
sponding -alkoxycarbamates in the presence of a Lewis acid ap-
pears to be one of the more convenient ones (Scheme 1, R1¼OAlkyl,
a
* Corresponding authors. Tel.: þ33 (0)251125409; fax: þ33 (0)251125402 (E.L.G.);
tel.: þ33 (0)235592905/148399; fax: þ33 (0)235148423 (T.B.).
E-mail addresses: thierry.besson@univ-rouen.fr (T. Besson), erwan.legrognec@
univ-nantes.fr (E. Le Grognec).
reactions.
Considering
the
preparation
of
a-ethoxy-
carbamates by reaction of diethyl pyrocarbonate (DEPC) with an
imine in ethanol, we assumed that the strong dipolar momentum
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.023

A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
9181
of both reagents and solvent would allow the reaction to benefit
from significant microwave heating.
of benzaldehyde was attributed to a partial hydrolysis of the imine
due to the presence of some fine powder of MgSO4. Under micro-
wave irradiation, desorption of water from MgSO4 should occur and
might be responsible for the hydrolysis of the imine. Additionally, it
has to be noted that DEPC rapidly decomposes in the presence of
moisture. The use of molecular sieves 4 Å instead of MgSO4 was
then preferred for the preparation of the imine, which was easily
isolated after filtration. Following this procedure, a significant en-
hancement of the conversion was observed (85%, entry 8, Table 1)
confirming our assumption on the hydrolysis of the imine. How-
ever, due to the liberation of CO2 during this reaction, to the nature
of the solvent (2.3 ml of ethanol) and to the reaction conditions
(150 ꢁC, 350 W, 15 min with a 3 min ramp in a sealed tube of 5 ml),
the pressure was estimated to be too close from the safety pressure
(reported to be around 14 bar by Milestone). In order to avoid the
breakage of the pressure valve, we decided to work at 130 ꢁC in-
stead of 150 ꢁC and then a 77% conversion could be obtained after
2. Results and discussion
The generation of a-ethoxycarbamates was initially carried out
using the imine prepared from reaction of benzaldehyde and
allylamine in dichloromethane in the presence of MgSO4 at room
temperature (Scheme 2). The imine was isolated in a quantitative
yield after filtration and evaporation of the solvent. We treated the
imine with 1.2 equiv of diethyl pyrocarbonate (DEPC) in ethanol at
70 ꢁC during 24 h according to Hiemstra and Speckamp.3 In spite of
numerous attempts, we encountered some difficulties to reproduce
the high yields reported3,6e and a low conversion of 15% in 1a was
only observed by 1H NMR (Table 1, entry 1). The conversion remains
low by using 2 equiv of DEPC (22%, Table 1, entry 2) or moderate
with 4 equiv of DEPC (59%, Table 1, entry 3).
EtO
O
OEt
O
O
O
O
MgSO4
(DEPC)
N
N
OEt
OEt
H
+
H2N
CH2Cl2, rt
H
EtOH, heating
1a
Scheme 2.
15 min (entry 9, Table 1). By extending the reaction time to 30 min,
the conversion was slightly improved to 80% (entry 10, Table 1) and
we decided to keep conditions of entry 9 to get a reproducible and
rapid preparation of 1a. The use of a 2 equiv of DEPC, which was not
justified by considering the stœchiometry of the reaction can be
explained by the facile thermal decomposition of DEPC and by the
scale of the experiment (5 mmol).15 A control experiment involving
a thermal activation with an imine prepared in the presence of
molecular sieves was also carried out (entry 11, Table 1) and did not
improved the low yield obtained previously (entry 2, Table 1).
Having established the experimental conditions allowing good
conversions for 1a, we examined various imines derived from
benzaldehydes in order to evaluate the scope of the method. Good
to excellent conversions were obtained for the preparation of
Table 1
Experimental conditions used for the preparation of
a
-ethoxycarbamate 1a
Entry DEPC (equiv) Conditions, temperature Reaction time Conversiona (%)
1
2
3
1.2
2
4
D
D
D
, 70 ꢁ
, 70 ꢁ
, 70 ꢁ
C
C
C
24 h
24 h
24 h
15b
22b
59b
58b
64b
62b
50b
85d
77d
80d
25d
4
5
6
7
8
9
10
11
2
4
2
2
2
2
2
2
MW (150 W), 110 ꢁ
MW (150 W), 110 ꢁ
MW (200 W), 120 ꢁ
MW (350 W), 150 ꢁ
MW (350 W), 150 ꢁ
MW (350 W), 130 ꢁ
MW (350 W), 130 ꢁ
C
C
C
C
C
C
C
15 min
15 min
20 min
15 minc
15 minc
15 minc
30 minc
24 h
D C
, 70 ꢁ
Determined by 1H NMR on the crude reaction mixture.
Imine prepared using MgSO4.
3 min ramp with a power input of 350 W.
Imine prepared using molecular sieves 4 Å.
a
a-ethoxycarbamates derived from benzaldehyde. The use of
b
c
methyl-, butyl-, butenyl- and propargylamine allowed conversions
between 71 and 100% (entries 2–5, Table 2). A lower conversion was
obtained with the imine derived from benzaldehyde and benzyl-
amine (52% after 15 min, entry 6, Table 2). This result can be
explained by the higher stability of this imine, which can be easily
purified on silica gel. As observed previously for the preparation of
1a (entry 10, Table 1), the extension of the reaction time to 30 min
did not improved significantly the conversion (61% after 30 min,
footnote c, Table 2). These last results confirm that a prolonged
d
We then decided to consider the incidence of a higher tem-
perature under pressurized conditions for the preparation of 1a. To
present a synthetic work with a facile and rapid process, which can
be readily run on different scale, we decided to perform these new
experiments under microwave irradiation conditions using the
novel ‘hybrid’ microwave platform MultiSYNTHÒ (Milestone S.r.l,
Italy).14 Reaction conditions were optimized by varying applied
power and temperature (measured by both fibre-optic contact
thermometer and infrared pyrometer). By using 2 equiv of DEPC
and carrying out the reaction with a fixed power input of 150 W
during 15 min, a conversion of 58% was obtained (entry 4, Table 1).
The use of an excess (4 equiv) of DEPC did not improve significantly
the reaction conversion under these conditions (64%, entry 5, Table
1). A moderate conversion was also obtained under 200 W during
20 min (62%, entry 6, Table 1). By controlling the reaction temper-
ature at 150 ꢁC and allowing an available power of 350 W, a mod-
erate conversion was also observed (50%, entry 7). At this stage,
a careful examination of the 1H NMR of the crude reaction mixture
indicates the presence of benzaldehyde. As the imine was obtained
with a complete conversion and dry ethanol was used, the presence
reaction time does not improve the conversion in
a-ethoxy-
carbamate due to thermal decomposition of DEPC. This known
phenomenon can be observed for usual thermal heating of this
reactant after 1 h in refluxing benzene.16 Recently, data were pub-
lished on the possibility of microwaves to activate thermal de-
composition of reactants into reactive or unreactive chemical
species.17 On behalf of the good yields obtained, we assume that the
temperature and the pressure accelerate the reactivity of DEPC
instead of its degradation. Our strict control of reaction parameters
(temperature and reaction time) confirms the possibility of oper-
ational benefits. Its usefulness affords in our case good to high
conversions compared to traditional heating conditions. In addi-
tion, the reaction time was significantly reduced from 24 h or 16 h
to 15 min.

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A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
Table 2
Scope of the synthesis of a-ethoxycarbamates derived from benzaldehydes
Entry
Aldehyde
Amine
a
-Ethoxycarbamates
Conversiona (%)
77 (22)
Yieldb (%)
70
EtO2C
O
N
1
1a
1b
NH2
H
H
OEt
EtO2C
O
O
N
2
3
Me–NH2
100 (84)
71 (36)
98
66
OEt
EtO2C
N
N
1c
NH2
H
H
H
OEt
OEt
EtO2C
EtO2C
O
O
4
5
1d
1e
100 (41)
74 (6)
87
68
NH2
N
NH2
OEt
O
EtO2C
H
O
N
NH2
6
7
1f
52c (19)
47
89
OEt
O
EtO
N
H
H
2a
95 (30)
NH2
OEt
OEt
MeO
MeO
O2N
O
O
EtO
O
N
8
3a
47 (15)
35
NH2
O2N
O
EtO
N
H
9
4a
89 (17)
77
NH2
OEt
Cl
Cl
a
Conversion determined by 1H NMR on the crude reaction mixture. Conversion obtained by microwave irradiation (2 equiv of DEPC, 15 min at 130 ꢁC, with 3 min ramp and
a power input of 350 W). Conversions in brackets were obtained by thermal heating at 70 ꢁC using 2 equiv of DEPC during 16 h.
b
Yield obtained after flash chromatography following the microwave heating procedure.
The conversion was only improved to 61% by extending the reaction time to 30 min.
c
The electron-donating or withdrawing property of the imine
was also examined and was shown to have a dramatic influence on
the reaction course. As expected, the use of p-methoxy-
benzaldehyde affords a higher conversion (95%, entry 7, Table 2)
and reaction with the imine derived from p-nitrobenzaldehyde
exhibits a moderate 47% conversion (entry 8, Table 2). These results
were in good agreement with the trend also observed under ther-
mal heating and can be explained by a simple consideration of the
electronic effect. However, a high conversion was obtained for the
-ethoxycarbamate 4a derived from m-chlorobenzaldehyde (89%,
a
entry 9, Table 2) in spite of the inductive effect of the halogen atom,
while conversion under thermal heating was lower than for 1a (in
agreement with the electronic effect of the m-Cl substituent). This
apparent difference observed for these two heating modes was
subsequently re-examined by considering two competitive exper-
iments under microwave irradiation mode (Scheme 3), which

A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
9183
O
O
O
N
N
N
OEt
N
OEt
N
N
OEt
OEt
DEPC (1 equiv.)
+
H
+
H
+
OEt
OEt
+
H
EtOH
MW, 130 °C
15min, 350W
MeO
MeO
Cl
Cl
4a
2a
1a
Product ratioa
Entry
Substrate stoechiometry
0.5
0
0
0.5
0.5
60
-
-
40
33
1
2
0.5
67
a Product ratio measured on the crude reaction mixture by 1H NMR
Scheme 3.
Table 3
Scope of the preparation of
a
-ethoxycarbamates not derived from benzaldehyde
Entry
Aldehyde
Amine
Product
Yielda (%)
91 (85)
Ratiob (%)
100/0
EtO2C
O
O
N
O
1
5a
6f
NH2
H
OEt
EtO2C
O
N
NH2
2
3
84 (68)
66 (71)
100/0
100/0
H
OEt
EtO2C
O
O
N
7a
NH2
NH2
O
O
H
OEt
O
EtO2C
N
N
H
O
OEt
OEt
O
4
8a/8a0
71 (70)
70/30
O
EtO2C
O
5
6
9a/9a0
82 (89)
60 (78)
55/45
46/54
NH2
NH2
BnO
H
BnO
OBn
H
OBn
EtO2C
N
10a/10a0
O
OEt
O
O
O
N
N
N
CO2Bn
OMe
CO2Bn
CO2Et
OMe
7
11a/11a0
12a/12a0
58 (57)
60 (57)
75/25
91/9c
O
O
NH2
NH2
O
O
H
EtO
OMe
OMe
OMe
OMe
O
O
O
O
H
8
EtO2C
OMe
N
OEt
OMe
O
a
Yields obtained after chromatography on silica gel (conversions were complete); reaction conditions: 2 equiv of DEPC, 3 min at 70 ꢁC and a power input of 150 W; yields in
brackets correspond to isolated yields obtained after flash chromatography following the reaction conditions: thermal heating, 70 ꢁC, 2 equiv of DEPC, 16 h.
b
a
-Ethoxycarbamate/
a
-ethoxycarbonate ratio evaluated by 1H NMR.
c
The -ethoxycarbonate has not been isolated in this case.
a

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A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
points out a sequence in agreement with the electronic effect and
an unexplained higher yield obtained for 4a under microwave
irradiation.
pressure of the reaction. However, this unexpected by-product does
not detract the synthetic appeal of the present preparation of
a-ethoxycarbamates since both
a-ethoxycarbonates and the
The results displayed in Table 2 demonstrate that the microwave
irradiation mode affords a significant enhancement of the conver-
sion and a dramatic reduction of the reaction time compared to the
a
-ethoxycarbamates should lead to the similar iminium in-
termediates in the presence of a Lewis acid affording the same
adduct in the presence of nucleophiles.
thermal heating one. It has to be noted that all the
a-ethoxy-
carbamates reported in Table 2 have been isolated by flash chro-
matography on silica gel in good yields and were fully characterized
(see Experimental section).
3. Conclusion
The present work describes an efficient preparation of a library
We then extended our work on other imines not derived from
benzaldehydes. By considering furfuraldehyde and allylamine, no
trace of the desired a-ethoxycarbamate 5a was observed using our
of
a-ethoxycarbamate derivatives or useful equivalents able to
furnish N-acyliminium intermediates in the presence of Lewis
acids. The microwave irradiation mode allows their rapid syntheses
often in higher yields and always in a shorter reaction time com-
pared to the classical thermal heating. In the case of the synthesis of
previous optimized conditions. The 1H NMR spectrum only reveals
decomposition indicating that our conditions were too harsh. By
reducing the reaction time to 3 min, some decomposition was also
observed but with a conversion in 5a about 85% (determined by 1H
NMR). Then, by decreasing the reaction temperature to 70 ꢁC and
with a power input at 150 W, we found that a high conversion (91%)
could be obtained. By extending these conditions to other imines,
chiral
a-ethoxycarbamates, the formation of a-ethoxycarbonates
was also observed. These reactive precursors are useful for the
synthesis of nitrogen-containing compounds and work is currently
in progress in our group in order to exploit their potential in highly
diastereoselective reactions involving
g-substituted allyltins.
a complete conversion in a-ethoxycarbamates was systematically
observed. Aliphatic derivative 6f or benzyloxy derivative 7a was
isolated in 84% and 66% yields, respectively, after flash chromato-
graphy (entries 2 and 3, Table 3). We also examined the preparation
4. Experimental
4.1. General
of chiral
a-ethoxycarbamates. The cyclohexylidene- and the
dibenzyloxy-glyceraldehyde derivatives were obtained in good
yields (entries 4 and 5, Table 3), while the Garner type aldehyde
furnished a moderate 60% yield (entry 6, Table 3). Similarly, two
functionalized aldehydes developed by Ley18 were considered and
Aldehydes and amines were purchased from commercial sup-
pliers and used without further purification. Garner aldehyde,19 (2S,
5R, 6R)-5,6-dimethoxy-5,6-dimethyl-[1,4] dioxane-2-carbaldehy-
de18a and (2R, 5R, 6R)-5,6-dimethoxy-5,6-dimethyl-[1,4] dioxane-
2-carbaldehyde,18b (2R)-2,3-O-cyclohexylidene-glyceraldehyde,20
(2R)-2,3-dibenzyl-glyceraldehyde21 were prepared according to
previous described procedure. Diethyl pyrocarbonate was pur-
chased from Acros. NMR spectra were recorded on a Bruker Avance
300 spectrometer operating at 300.13 MHz for 1H, 75.47 MHz for
13C and on a Bruker ARX 400 spectrometer operating at 400.13 MHz
for 1H, 100.62 MHz for 13C. Chemical shifts are given in parts per
furnished two chiral
a-ethoxycarbamates. Despite the complete
conversions observed on the crude reaction mixture by 1H NMR,
the yields obtained for these compounds were about 60%. The
highly functionalized structures of these compounds, which can
decompose on silica gel, could explain these results. For these
functionalized imines reported in Table 3, the reduction of the re-
action time constitutes the major benefit of these new conditions
performed under microwave irradiation mode since yields
obtained by the two heating modes are similar (yields increased for
5a and 6f, similar yields for 8a, 11a and 12a, decreased in the case of
7a, 9a and 10a).
million as
d
values related to tetramethylsilane (1H, 13C). Mass
spectra were obtained in EI mode (70 eV) using a quadrupolar
analyser (HP apparatus, Engine 5989A) in direct introduction mode.
´
HRMS analyses were performed in Rennes (Centre Regional de
Curiously, the formation of a-carbonates derivatives was also
Mesures Physiques de l’Ouest, Univ. Rennes 1) and in Lyon (Centre
observed in these last five examples. The formation of the latter can
be explained by the reaction of an ethyl carbonate on the in-
termediate iminium. The presence of an electronegative atom (oxy
´
Commun de Spectrometrie de Masses, Univ Lyon 1). IR spectra were
recorded with a Bruker IFS Vector 22 apparatus. Ethanol was dis-
tilled from CaH2. TLC analyses were carried on silica-coated plates
(Merck Kieselgel 60F254). All reactions were carried out under an
argon atmosphere.
gen) in the b-position to the iminium could reinforce the electro-
philicity of the corresponding iminium and facilitate the reaction
with the ethyl carbonate anion, which can occur before its de-
carboxylation, instead of the ethoxy one. A control experiment
carried out with the imine derived from Garner aldehyde in a sealed
tube and under classical thermal heating also affords a significant
amount (28%) of the carbonate (Scheme 4).
The ‘hybrid’ microwave platform MultiSYNTHÒ (Milestone S.r.l.)
is a novel dedicated microwave system for synthetic applications. It
allows a fast reaction optimization providing high energy density in
a single-mode like configuration and an efficient scale-up (maxi-
mumworking volume 300 ml) through parallel synthesis in a multi-
H
OEt
OCO2Et
N
sealed tube
O
O
N
N
O
O
O
+
+
N
N
N
CO2Et
CO2Bn
CO2Et
EtO
O
OEt
CO2Bn
CO2Bn
10a
10a'
28%
54%
oil bath, 85 °C, 30 min, 54%
72%
46%
MW, 150W, 70 °C, 3 min, 60%
Scheme 4.
This last experiment indicates that the carbonate formation is
not the result of a specific microwave effect and is simply due to the
mode configuration. The instrument features a special shaking
system that ensures high homogeneity of the reaction mixtures. It is

A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
9185
equipped with an indirect pressure control through pre-calibrated
springs at the bottom of the vessels shields and with both, contact-
less infrared pyrometer (IRT) and fibre-optic contact thermometer
(FO) for accurate temperature measurement. It is noteworthy that
the IRT can be calibrated directly on the temperature read by the FO
to ensure the highest accuracy and reproducibility.
3.55 (m, 1H), 3.24–3.20 (m, 2H),1.57–1.36 (m, 2H),1.14 (m, 8H), 0.82
(t, 3H, J¼7.3 Hz); 13C NMR (100 MHz, C6D6, 340 K)
d 157.1, 142.2,
128.4–126.9 (5C), 85.6, 63.5, 61.4, 41.9, 32.5, 20.6, 15.1, 14.8, 13.9; CI/
NH3-HRMS: m/z calcd for C16H29N2O3 [MþNH4]þ 297.2178 found
297.2169.
4.2.4. Ethyl
N-(but-3-enyl)-N-(ethoxyphenylmethyl)carbamate
4.1.1. Procedure for the preparation of
a-ethoxycarbamates by ther-
(1d). Yield 446 mg (87%); IR (neat) cmꢂ1 2977, 1700, 1413, 1088,
912, 710; Rf (hexanes/Et2O 9/1)¼0.45; 1H NMR (400 MHz, C6D6,
mal heating. To a solution of imine freshly prepared (4.71 mmol) in
ethanol (25 ml) in a round-bottom flask, was added diethyl pyro-
carbonate (1.53 g, 9.42 mmol). The reaction mixture was stirred
and heated to 70 ꢁC for 16 h. The reaction mixture was concen-
trated under reduced pressure and the crude product was analysed
by NMR to measure the conversion rate. Purification by flash
chromatography on silica gel using Et2O/hexanes 1/9 or AcOEt/
340 K)
d 7.55–7.02 (m, 5H), 6.60 (br s, 1H), 5.50 (m, 1H), 4.87 (m,
2H), 4.16 (q, 2H, J¼7.0 Hz), 3.64 (m, 1H), 3.46 (m, 1H), 3.28 (m, 1H),
3.10 (m, 1H), 2.31 (m, 1H), 2.10 (m, 1H), 1.13 (t, 3H, J¼7.0 Hz), 1.08 (t,
3H, J¼7.0 Hz); 13C NMR (100 MHz, C6D6, 340 K)
d 157.1, 140.0, 136.3,
129.6–126.9 (5C), 115.9, 85.9, 63.6, 61.4, 42.0, 34.4, 15.0, 14.7; (FABþ,
3-nitrobenzylalcohol matrix)-HRMS: m/z calcd for C16H24NO3
[MþH]þ 278.1756 found 278.1743.
hexanes 1/9 as eluent gave the desired
a colourless oil.
a-ethoxycarbamates as
4.2.5. EthylN-(ethoxyphenylmethyl)-N-propargylcarbamate(1e). Yield
329 mg (68%); IR (neat) cmꢂ1 2979, 1705, 1443, 1402, 1260, 1091,
697; Rf (hexanes/Et2O 9/1)¼0.45; 1H NMR (400 MHz, C6D6, 340 K)
4.1.2. Typical procedure for the preparation of
a-ethoxycarbamates
derived from benzaldehyde under microwave heating. A solution of
a freshly prepared imine (1.85 mmol) and diethyl pyrocarbonate
(0.60 g, 3.7 mmol) in dry ethanol (2.3 ml) was prepared in a sealed
5 ml vial. The mixture was irradiated during 15 min at a tempera-
ture maintained at 130 ꢁC and the maximal power output at 350 W.
The reaction vessel was rapidly cooled to ambient temperature and
the reaction mixture was concentrated under reduced pressure.
Purification by flash chromatography on silica gel using EtOAc/
hexanes 1/9 as eluent gave the desired product as a colourless oil.
d
7.52–7.50 (m, 2H), 7.16–7.08 (m, 3H), 6.67 (br s, 1H), 4.16 (q, 2H,
J¼7.0 Hz), 3.81 (m, 1H), 3.80 (m, 1H), 3.60 (d, 1H, J¼16.0 Hz), 3.51
(m, 1H), 1.77 (br s, 1H), 1.18 (t, 3H, J¼7.0 Hz), 1.09 (t, 3H, J¼7.0 Hz);
13C NMR (100 MHz, C6D6, 340 K)
d 156.5, 139.2, 128.5–126.9 (5C),
85.7, 81.2, 69.8, 63.8, 61.9, 31.3, 14.9, 14.6; (FABþ, 3-nitro-
benzylalcohol matrix)-HRMS: m/z calcd for C15H20NO3 [MþH]þ
262.1443 found 262.1420.
4.2.6. Ethyl N-benzyl-N-(ethoxyphenylmethyl)carbamate (1f). Yield
272 mg (47%); IR (neat) cmꢂ1 3064, 3032, 2978, 2932, 1699, 1451,
1412, 1212, 1089, 1030, 699; Rf (hexanes/Et2O 9/1)¼0.45; 1H NMR
4.1.3. Typical procedure for the preparation of
a-ethoxycarbamates
not derived from benzaldehydes under microwave heating. A solution
of a freshly prepared imine (1.85 mmol) and diethyl pyrocarbonate
(0.60 g, 3.7 mmol) in dry ethanol (2.3 ml) was prepared in a sealed
5 ml vial. The mixture was irradiated during 3 min at a temperature
maintained at 70 ꢁC and the maximal power output at 150 W. The
reaction vessel was rapidly cooled to ambient temperature and the
reaction mixture was concentrated under reduced pressure. Purifi-
cation by flash chromatography on silica gel using EtOAc/hexanes 1/9
as eluent gave the desired product as a colourless oil.
(400 MHz, C6D6, 340 K)
d 7.54–7.01 (m, 10H), 6.77 (br s, 1H), 4.68–
4.05 (m, 4H), 3.45 (m, 2H), 1.01 (m, 6H); 13C NMR (100 MHz, C6D6,
340 K) d 157.2, 139.9, 139.7, 128.7–126.7 (10C), 86.3, 63.6, 61.7, 46.0,
14.6,14.4; (FABþ, 3-nitrobenzylalcohol matrix)-HRMS: m/z calcd for
C19H24NO3 [MþH]þ 314.1756 found 314.1758.
4.2.7. Ethyl N-allyl-N-[ethoxy-(4-methoxyphenyl)methyl]carbamate
(2a). Yield 483 mg (89%); IR (neat) cmꢂ1 2977, 2933, 2837, 1699,
1451, 1386, 1213, 1036, 916; Rf (hexanes/Et2O 9/1)¼0.48; 1H NMR
4.2. Characterization of the
a
-ethoxycarbamates
(500 MHz, C6D6, 340 K)
d
7.44 (d, 2H, J¼9.0 Hz), 6.78 (d, 1H,
J¼9.0 Hz), 6.70 (m, 1H), 5.85 (m, 1H), 4.95 (d, 1H, J¼17.0 Hz), 4.87 (d,
1H, J¼10.5 Hz), 4.16 (q, 2H, J¼7.0 Hz), 3.86–3.74 (m, 1H), 3.69–3.57
(m, 2H), 3.47 (m, 1H), 3.35 (s, 3H), 1.13 (t, 3H, J¼7.0 Hz), 1.07 (t, 3H,
4.2.1. Ethyl N-allyl-N-(ethoxyphenylmethyl)carbamate (1a). Yield
341 mg (70%); IR (neat) cmꢂ1 2978, 2932, 1699, 1318, 1258, 1090,
915, 698; Rf (hexanes/Et2O 9/1)¼0.45; 1H NMR (400 MHz, C6D6,
J¼7.0 Hz); 13C NMR (125 MHz, C6D6, 340 K)
d 162.2, 160.2, 136.0,
340 K)
d
7.52, 7.00 (m, 5H), 6.66 (br s, 1H), 5.68 (m, 1H), 4.87 (br d,
132.0, 128.2 (2C), 116.1, 114.0 (2C), 85.7, 65.7, 61.4, 54.9, 44.6, 15.0,
1H, J¼17.2 Hz), 4.80 (br d, 1H, J¼10.0 Hz), 4.11 (q, 2H, J¼7.0 Hz),
14.7; CI/NH3-MS: m/z 264 [(MþNH3)ꢂEtOH].
3.71–3.31 (m, 4H), 1.09 (t, 3H, J¼7.0 Hz), 1.03 (t, 3H, J¼7.0 Hz); 13C
NMR (100 MHz, C6D6, 340 K)
d
157.2, 139.8, 135.7, 130.3–126.8 (5C),
4.2.8. Ethyl
N-allyl-N-[ethoxy-(4-nitrophenyl)methyl]carbamate
115.9, 85.7, 63.4, 61.3, 44.6, 14.5, 14.7; (FABþ, 3-nitrobenzylalcohol
matrix)-HRMS: m/z calcd for C15H22NO3 [MþH]þ 264.1600 found
264.1627.
(3a). Yield 199 mg (35%); IR (neat) cmꢂ1 2978, 2933, 2835, 1700,
1523, 1350, 1259, 1084; Rf (hexanes/Et2O 9/1)¼0.43; 1H NMR
(400 MHz, C6D6, 340 K)
d
7.84 (d, 2H, J¼8.8 Hz), 7.27 (d, 1H,
J¼8.8 Hz), 6.51 (m, 1H), 5.60 (m, 1H), 4.82 (br d, 1H, J¼15.3 Hz), 4.78
(br d, 1H, J¼10.1 Hz), 4.11 (q, 2H, J¼7.1 Hz), 3.63–3.49 (m, 2H), 3.42–
3.31 (m, 2H), 1.06 (t, 3H, J¼7.0 Hz), 1.05 (t, 3H, J¼7.1 Hz); 13C NMR
4.2.2. Ethyl N-(ethoxyphenylmethyl)-N-methylcarbamate (1b). Yield
430 mg (98%); IR (neat) cmꢂ1 3032, 2978, 1703, 1450, 1397, 1318,
1153, 1090, 714; Rf (hexanes/Et2O 9/1)¼0.45; 1H NMR (400 MHz,
(100 MHz, C6D6, 340 K) d 156.9, 148.4, 146.2, 135.2, 127.7 (2C), 123.4
C6D6, 340 K)
d
7.64–7.14 (m, 5H), 6.69 (br s, 1H), 4.21 (q, 2H,
(2C), 116.6, 84.9, 63.8, 61.8, 44.7, 14.8, 14.6; CI/NH3-MS: m/z 263
[(MþH)ꢂEtOH].
J¼7.2 Hz), 3.61–3.32 (m, 2H), 2.61 (br s, 3H), 1.60 (m, 6H); 13C NMR
(100 MHz, C6D6, 340 K)
d 157.1, 139.6, 129.0–126.7 (5C), 85.4, 63.3,
61.5, 27.3,15.0,14.8; (FABþ, 3-nitrobenzylalcohol matrix)-HRMS: m/
z calcd for C13H20NO3 [MþH]þ 238.1443 found 238.1460.
4.2.9. Ethyl
N-allyl-N-[ethoxy-(3-chlorophenyl)methyl]carbamate
(4a). Yield 424 mg (77%); IR (neat) cmꢂ1 2978, 2932, 1699, 1576,
1385, 1258, 1097, 1076, 924, 741; Rf (hexanes/Et2O 9/1)¼0.45; 1H
4.2.3. Ethyl N-butyl-N-(ethoxyphenylmethyl)carbamate (1c). Yield
341 mg (66%); IR (neat) cmꢂ1 2960, 2873, 1699, 1414, 1291, 1089,
708; Rf (hexanes/Et2O 9/1)¼0.45; 1H NMR (400 MHz, C6D6, 340 K)
NMR (500 MHz, C6D6, 340 K)
d
7.63 (br s, 1H), 7.22 (d, 1H, J¼7.5 Hz),
7.07 (d, 1H, J¼8.0 Hz), 6.89 (m, 1H), 6.55 (m, 1H), 4.86 (br d, 1H,
J¼17.6 Hz), 4.82 (br d, 1H, J¼10.5 Hz), 4.11 (q, 2H, J¼7.0 Hz), 3.80–
3.30 (m, 4H), 1.08–1.02 (m, 6H); 13C NMR (125 MHz, C6D6, 340 K)
d
7.60–7.08 (m, 5H), 6.74 (m,1H), 4.21 (q, 2H, J¼7.2 Hz), 3.71 (m,1H),

9186
A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
d
156.8, 142.1, 135.5, 134.8, 129.7, 128.3, 127.3, 125.1, 116.3, 85.0, 65.7,
3.90–4.30 (m, 8H), 1.25–1.95 (m, 10H), 1.14 (m, 3H), 1.04 (t, 3H,
61.6, 44.7, 14.8, 14.6; CI/NH3-MS: m/z 252 [(MþH)þꢂEtOH].
J¼7.2 Hz); Second diastereomer: 1H NMR (400 MHz, C6D6, 340 K)
d
6.73 (d, 1H, J¼8.0 Hz), 5.92 (ddt, 1H, J¼17.2, 10.4, 6.0 Hz), 5.16 (dq,
4.2.10. Ethyl N-allyl-N-(ethoxy-furan-2-ylmethyl)carbamate (5a). Yield
426 mg (91%); IR (neat) cmꢂ1 2980, 2934, 1823, 1763, 1704, 1409,
1260, 1156, 1092, 1003, 883, 739; Rf (hexanes/AcOEt 9/1)¼0.48; 1H
1H, J¼17.2, 1.2 Hz), 5.04 (dq, 1H, J¼10.4, 1.2 Hz), 4.41 (dt, 1H, J¼8.0,
6.0 Hz), 3.90–4.30 (m, 8H), 1.25–1.95 (m, 10H), 1.14 (m, 3H), 1.05 (t,
3H, J¼7.2 Hz); 13C NMR (100 MHz, C6D6, 340 K)
d 156.2, 156.0, 155.3,
NMR (400 MHz, C6D6, 340 K)
d
7.15 (s, 1H), 6.76 (m, 1H), 6.46 (s, 1H),
154.8, 136.3, 135.9, 117.4, 116.7, 112.1, 111.6, 85.9, 85.7, 76.7, 74.7,
67.2–62.6 (6C), 47.1, 46.9, 37.3–36.2 (4C), 26.2–24.8 (6C), 15.10–14.6
(4C).
6.16 (s, 1H), 5.86 (m, 1H), 5.07 (br d, 1H, J¼17.2 Hz), 4.99 (br d, 1H,
J¼10.0 Hz), 4.19 (q, 2H, J¼7.0 Hz), 4.01–3.82 (m, 2H), 3.67 (m, 1H),
3.55 (m, 1H), 1.18 (t, 3H, J¼7.0 Hz), 1.13 (t, 3H, J¼7.0 Hz); 13C NMR
(100 MHz, C6D6, 340 K)
d
152.5, 149.1, 142.1, 135.6, 115.8, 110.4,
4.2.15. Ethyl N-allyl((2R)-2,3-bis(benzyloxy)-1-ethoxypropyl)carbamate
(9a). Yield 397 mg, (51%); Attempts to separate by chromatography
the two diastereomers obtained as a mixture (ratio 40/60) were
unsuccessful. Rf (hexanes/AcOEt 9/1)¼0.29; IR (neat) cmꢂ1 3064,
3030, 2977, 1699, 1097, 921, 736, 698; ESI-HRMS: m/z calcd for
C25H33NO5Na [MþNa]þ 450.2256 found 450.2259; 1H NMR
108.5, 81.9, 63.7, 61.6, 44.9, 14.9, 14.6; CI/NH3-MS: m/z 252
[(MþH)þꢂEtOH].
4.2.11. Ethyl N-benzyl-N-(1-ethoxy-2-methylpropyl)carbamate
(6f). Yield 434 mg (84%); IR (neat) cmꢂ1 2975, 2930, 1702, 1415,
1331, 1153, 1083, 949, 699; Rf (hexanes/AcOEt 9/1)¼0.43; 1H NMR
(400 MHz, C6D6, 340 K)
d 7.08–7.35 (m, 10H), 6.03 (m, 1H), 5.12 (d,
(400 MHz, C6D6, 340 K)
d
7.58–7.11 (m, 5H), 5.17 (m, 1H), 4.41 (m,
1H, J¼6.2 Hz), 4.97 (d, 1H, J¼10.4 Hz), 4.36–4.86 (m, 5H), 4.08 (m,
2H), 4.11 (m, 2H), 3.31–3.08 (m, 2H), 1.87 (m,1H), 1.02–0.95 (m, 9H),
2H), 3.67–3.87 (m, 5H), 3.41 (m, 2H), 0.95–1.07 (m, 6H); 13C NMR
0.77 (m, 3H); 13C NMR (100 MHz, C6D6, 340 K)
d
157.4, 140.5, 129.0–
(100 MHz, C6D6, 340 K) d 156.9, 139.6, 139.3, 136.7, 136.3, 128.6–
127.5 (10C), 116.3, 115.8, 87.3, 85.6, 80.4, 78.9, 74.1–71.2 (3C), 64.5,
63.7, 61.8, 61.3, 45.4, 44.9, 15.0, 14.7.
127.1 (5C), 92.3, 63.8, 61.3, 45.2, 32.0, 19.4, 18.3, 14.8, 14.7; (FABþ, 3-
nitrobenzylalcohol matrix)-HRMS: m/z calcd for C16H26NO3
[MþH]þ 280.1913 found 280.1916.
4.2.16. Ethyl N-allyl((2R)-2,3-bis(benzyloxy)-1-(ethoxycarbonyloxy)pro-
pyl)carbamate (9a0). Yield 330 mg (38%); Attempts to separate by
chromatography the two diastereomers obtained as a mixture
(ratio 44/56) were unsuccessful. Rf (hexanes/AcOEt 9/1)¼0.19; 1H
4.2.12. Ethyl N-allyl-N-(2-benzyloxy-1-ethoxyethyl)carbamate
(7a). Yield 375 mg (66%); IR (neat) cmꢂ1 2978, 2932, 1703, 1318,
1268, 1111, 698; Rf (hexanes/AcOEt 9/1)¼0.54; 1H NMR (400 MHz,
C6D6, 340 K)
d
7.35–7.17 (m, 5H), 6.02 (m, 1H), 5.84 (m, 1H), 5.20 (br
NMR (300 MHz, CDCl3, 300 K) d 7.40–7.26 (m, 10H), 6.49 (d, 1H,
d, 1H, J¼17.2 Hz), 5.06 (br d, 1H, J¼9.6 Hz), 4.50 (m, 2H), 4.18 (m,
J¼7.5 Hz), and 6.41 (d, 1H, J¼8.1 Hz) for the second isomer, 5.80 (m,
1H), 5.20–5.00 (m, 2H), 4.45–4.75 (m, 4H), 4.20–4.10 (m, 2H), 4.20–
3.55 (m, 7H), 1.35–1.15 (m, 6H); No 13C NMR experiment could be
recorded due to the unstability of the products.
2H), 3.94 (m, 2H), 3.63 (m, 3H), 3.49 (m, 1H), 1.16 (m, 6H); 13C NMR
(100 MHz, C6D6, 340 K) d 156.6, 139.2, 136.7, 128.5–127.7 (5C), 115.5,
85.0, 73.5, 70.9, 63.8, 61.3, 44.2, 15.0, 14.6; (FABþ, 3-nitro-
benzylalcohol matrix)-HRMS: m/z calcd for C17H26NO4 [MþH]þ
308.1862 found 308.1862.
4.2.17. Benzyl 4-{[allyl(ethoxycarbonyl)amino](ethoxy)methyl}-2,2-
dimethyl-1,3-oxazolidine-3-carboxylate (10a). Yield 264 mg (34%);
Attempts to separate by chromatography the two diastereomers
obtained as a mixture (ratio 86/14) were unsuccessful. Rf (hexanes/
AcOEt 9/1)¼0.72; IR (neat) cmꢂ1 3068, 3032, 2978,1879,1704,1404,
1257, 1088, 699. ESI-HRMS: m/z calcd for C22H32N2O6Na [MþNa]þ
443.2158 found 443.2159.
4.2.13. Ethyl
N-[(R)-1,4-dioxaspiro[4.5]dec-2-yl-ethoxymethyl]-N-
(prop-2-en-1-yl)carbamate (8a). Yield 294 mg (44%); IR (neat)
cmꢂ1 2935, 1705, 1100, 926; ESI-HRMS: m/z calcd for C17H29NO5Na
[MþNa]þ 350.1943 found 350.1942. Diastereomeric ratio (43/57).
First eluted diastereomer: Rf (hexanes/AcOEt 9/1)¼0.64; 1H NMR
(400 MHz, C6D6, 340 K)
d
6.03 (ddt,1H, J¼16.0,10.8, 6.0 Hz), 5.40 (m,
Major diastereomer: 1H NMR (400 MHz, C6D6, 340 K)
d 7.06–
1H), 5.16 (d, 1H, J¼16 Hz), 5.01 (d, 1H, J¼10.8 Hz), 4.15–4.05 (m, 2H),
4.05–4.00 (m, 1H), 3.97 (m, 1H), 3.92–3.83 (m, 3H), 3.42 (dq, 1H,
J¼9.6, 7.2 Hz), 3.27 (bdq,1H, J¼9.6, 7.2 Hz),1.80–1.20 (m,10H),1.05 (t,
3H, J¼7.2 Hz), 0.97 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, C6D6, 340 K)
7.26 (m, 5H), 5.93 (m, 1H), 5.49 (m, 1H), 4.90–5.24 (m, 4H), 3.95–
4.15 (m, 5H), 3.60–3.75 (m, 2H), 3.35–3.50 (m, 1H), 3.15–3.30 (m,
1H), 1.80 (s, 3H), 1.46 (s, 3H), 1.05 (t, 1H, J¼7.2 Hz), 0.96 (t, 3H,
J¼7.2 Hz); Minor isomer (meaningful signals): 1H NMR (C6D6,
d
157.4, 137.2, 116.2, 111.1, 87.6, 75.1, 67.9, 63.9, 61.9, 44.6, 37.5, 36.1,
400 MHz, 340 K) d 5.85 (m, 1H), 5.55 (m, 1H), 4.20 (m, 1H), 3.80–
19
26.2, 25.0, 24.8, 15.2, 15.4; [
a
]
þ12.4 (c 0.7, CHCl3). Second eluted
3.90 (m, 1H), 3.55–3.60 (m, 1H); Major isomer 13C NMR (100 MHz,
C6D6, 340 K) 156.4, 153.3, 137.4, 136.7, 127.8–128.7 (5C), 116.0, 95.2,
D
diastereomer: Rf (hexanes/AcOEt 9/1)¼0.51; 1H NMR (400 MHz,
d
C6D6, 340 K)
d
5.85 (m,1H), 5.50 (m,1H), 5.04 (d,1H, J¼17.2 Hz), 4.90
86.0, 67.3, 65.7, 61.2, 61.2, 58.8, 45.9, 27.3, 24.4, 14.7, 14.6; Minor
(d, 1H, J¼10.4 Hz), 4.22 (br q, 1H, J¼6.8 Hz), 4.05 (dq, 1H, J¼13,
7.2 Hz), 4.03 (dq, 1H, J¼13, 7.2 Hz), 3.80–3.90 (m, 4H), 3.36–3.53 (m,
2H), 1.85–1.15 (10H), 1.07 (t, 3H, J¼7.2 Hz), 1.00 (t, 3H, J¼7.2 Hz); 13C
isomer (meaningful signal) 13C NMR (C6D6, 400 MHz, 340 K)
86.6, 67.1, 65.2, 64.5, 61.5, 59.2, 44.2, 27.5, 24.0.
d 94.9,
NMR (100 MHz, C6D6, 340 K)
d
157.1, 136.8, 117.0, 111.5, 87.6, 78.0,
4.2.18. (4S)-Benzyl 4-(5-allyl-4,8-dioxo-3,7,9-trioxa-5-azaundecan-
6-yl)-2,2-dimethyloxazolidine-3-carboxylate (10a0). Yield 223 mg,
(26%); Attempts to separate by chromatography the two di-
astereomers obtained as a mixture (ratio 63/37) were unsuccessful.
Rf (hexanes/AcOEt 9/1)¼0.47; IR (neat) cmꢂ1 3067, 2982, 2938,
1759, 1709, 1404, 1244, 1091, 699; ESI-HRMS: m/z calcd for
C23H32N2O7Na [MþNa]þ 487.2056 found 487.20587.
19
66.7, 64.7, 62.1, 45.1, 37.4, 36.5, 26.2, 25.0, 24.8,15.5,15.1. [
1.0, CHCl3).
a]
þ7.5 (c
D
4.2.14. ((R)-1,4-Dioxaspiro[4.5]dec-2-yl)-[(prop-2-en-1-yl-ethoxy-
carbonyl)amino]methyl ethyl carbonate (8a0). Yield 202 mg
(27%); Attempts to separate by chromatography the two di-
astereomers obtained as a mixture (50/50) were unsuccessful. Rf
(hexanes/AcOEt 9/1)¼0.42; IR (neat) cmꢂ1 2935, 1757, 1714, 1202,
1144, 925; ESI-HRMS: m/z calcd for C18H29NO7Na [MþNa]þ
394.1842 found 394.18445.
Major diastereomer: 1H NMR (400 MHz, C6D6, 340 K)
d 7.40–7.10
(m, 5H), 6.65 (d, 1H, J¼7.2 Hz), 5.95 (m, 1H), 5.23–4.92 (m, 4H), 4.36
(m, 1H), 4.15–3.75 (m, 7H), 3.71 (m, 1H), 1.78 (s, 3H), 1.44 (s, 3H),
1.04 (m, 3H), 0.97 (m, 3H); Minor diastereomer (meaningful sig-
First diastereomer: 1H NMR (400 MHz, C6D6, 340 K)
d
6.80 (d, 1H,
nals) 1H NMR (C6D6, 400 MHz, 340 K)
d
6.83 (d, 1H, J¼8.4 Hz), 5.80
(m,1H), 4.48 (m,1H), 3.62 (m, 1H),1.50 (s, 3H); Major diastereomer:
13C NMR (100 MHz, C6D6, 340 K)
155.5–153.1 (3C), 137.1, 135.7,
J¼7.6 Hz), 6.10 (ddt, 1H, J¼17.2, 10.4, 5.6 Hz), 5.29 (dq, 1H, J¼17.2,
1.6 Hz), 5.12 (dq, 1H, J¼10.4, 1.6 Hz), 4.57 (dt, 1H, J¼7.6, 5.9 Hz),
d

A. Lumbroso et al. / Tetrahedron 65 (2009) 9180–9187
9187
116.3, 95.50, 84.20, 67.40, 65.2–61.8 (3C), 58.4, 47.8, 27.5, 23.5, 14.6,
14.1; Minor diastereomer (meaningful signals) 13C NMR (C6D6,
340 K) d 157.0, 136.5, 115.7, 100.7, 100.2, 86.2, 68.8, 63.5, 63.0, 61.2,
48.5, 44.3, 47.9, 18.7, 18.4, 14.9, 14.7; Minor diastereomer (mean-
400 MHz, 340 K)
67.6, 58.6, 46.1.
d
154.5–153.1 (3C), 137.3, 135.4, 116.6, 95.3, 84.4,
ingful signals) 13C NMR (C6D6, 125 MHz, 340 K)
15.6, 15.4.
d 101.9, 70.5, 61.4,
4.2.19. Ethyl N-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-
yl(ethoxy)methyl]-N-(prop-2-en-1-yl)carbamate (11a). Yield 325 mg,
(49%); Attempts to separate by chromatography the two di-
astereomers obtained as a mixture (ratio 20/80) were unsuccessful.
Rf (hexanes/AcOEt 9/1)¼0.49; IR (neat) cmꢂ1 2978, 1705,1142, 1039,
879; ESI-HRMS: m/z calcd for C17H31NO7Na [MþNa]þ 384.1998
found 384.1998.
Acknowledgements
We thank the CNRS and the ICSN (A.L. Ph.D. fellowship), the
MESR (F.C. Ph.D. fellowship) for financial support. T.B. thanks
Milestone S.r.l. (Italy) for financial and technical support.
Major diastereomer: 1H NMR (400 MHz, C6D6, 340 K)
d 6.04 (m,
References and notes
1H), 5.35 (m, 1H), 5.18–4.90 (m, 2H), 4.16–3.98 (m, 4H), 3.83–3.68
(m, 3H), 3.49–3.40 (m, 1H), 3.28–3.18 (m, 1H), 3.11 and 3.08 (s, 6H),
1.27–1.24 (s, 6H), 1.07–0.99 (t, 3H, J¼6.8 Hz), 0.97 (t, 3H, J¼6.8 Hz);
Minor diastereomer (meaningful signals): 1H NMR (C6D6, 400 MHz,
1. (a) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, Chapter 4.5; (b) Maryanoff,
B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004,
104, 1431–1628; (c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817–3856; (d) Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun. 2009, 874–
889; (e) Yazici, A.; Pyne, S. G. Synthesis 2009, 339–368; (f) Yazici, A.; Pyne, S. G.
Synthesis 2009, 513–541.
2. Yamamoto, Y.; Nakada, T.; Nemoto, H. J. Am. Chem. Soc. 1992, 114, 121–125.
3. Esch, P. M.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1992, 48, 3445–3462.
4. (a) Dhimane, H.; Vanucci, C.; Lhommet, G. Tetrahedron Lett. 1997, 38, 1415–1418;
(b) Remuson, R. Beilstein J. Org. Chem. 2007, 3, 1–7; (c) Remuson, R.; Gelas-
Mialhe, Y. Mini-Rev. Org. Chem. 2008, 5, 193–208; (d) Veerman, J. J. N.; Bon, R.
S.; Hue, B. T. B.; Girones, D.; Rutjes, F. P. J. T.; van Maarseveen, J. H.;
Hiemstra, H. J. Org. Chem. 2003, 68, 4486–4494.
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4367–4416; (c) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701–4704;
(d) Berkheij, M.; Dijkink, J.; David, O. R. P.; Sonke, T.; IJzendoorn, D. R.; Blaauw,
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2008, 914–924; (e) Mentink, G.; van Maarseveen, J. H.; Hiemstra, H. Org. Lett.
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6. (a) Schuch, C. M.; Pilli, R. A. Tetrahedron: Asymmetry 2000, 11, 753–764;
(b) Klitzke, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605–5608; (c) Yamamoto,
Y.; Schmid, M. J. Chem. Soc., Chem. Commun. 1989, 1310–1312; (d) Marshall, J. A.;
Gill, K.; Seletsky, B. M. Angew. Chem., Int. Ed. 2000, 39, 953–956; (e) Chevallier, F.;
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Quintard, J.-P. Org. Biomol. Chem. 2004, 2, 3128–3133.
340 K)
d
5.90 (m, 1H), 5.42 (m, 1H), 3.20 (s, 3H); Major di-
156.8, 136.6, 116.0,
astereomer: 13C NMR (100 MHz, C6D6, 340 K)
d
98.6, 98.5, 86.5, 67.3, 63.7, 61.5, 61.4, 48.1, 47.6, 45.3, 17.9 (2C), 14.9
(2C); Minor diastereomer (meaningful signals): 13C NMR (C6D6,
400 MHz, 340 K) d 136.0, 116.7, 99.7, 98.4, 86.3, 69.2, 64.5, 60.6, 60.1,
45.1, 17.8 (2C), 14.6 (2C).
4.2.20. N-[(2R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxan-2-
yl][(ethoxycarbonyl)-N-(prop-2-en-1-yl)amino]methyl ethyl carbonate
(11a0). Yield 69 mg (9%); Attempts to separate by chromatography
the two diastereomers obtained as a mixture (ratio 42/58) were
unsuccessful. Rf (hexanes/AcOEt 9/1)¼0.33; IR (neat) cmꢂ1 3080,
2987, 2949, 2833, 1758, 1714, 1374, 1264, 1143, 1120, 1038, 789; ESI-
HRMS: m/z calcd for C18H31NO9Na [MþNa]þ 428.1897 found
428.1897.
Major diastereomer: 1H NMR (400 MHz, C6D6, 340 K)
d 6.55 (d,
1H, J¼6.5 Hz), 6.07 (ddt, 1H, J¼16.2, 10.3, 6.2 Hz), 5.10 (dq, 1H,
J¼16.2, 2.8, 1.2 Hz), 4.94 (m, 1H, J¼10.3, 2.8, 1.2 Hz), 4.5–4.4 (m, 1H),
4.30–3.70 (m, 7H), 3.59 (dd, 1H, J¼10.8, 3.2 Hz), 3.20–3.00 (s, 6H),
1.29–1.25 (s, 6H), 0.98 (t, 3H, J¼7.0 Hz), 0.90 (t, 3H, J¼7.2 Hz); Minor
diastereomer (meaningful signals) 1H NMR (C6D6, 400 MHz, 340 K)
7. Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409–3410.
8. Karsten, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 35, 6275–
6278.
9. Pierce, J. G.; Waller, D. L.; Wipf, P. J. Organomet. Chem. 2007, 692, 4618–4629.
10. Roy, B.; Pe´rez-Luna, A.; Ferreira, F.; Botuha, C.; Chemla, F. Tetrahedron Lett. 2008,
49, 1534–1537.
11. (a) Millot, N.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis 2000, 941–948;
(b) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497–1499.
d
6.68 (d, 1H, J¼8.5 Hz), 5.86 (ddt, 1H, J¼16.4, 10.4, 6.0 Hz), 5.2 (dq,
1H, J¼16.4, 3.2, 1.6 Hz), 5.02 (m, 1H, J¼10.4, 2.8, 1.2 Hz), 3.47 (dd,1H,
J¼12, 3.2 Hz), 1.0 (t, 3H, J¼6.8 Hz), 0.91 (t, 3H, J¼7.2 Hz); Major di-
astereomer: 13C NMR (100 MHz, C6D6, 340 K)
d 154.8–156.3 (2C),
12. Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60, 5011–5015.
13. For a recent book see:Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH GmbH & KGaA: Weinheim, 2006.
135.6, 117.8, 99.0–100.4 (2C), 84.7, 68.6, 60.4–64.8 (3C), 47.6–48.6
(3C), 18.3–18.5 (2C), 14.6–15.0 (2C); Minor diastereomer, mean-
ingful signals 13C NMR (C6D6, 400 MHz, 340 K):
67.8, 60.4–64.8 (3C).
d 136.4, 116.9, 84.8,
14. Detailed description, pictures and applications of this novel reactor system are
available at www.milestonesrl.com and were recently published in: Leadbeater,
N. E.; Schmink, J. R. Tetrahedron 2007, 63, 6764–6773.
15. It has to be noted that DEPC was checked by 1H NMR after receiving from
ACROS and the spectrum already exhibits some decomposition.
4.2.21. Ethyl N-[(2S,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-
yl(ethoxy)methyl]-N-(prop-2-en-1-yl)carbamate (12a). Yield 206 mg,
(60%); Attempts to separate by chromatography the two di-
astereomers obtained as a mixture (ratio 93/7) were unsuccessful.
Rf (hexanes/AcOEt 9/1)¼0.36; IR (neat) cmꢂ1 3079, 2978, 2833,
1706, 1374, 1249, 1117, 947, 877, 774. ESI-MS: m/z 745.4 [2MþNa]þ,
384.2 [MþNa]þ.
16. In
a a complete de-
control experiment, we have observed by 1H NMR
composition of DEPC when heated during 1 h in the sealed vial and under the
reaction conditions in C6D6. No decomposition products could be however
identified.
17. (a) Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T.
Tetrahedron Lett. 2008, 49, 7033–7036; (b) Me´sangeau, C.; Yous, S.; Pe´re`s, B.;
Lesieur, D.; Besson, T. Tetrahedron Lett. 2005, 46, 2465–2468; (c) Wan, Y.;
Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67, 6232–6235.
18. (a) Ley, S. V.; Michel, P. Synthesis 2004, 147–150; (b) Michel, P.; Ley, S. V. Syn-
thesis 2003, 1598–1602.
Major diastereomer: 1H NMR (500 MHz, C6D6, 340 K)
d 6.40 (m,
1H), 5.73–5.54 (m, 1H), 5.16 (br d, 1H, J¼16.5 Hz), 5.02 (br d, 1H,
J¼10.0 Hz), 4.19–3.70 (m, 7H), 3.51–3.40 (m, 1H), 3.36–3.20 (m, 4H),
3.16 (s, 3H), 1.36 (s, 3H),1.33 (s, 3H), 1.04 (br t, 3H, J¼7.0 Hz), 0.96 (br
t, 3H, J¼7.0 Hz); no meaningful signals for the minor diastereomer
has be identified from the mixture; 13C NMR (125 MHz, C6D6,
19. Marshall, J. A.; Beaudoin, S. J. Org. Chem. 1996, 61, 581–586.
20. (a) Yin, H.; Franck, R. W.; Chen, S. L.; Quigley, G. J.; Todaro, L. J. Org. Chem. 1992,
57, 644–651; (b) Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F. Synthesis
1989, 64–65.
21. (a) Xia, J.; Hui, Y.-Z. Tetrahedron: Asymmetry 1997, 8, 451–458; (b) van Boeckel,
C. A. A.; Visser, G. M.; van Boom, J. H. Tetrahedron 1985, 41, 4557–4565.