Synthesis of (E)-α-hydroxy-β,γ-unsaturated amides with high selectivity from α,β-epoxyamides by using catalytic samarium diiodide or triiodide

Article abstract of DOI:10.1002/chem.200305375

The highly stereoselective synthesis of (E)-α-hydroxy-β,γ- unsaturated amides starting from α,β-epoxyamides, by using catalytic SmI₂ or SmI₃, was achieved. This transformation can also be carried out by using SmI₂ generate

Full text of DOI:10.1002/chem.200305375

FULL PAPER
Synthesis of (E)-a-Hydroxy-b,g-Unsaturated Amides with High Selectivity
from a,b-Epoxyamides by Using Catalytic Samarium Diiodide or Triiodide
Josÿ M. ConcellÛn,* Pablo L. Bernad, and Eva Bardales[a]
Abstract: The highly stereoselective
synthesis of (E)-a-hydroxy-b,g-unsatu-
rated amides starting from a,b-epoxy-
amides, by using catalytic SmI2 or
SmI3, was achieved. This transforma-
tion can also be carried out by using
SmI2 generated in situ from samarium
powder and diiodomethane. The start-
ing compounds 1 are easily prepared
by the reaction of enolates derived
from a-chloroamides with ketones at
À788C. A mechanism to explain this
transformation has been proposed. Cy-
clopropanation of (E)-a-hydroxy-b,g-
unsaturated amides has been per-
formed to demonstrate their synthetic
applications.
Keywords: amides
¥ homogenous
catalysis ¥ isomerization ¥ samarium
Introduction
droxy-b,g-unsaturated amides starting from readily available
a,b-epoxyamides 1, in which the oxirane ring is tetra- or tri-
substituted, by using catalytic amounts of SmI2 or SmI3. This
transformation can also be carried out by using catalytic
amounts of SmI2 generated in situ from a mixture of samari-
um powder and diiodomethane. The new C=C double bond
is generated with high to total regio- and E stereoselectivity.
A mechanism has been proposed to explain this transforma-
tion. Finally, one example of cyclopropanation of the ob-
tained a-hydroxy-b,g-unsaturated amides, has also been per-
formed to demonstrate their synthetic applications.
The isomerisation of oxiranes[1] to allylic alcohols is a valua-
ble transformation in organic synthesis and has been accom-
plished by a variety of reagents including 1) organoselenium
compounds,[2] 2) dialkylaluminum amides,[3] 3) alkylboron
trifluoromethanesulfonates,[4] 4) silyl iodides,[5] 5) boron tri-
fluoride etherate[6] and 6) various dialkylamides.[7] These re-
agents have their own limitations, including poor yields or
diastereoselectivity, and failure to react with certain types of
oxiranes. However, transformations of a,b-epoxycarbonyl
compounds into a-hydroxy-b,g-unsaturated carbonyl com-
pounds have been very scarcely reported, and in these cases
the C=C bond is generated with low diastereoselectivity.[8]
In addition to the best of our knowledge, no transformation
of oxiranes into allylic alcohols, with catalytic SmI2 or SmI3
has been described, and only two examples of the synthesis
of a-hydroxy-b,g-unsaturated amides have been reported.[9]
On the other hand, a-hydroxyamides show synthetic po-
tential,[10] and some possess anticancer properties.[11] More-
over, the allylic alcohol moiety is an important building
block in organic synthesis.[12] For these reasons, synthesis of
a-hydroxy-b,g-unsaturated amides[13] are of much interest.
We recently reported a new methodology to obtain aro-
matic a-hydroxyamides from a,b-epoxyamides,[14] and a,b-
unsaturated esters from a,b-epoxy esters[15] by using samari-
um diiodide. We describe a novel synthesis of (E)-a-hy-
Results and Discussion
Preparation of (E)-a-hydroxy-b,g-unsaturated amides by
using catalytic samarium diiodide or triiodide: The reaction
was first attempted with 2.5 equivalents of SmI2 in THF at
room temperature (RT). Treatment of aromatic a,b-epoxy-
amides in which the oxirane ring is tri- or tetrasubstituted,
with 2.5 equivalents of SmI2 in THF,[16] gave a mixture of
(E)-a-hydroxy-b,g-unsaturated amides and a,b-unsaturated
amides.[17] When lower amounts of SmI2 were used, higher
yields of (E)-a-hydroxy-b,g-unsaturated amides were ob-
tained, and consequently the yield of a,b-unsaturated
amides decreased. Thus, treatment of a,b-epoxyamides with
0.5 equivalents of SmI2 in THF at RT gave (E)-a-hydroxy-
b,g-unsaturated amides as the only product, in high yield,
and generated the C=C double bond with high diastereose-
lectivity (Scheme 1 and Table 1). When the amount of SmI2
was decreased to 0.2 equivalents, similar results were ach-
ieved.[18]
[a] Dr. J. M. ConcellÛn, Dr. P. L. Bernad, Dr. E. Bardales
Departamento de QuÌmica Orgµnica e Inorgµnica
Facultad de QuÌmica, Universidad de Oviedo
E-33071 Oviedo (Spain)
Tri- or tetrasubstituted a,b-epoxyamides 1 were prepared
by reacting the lithium enolate of chloroamides (generated
Fax : (+34)98-510-3446
E-mail: jmcg@sauron.quimica.uniovi.es
2445
Chem. Eur. J. 2004, 10, 2445 2450
DOI: 10.1002/chem.200305375
¹ 2004Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

FULL PAPER
Table 1. Synthesis of (E)-a-hydroxy-b,g-unsaturated amides 2.
Entry[a]
2
R1
R2
R3
R4
t [h]
T [8C]
de [%][b]
Yield [%][c]
1
2
3
2a
2b
2b
2b
2b
H
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
iPr
iPr
iPr
iPr
iPr
2
25
25
À25
À50
À78
91
76
74
74
74
Et
Et
Et
Et
0.166
47
66
71
80
0.166
0.166
2
4
5[d]
6
2c
H
Et
2
25
84
7
8
9
2d
2e
2 f
2g
2h
2i
H
Ph
Et
Ph
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
2
2
2
12
2
25
25
25
67
82
71
42
86
45
Me
Me
allyl
>98
>98
>98
10[e]
11
12[e]
À50
-(CH2)4-
Me
25
C5H11
12
À50
>98
[a] Unless otherwise noted, reactions were carried out with 0.5 equivalents of SmI2. [b] Diastereoisomeric excess (de) was determined by GC-MS, and
300 MHz 1H and 13C NMR analysis of the crude products. [c] Isolated yield after column chromatography based on compound 1. [d] The reaction was
carried out with 1 equivalent of SmI2. [e] The reaction was carried out with 2 equivalents of SmI2.
place starting from tetrasubstituted a,b-epoxyamides with
R1 =Ph and R4 =iPr (R2 =Me and Et, R3 =Me), and the
starting compound 1 was recovered.
The diastereoisomeric excess of the generated C=C
double bond was determined on the crude reaction products
by GC-MS and 1H NMR spectroscopy, and the E stereo-
chemistry of the b,g-unsaturated amides 2 was assigned by
NOESY experiments on products 2e and 2 f. The stereo-
chemistry of the other compounds 2 was assigned by analo-
gy.
Scheme 1. Synthesis of (E)-a-hydroxy-b,g-unsaturated amides 2.
by treatment of a-chloroamides with lithium diisopropyl-
amide at À858C) with different ketones at À788C, and
warming the reaction mixture to RT (Scheme 2).
The same isomerisation reaction from a,b-epoxyesters, by
using SmI2, was not observed and a,b-unsaturated esters
Better diastereoselectivity was obtained when starting
from tetrasubstituted rather than trisubstituted a,b-epoxy-
amides. In this case, higher diastereoselectivity was obtained
at lower temperatures (Table 1, entries 2 5). It is worth
noting that although 1:1 mixtures of diastereoisomers of
starting compounds 1 were used in these reactions, the
double bonds of amides 2 were obtained with high or total
E stereoselectivity.
Scheme 2. Synthesis of a,b-epoxyamides 1.
When R1 and R2 in the epoxyamides 1 have hydrogen
atoms at Cg what can be eliminated, two regioisomers a-hy-
droxy-b,g-unsaturated amides are possible. For this reason,
the regioselectivity of the reaction was also studied. Thus,
when an internal or terminal C=C double bond could be
generated, the reaction led to an internal thermodynamical-
ly more stable alkene as the major product (Table 2).
Higher regioselectivity was also obtained at lower tempera-
tures (Table 2). The regioselectivity of the reactions from 1g
and 1i and the structure of the major product were deter-
mined by NMR spectroscopy.
The reaction of epoxyamides at low temperature (À508C
or À788C) was carried out using higher amounts of SmI2
(see Table 1, entries 5, 10 and 12, and Table 2, entries 2, 3
and 5) as very long reaction times were necessary when
using lower amounts of SmI2. The reaction time in the case
of tetrasubstituted epoxyamides at low temperatures was
longer than those from trisubstituted epoxyamides (Table 1,
entries 4and 10), probably due to steric hindrance.
were isolated instead of the corresponding a-hydroxy-b,g-
unsaturated esters.[15] In the case of a,b-epoxyamides the re-
action seems to be general and a-hydroxy-b,g-unsaturated
amides 2 can be obtained from tri- or tetrasubstituted a,b-
epoxyamides[19] with the oxirane ring bearing aliphatic or ar-
omatic substituents (Table 1). However, no reaction took
Abstract in Spanish: Se describe la sÌntesis con alta estereose-
lectividad de (E)-a-hidroxiamidas-b,g-insaturadas a partir de
a,b-epoxiamidas, mediante el empleo de diyoduro o triyodu-
ro de samario catalÌtico. Esta transformaciÛn se puede llevar
a cabo con diyoduro de samario generado in situ a partir de
samario en polvo y diyodometano. Los productos de partida
1 son fµcilmente preparados por tratamiento de a-cloroami-
das con cetonas a À788C. Se propone un mecanismo para ex-
plicar el proceso. Se ha llevado a cabo la ciclopropanaciÛn
de (E)-a-hidroxiamidas-b,g-insaturadas para demostrar sus
aplicaciones sintÿticas.
The transformation of epoxyamides 1 into 2 can also be
carried out with SmI3, instead of SmI2, and similar yields
2446
¹ 2004Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2445 2450

(E)-a-Hydroxy-b,g-Unsaturated Amides
2445 2450
Table 2. Regioselectivity of the synthesis of (E)-a-hydroxy-b,g-unsaturated amides 2 (R2 =R3 =Me, R4 =Et).
mixture of Sm and CH2I2 by
using a stereospecific methodol-
Entry[a]
2
R1
t [h]
T [8C]
Ratio[b]
de [%][c]
Yield [%][d]
ogy
previously
described
1
2g
2g
2i
2i
2i
allyl
allyl
C5H11
C5H11
C5H11
0.5
12
12
0.5
48
25
1:1
5:1
5:1
1:1
3:1
>98
>98
>98
>98
>98
54
42
45
61
61
2[e]
3[e]
4
À50
À50
25
À25
(Scheme 3).[25]
Mechanism: The synthesis of
product 2 could be explained
(Scheme 4) by assuming that it
is produced by catalytic SmI3.[26]
Thus, the reaction is initiated
by the coordination of samari-
5[f]
[a] Unless otherwise noted, reactions were carried out with 0.5 equivalents of SmI2. [b] Ratio of internal/termi-
nal C=C double bonds Determined by 300 MHz 1H and 13C NMR analysis of the crude products. [c] Diaster-
eoisomeric excess (de) determined by GC-MS, and 300 MHz 1H and 13C NMR analysis of the crude products.
[d] Isolated yield after column chromatography based on compound 1. [e] The reaction was carried out with
2 equivalents of SmI2. [f] The reaction was carried out with 1 equivalent of SmI2.
were obtained. However, SmI2 is preferred because cleaner
products 2 are obtained. Probably, the lower solubility of
SmI3 in THF relative to that of SmI2 could explain this
result (see below in the section on the mechanism).
Scheme 3. Cyclopropanation of compound 2e.
Synthesis of (E)-a-hydroxy-b,g-unsaturated amides by using
samarium diiodide generated in situ: A limitation of the
synthetic applications of SmI2 is its high sensitivity to oxida-
tion by air that requires careful manipulation and storage.
For these reasons, the use of the cheaper and more stable
metallic samarium is more desirable. Thus, SmI2 can be pre-
pared in situ (for example, from diiodomethane and powder
metallic samarium) in the presence of the starting organic
compound,[20] and the total reaction time (generation of
SmI2 + reaction of SmI2) is then shorter than that obtained
by using pre-formed SmI2.
For this reason, an easier and simpler methodology to
prepare (E)-a-hydroxy-b,g-unsaturated amides has been de-
veloped, by using SmI2 generated in situ from a mixture of
metallic Sm and diiodomethane. Results in Table 3 show
that similar yields and diastereoisomer excess were obtained
using this methodology.
Scheme 4. Mechanistic proposal for the synthesis of (E)-a-hydroxy-b,g-
unsaturated amides.
Table 3. Synthesis of (E)-a-hydroxy-b,g-unsaturated amides 2 by using SmI2 generated in situ.
um with both oxygen atoms of
1. The coordination of samari-
um with the oxirane ring produ-
ces a similar effect to that of a
Lewis acid, and facilitates its
opening. This initial chelation is
favoured by the electron-donat-
ing capacity of the nitrogen
atom and could explain the ab-
sence of isomerisation of a,b-
epoxyesters. An abstraction of
a proton bonded to a Cg atom,
by a base (for example alkoxy-
Entry[a]
2
R1
R2
R3
R4
de [%][b]
Yield [%][c]
69
1
2a
H
Ph
H
iPr
2
2c
H
Et
85
3
4
5
2d
2e
2 f
H
Me
Me
Ph
Et
Ph
Me
Me
Me
Et
Et
Et
72
82
68
>98
>98
[a] Reactions were carried out with 0.5 equivalents of SmI2 at 258C for 2 h. [b] Diastereoisomeric excess (de)
determined by GC-MS, and 300 MHz 1H and 13C NMR analysis of the crude products. [c] Isolated yield after
column chromatography based on compound 1.
Functional groups of compounds 2 have very different re-
activities, and consequently they can be transformed selec-
tively into other products. To illustrate this potential, com-
pound 2e was cyclopropanated owing to the properties,[21]
synthetic usefulness,[22] and applications in mechanistic stud-
ies[23] of the cyclopropyl group. Moreover, cyclopropane de-
rivatives with hydroxy and carboxyl functionalities have im-
portant biological effects.[24] Thus, cyclopropanation of the
C=C double bond of 2e was carried out in 71% yield with a
samarium species), produces the oxirane ring-opening, af-
fording 4. Tentatively, we propose an anti-elimination pro-
cess of a proton from the Cg position resulting in the two
possible transition states I and II (Scheme 4, and Figure 1).
Transition state I would be preferred due to the lack of
steric hindrance between the R1 and CR3OCONR4 groups.
2
Elimination from I affords a trisubstituted (E)-a-hydroxy-
b,g-unsaturated amide 2. A product-like transition state
could justify the preferential formation of the more thermo-
2447
Chem. Eur. J. 2004, 10, 2445 2450
www.chemeurj.org
¹ 2004Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. M. ConcellÛn et al.
FULL PAPER
analysis calcd (%) for C16H23NO2: C 73.53, H 8.87, N 5.36; found: C
73.47, H 8.79, N 5.38.
2,3-Epoxy-N,N-diisopropyl-3-phenylhexanamide
(1b):
1H NMR
(200 MHz, CDCl3): d=7.28 7.01 (m, 5H), 4.04 3.90 (m, 1H), 3.45 (s,
1H), 3.04 2.89 (m, 1H), 2.31 1.02 (m, 4H), 0.96 (d, J=6.7 Hz, 3H), 0.95
(t, J=6.7 Hz, 3H), 0.83 0.72 ppm (m, 9H); 13C NMR (50 MHz, CDCl3):
d=163.7 (C), 135.7 (C), 127.1 (CH), 126.9 (CH), 126.3 (CH), 65.0 (C),
62.1 (CH), 47.2 (CH), 44.9 (CH), 37.5 (CH2), 20.2 (CH3), 19.4(CH ), 19.1
3
Figure 1. Proposed transition states.
(CH3), 17.4(CH ), 13.4ppm (CH 3); IR (neat): n˜ =2968, 1648, 1446, 1371,
2
1043 cmÀ1; Rf =0.3 (hexane/AcOEt 3:1); elemental analysis calcd (%) for
C18H27NO2: C 74.70, H 9.40, N 4.84; found: C 74.61, H 9.31, N 4.79.
dynamically stable product containing the C=C double bond
in an internal position.
N,N-Diethyl-1,2,3,4-tetrahydronaphtalene-1-spiro-2’-oxirane-3’-carbox-
amide (1c): 1H NMR (200 MHz, CDCl3): d=7.31 6.99 (m, 4H), 3.70 (s,
1H), 3.67 3.00 (m, 4H), 2.99 1.82 (m, 6H), 1.23 1.05 ppm (m, 6H);
13C NMR (50 MHz, CDCl3): d=164.3 (C), 138.4 (C), 135.2 (C), 127.8
(CH), 127.1 (CH), 125.5 (CH), 122.5 (CH), 63.5 (CH), 59.7 (C), 40.2
(CH2), 38.9 (CH2), 28.4(CH 2), 26.5 (CH2), 20.8 (CH2), 13.4(CH 3),
12.0 ppm (CH3); IR (neat): n˜ =2935, 1639, 1460, 1381, 1077 cmÀ1; Rf =0.4
(hexane/AcOEt 1:1); elemental analysis calcd (%) for C16H21NO2: C
74.10, H 8.16, N 5.40; found: C 74.18, H 8.13, N 5.46.
Conclusion
We have described a simple and general methodology to
obtain (E)-a-hydroxy-b,g-unsaturated amides by treatment
of tri- or tetrasubstituted a,b-epoxyamides with catalytic
SmI2 or SmI3. These elimination reactions proceed with
total or high diastereoselectity and regioselectivity, and a
mechanism to explain these results has been proposed. This
isomerisation reaction can also be carried out by using SmI2
generated in situ. Cyclopropanation of the b,g-unsaturated
amides has also been carried out to illustrate their synthetic
applications.
2,3-Epoxy-N,N-diethyl-2-methyl-3-phenylbutanamide (1d): The data
were in agreement with those given in reference [17a].
1
2,3-Epoxy-N,N,3-triethyl-2-methylpentanamide (1e): H NMR (200 MHz,
CDCl3): d=3.66 3.26 (m, 4H), 1.83 1.27 (m, 4H), 1.51 (s, 3H), 1.17 (t,
J=7.2 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H), 0.99 (t, J=7.4Hz, 3H), 0.98 ppm
(t, J=7.4Hz, 3H); 13C NMR (75 MHz, CDCl3): d=169.3 (C), 67.7 (C),
66.0 (C), 40.9 (CH2), 39.2 (CH2), 24.8 (CH2), 21.6 (CH2), 16.6 (CH3), 13.7
(CH3), 12.0 (CH3), 8.6 (CH3), 8.2 ppm (CH3); IR (neat): n˜ =2972, 1637,
1462, 1380, 1113 cmÀ1; Rf =0.5 (hexane/AcOEt 1:1); elemental analysis
calcd (%) for C12H23NO2: C 67.57, H 10.87, N 6.57; found: C 65.65, H
10.80, N 6.49.
2,3-Epoxy-N,N-diethyl-2-methyl-3-phenylpentanamide (1 f): The data
were in agreement with those given in reference [17a].
Experimental Section
2,3-Epoxy-N,N-diethyl-2,3-dimethylhep-6-enamide (1 g): Data on a 50:50
mixture of diastereoisomers: 1H NMR (300 MHz, CDCl3): d=5.95 5.75
(m, 2H), 5.11 4.94 (m, 4H), 3.67 3.27 (m, 8H) 2.47 2.09 (m, 4H), 1.83
1.42 (m, 4H), 1.54 (s, 6H), 1.36 (s, 3H), 1.27 (s, 3H), 1.21 (t, J=7.0 Hz,
6H), 1.14(t, J=7.0 Hz, 3H), 1.13 ppm (t, J=7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=169.3 (2C), 137.6 (CH), 137.1 (CH), 114.5 (CH2),
113.9 (CH2), 65.4 (C), 65.2 (C), 64.0 (C), 63.8 (C), 41.2 (CH2), 41.0
(CH2), 39.5 (CH2), 39.2 (CH2), 35.2 (CH2), 32.3 (CH2), 29.0 (CH2), 28.6
(CH2), 19.6 (CH3), 16.9 (CH3), 16.6 (CH3), 16.3 (CH3), 13.8 (CH3), 13.7
General: Reactions requiring an inert atmosphere were conducted under
dry nitrogen, and the glassware was oven dried at 1208C. THF was distil-
led from sodium/benzophenone immediately prior to use. All reagents
were purchased from Aldrich or Merck and were used without further
purification. Samarium diiodide was prepared by reaction of CH2I2 with
samarium powder.[16] Silica gel for flash chromatography was purchased
from Merck (200î450 mesh), and compounds were visualised on analyti-
cal thin-layer chromatograms (TLC) by UV light (254nm). 1H NMR
spectra were recorded at 200 or 300 MHz. 13C NMR spectra and DEPT
experiments were determined at 50 or 75 MHz. Chemical shifts are given
in ppm relative to tetramethylsilane (TMS), which was used as an inter-
nal standard, and coupling constants (J) are reported in Hz. GC-MS and
HRMS were measured at 70 eV or by using FAB conditions. When
HRMS could not be measured on molecular ion the HRMS of a signifi-
(CH3), 12.1 ppm (2CH3); IR (neat): n˜ =2973, 1636, 1458, 1382, 1114 cmÀ1
;
Rf =0.3 (hexane/AcOEt 3:1); elemental analysis calcd (%) for
C13H23NO2: C 69.29, H 10.29, N 6.22; found: C 69.20, H 10.33, N 6.18.
N,N-Diethyl-2-methyl-1-oxaspiro[2.5]octane-2-carboxamide
(1h):
1H NMR (200 MHz, CDCl3): d=3.55 2.98 (m, 4H), 1.68 1.10 (m, 10H),
1.34(s, 3H), 1.02 (t, J=7.2 Hz, 3H), 0.95 ppm (t, J=7.2 Hz, 3H);
13C NMR (50 MHz, CDCl3): d=169.4(C), 65.9 (C), 65.7 (C), 41.1 (CH 2),
39.3 (CH2), 32.5 (CH2), 29.3 (CH2), 25.0 (CH2), 24.2 (CH2), 23.8 (CH2),
16.2 (CH3), 13.9 (CH3), 12.2 ppm (CH3); IR (neat): n˜ =2934, 1638, 1485,
1380, 1081 cmÀ1; Rf =0.4(hexane/AcOEt 1:1); elemental analysis calcd
(%) for C13H23NO2: C 69.29, H 10.29, N 6.22; found: C 69.37, H 10.35, N
6.21.
cant fragment is given. Only the most important IR absortions (cmÀ1
and the molecular ions and/or base peaks in MS are given.
)
General procedure for the synthesis of 2,3-epoxyamides (1): Lithium dii-
sopropylamide [prepared from MeLi (3.2 mL of 1.5m solution in diethyl
ether, 5 mmol) and diisopropylamine (0.8 mL, 5 mmol) in THF 25 mL at
08C] was added dropwise to a À788C stirred solution of the correspond-
ing 2-haloamide (4.5 mmol) in dry THF (4 mL). After stirring for 10 min,
a solution of the corresponding ketone (3.5 mmol) in dry THF (4.5 mL)
was added dropwise at À788C and the mixture was allowed to warm to
RT. The resulting solution was quenched with a saturated aqueous solu-
2,3-Epoxy-N,N-diethyl-2,3-dimethylnonanamide (1i): Data on
a 50:50
mixture of diastereoisomers: 1H NMR (200 MHz, CDCl3): d=3.62 3.18
(m, 8H), 1.60 1.37 (m, 26H), 1.47 (s, 6H), 1.26 (s, 6H), 1.07 (t, J=
7.0 Hz, 6H), 0.81 ppm (t, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d=169.7 (2C), 65.7 (C), 65.5 (C), 64.8 (C), 64.6 (C), 41.4 (CH2), 41.2
(CH2), 39.6 (CH2), 39.4(CH 2), 36.0 (2CH2), 31.4(CH 2), 31.3 (CH2), 29.3
(CH2), 29.1 (CH2), 25.0 (CH2), 24.5 (CH2), 22.3 (2CH2), 17.2 (CH3), 16.8
(CH3), 16.5 (CH3), 15.8 (CH3), 14.1 (CH3), 13.8 (CH3), 12.4(2CH 3),
12.0 ppm (2CH3); IR (neat): n˜ =2931, 1640, 1462, 1380, 1082 cmÀ1; Rf =
0.3 (hexane/AcOEt 3:1); elemental analysis calcd (%) for C15H29NO2: C
70.54, H 11.45, N 5.48; found: C 70.49, H 11.36, N 5.41.
tion of NH4Cl (20 mL). Crude 2,3-epoxyamides
column flash chromatography over silica gel (hexane/ethyl acetate) elut-
ing compound 1 as a mixture of cis/trans diastereoisomers.
1 were purified by
2,3-Epoxy-N,N-diisopropyl-3-phenylbutanamide
(1a):
1H NMR
(200 MHz, CDCl3): d=7.23 6.96 (m, 5H), 3.87 3.74(m, 1H), 3.04 (s,
1H), 2.97 2.84(m, 1H), 1.59 (s, 3H), 0.98 (d, J=6.7 Hz, 3H), 0.92 (d,
J=6.4Hz, 3H), 0.75 (d, J=6.7 Hz, 3H), 0.60 ppm (d, J=6.4Hz, 3H);
13C NMR (50 MHz, CDCl3): d=163.3 (C), 136.8 (C), 127.1 (CH), 127.0
(CH), 125.7 (CH), 63.3 (CH), 61.6 (C), 47.2 (CH), 44.7 (CH), 22.0 (CH3),
20.2 (CH3), 20.0 (CH3), 19.3 (CH3), 19.1 ppm (CH3); IR (neat): n˜ =2967,
1644, 1444, 1335, 1045 cmÀ1; Rf =0.2 (hexane/AcOEt 3:1); elemental
General procedure for the synthesis of (E)-a-hydroxy-b,g-unsaturated
amides (2): A solution of SmI2 (0.2 mmol) in THF (2.5 mL) was added,
under a nitrogen atmosphere, to a stirred solution of a,b-epoxyamide 1
(0.4mmol) in THF (2 mL) at 25 8C. When the reaction was carried out
by using in situ generated SmI2 (Table 1), CH2I2 (0.016 mL, 0.2 mmol)
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¹ 2004Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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(E)-a-Hydroxy-b,g-Unsaturated Amides
2445 2450
was added to a stirred solution of a,b-epoxyamide 1 (0.4mmol) and sa-
marium powder (0.034g, 0.23 mmol) in THF (2.4mL). The mixture was
stirred for 2 h at 258C, then quenched with aqueous HCl (0.1m, 15 mL)
and extracted with CH2Cl2 (3î5 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated in a vacuum affording the
crude (E)-a-hydroxy-b,g-unsaturated amides 2, which were then purified
by flash column chromatography on silica gel (hexane/AcOEt).
1H), 5.40 (br, 1H), 3.84 2.86 (m, 4H), 1.57 (d, J=6.9 Hz, 3H), 1.55 (s,
3H), 1.15 (t, J=7.0 Hz, 3H), 0.74ppm (t, J=7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=173.7 (C), 143.1 (C), 137.1 (C), 129.1 (CH), 127.6
(CH), 126.9 (CH), 123.1 (CH), 75.3 (C), 41.5 (CH2), 40.3 (CH2), 24.4
(CH3), 14.7 (CH3), 13.4(CH 3), 11.2 ppm (CH3); HMS (70 eV): m/z (%):
261 [M+] (<1), 244 (8), 161 (100), 117 (23), 100 (24); IR (neat): n˜ =3340,
1623, 1442 cmÀ1; Rf =0.3 (hexane/AcOEt 3:1); elemental analysis calcd
(%) for C16H23NO2: C 73.53, H 8.87, N 5.36; found: C 73.81, H 8.95, N
5.41.
N,N-Diisopropyl-2-hydroxy-3-phenylbut-3-enamide
(2a):
1H NMR
(300 MHz, CDCl3): d=7.58 7.28 (m, 5H), 5.52 (br, 1H), 5.26 (s, 1H),
4.99 4.96 (m, 1H), 4.88 4.85 (m, 1H), 3.77 3.64 (m, 1H), 3.48 3.35 (m,
1H), 1.46 (d, J=6.9 Hz, 3H), 1.36 (d, J=6.9 Hz, 3H), 1.13 (d, J=6.7 Hz,
3H), 1.03 ppm (d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=170.2
(C), 147.6 (C), 139.0 (C), 128.3 (CH), 127.9 (CH), 126.3 (CH), 115.7
(CH2), 71.4 (CH), 47.9 (CH), 46.2 (CH), 20.5 (CH3), 20.3 (CH3), 19.5
(CH3), 18.9 ppm (CH3); HMS (70 eV): m/z (%): 261 [M+] (<1), 244
(49), 128 (86), 86 (100), 44 (77); HRMS calcd for C16H23NO2: 261.1729;
found: 261.1729; IR (neat): n˜ =3396, 1639, 1446 cmÀ1; Rf =0.2 (hexane/
AcOEt 3:1); elemental analysis calcd (%) for C16H23NO2: C 73.53, H
8.87, N 5,36; found: C 73.21, H 8.91, N 5,41.
(E)-N,N-Diisopropyl-2-hydroxy-3-phenylhex-3-enamide (2b): 1H NMR
(200 MHz, CDCl3): d=7.41 7.23 (m, 5H), 5.85 (t, J=7.4Hz, 1H), 5.11
(s, 1H), 5.08 (br, 1H), 3.88 3.75 (m, 1H), 3.36 3.22 (m, 1H), 2.46 2.30
(m, 2H), 1.40 (d, J=6.7 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H), 1.11 (d, J=
6.7 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 1.00 ppm (d, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=170.7 (C), 140.5 (C), 138.0 (C), 136.7
(CH), 127.8 (CH), 127.1 (CH), 127.0 (CH), 68.4 (CH), 47.5 (CH), 46.2
(CH), 21.4(CH 2), 20.8 (CH3), 20.4(CH 3), 19.3 (2CH3), 13.9 ppm (CH3);
HMS (70 eV): m/z (%): 289 [M+] (<1), 272 (100), 128 (95), 77 (28);
HRMS calcd for C18H27NO2: 289.2042; found: 289.2160; IR (neat): n˜ =
3358, 1633, 1446 cmÀ1; Rf =0.4(hexane/AcOEt 3:1); elemental analysis
calcd (%) for C18H27NO2: C 74.70, H 9.40, N 4.84; found: C 74.99, H
9.46, N 4,77.
(E)-N,N-Diethyl-2-hydroxy-2,3-dimethylhepta-3,6-dienamide
(2g):
1H NMR (200 MHz, CDCl3): d=5.91 5.74(m, 1H), 5.61 (t, J=7.2 Hz,
1H), 5.33 (br, 1H), 5.09 4.93 (m, 2H), 3.57 3.27 (m, 4H), 2.88 2.82 (m,
2H), 1.59 (s, 3H), 1.54(s, 3H), 1.18 1.06 ppm (m, 6H); 13C NMR
(50 MHz, CDCl3): d=170.4(C), 137.8 (C), 136.0 (CH), 123.1 (CH), 115.1
(CH2), 75.6 (C), 41.5 (CH2), 41.0 (CH2), 32.2 (CH2), 23.5 (CH3), 13.5
(CH3), 12.7 (CH3), 12.2 ppm (CH3); HMS (70 eV): m/z (%): 225 [M+]
(<1), 208 (4), 184 (15), 125 (96), 100 (59); HRMS calcd for C13H23NO2:
225.1729; found: 225.1749; IR (neat): n˜ =3385, 1622 cmÀ1
; Rf =0.3
(hexane/AcOEt 3:1); elemental analysis calcd (%) for C13H23NO2: C
69.29, H 10.29, N 6.22; Found: C 68.98, H 10.18, N 6.34.
2-(Cyclohex-1-en-1-yl)-N,N-diethyl-2-hydroxypropanamide
(2h):
1H NMR (200 MHz, CDCl3): d=6.86 5.98 (m, 1H), 5.26 (br, 1H), 3.54
3.17 (m, 4H), 2.03 1.49 (m, 8H), 1.45 (s, 3H), 1.08 ppm (t, J=7.0 Hz,
6H); 13C NMR (75 MHz, CDCl3): d=173.7 (C), 138.8 (C), 122.3 (CH),
74.5 (C), 41.1 (CH2), 40.6 (CH2), 24.7 (CH2), 23.5 (CH2), 23.1 (CH3), 22.1
(CH2), 21.6 (CH2), 13.2 (CH3), 11.9 ppm (CH3); MS (70 eV): m/z (%):
225 [M+] (<1), 208 (5), 125 (100), 100 (51); HRMS calcd for C13H23NO2;
225.1729; found: 225.1759; IR (neat): n˜ =3364, 1621, 1446 cmÀ1; Rf =0.3
(hexane/AcOEt 3:1); elemental analysis calcd (%) for C13H23NO2: C
69.29, H 10.29, N 6.22; found: C 69.40, H 10.18, N 6.41.
(E)-N,N-Diethyl-2-hydroxy-2,3-dimethylnon-3-enamide (2i): 1H NMR
(200 MHz, CDCl3): d=5.57 (t, J=6.6 Hz, 1H), 5.27 (br, 1H), 3.53 3.20
(m, 4H), 2.09 1.99 (m, 2H), 1.54 (s, 3H), 1.49 (s, 3H), 1.47 0.78 ppm (m,
15H); 13C NMR (75 MHz, CDCl3): d=174.0 (C), 136.2 (C), 126.0 (CH),
75.5 (C), 41.3 (CH2), 40.8 (CH2), 31.5 (CH2), 28.7 (CH2), 27.7 (CH2), 23.5
(CH3), 22.3 (CH2), 13.8 (CH3), 13.4(CH 3), 12.5 (CH3), 12.1 ppm (CH3);
HMS (70 eV): m/z (%): 255 [M+] (<1), 238 (4), 155 (67), 100 (35), 57
(28); IR (neat): n˜ =3384, 1623 cmÀ1; Rf =0.3 (hexane/AcOEt 3:1); ele-
mental analysis calcd (%) for C15H29NO2: C 70.54, H 11.45, N 5.48;
found: C 70.81, H 11.54, N 5.32.
N,N-Diethyl-2-(3,4-dihydronaphtalen-1-yl)-2-hydroxyethanamide
(2c):
1H NMR (300 MHz, CDCl3): d=7.54(d, J=7.3 Hz, 1H), 7.21 7.02 (m,
3H), 5.97 (t, J=4.5 Hz, 1H), 5.08 (d, J=6.3 Hz, 1H), 4.46 (d, J=6.3 Hz,
1H), 3.64 3.05 (m, 4H), 2.74 (t, J=8.0 Hz, 2H), 2.32 2.26 (m, 2H), 1.16
(t, J=7.1 Hz, 3H), 1.06 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=171.4(C), 136.1 (C), 135.8 (C), 132.7 (C), 128.1 (CH), 127.5
(CH), 127.2 (CH), 126.5 (CH), 123.0 (CH), 69.2 (CH), 40.9 (CH2), 40.3
(CH2), 27.6 (CH2), 22.8 (CH2), 13.3 (CH3), 12.4ppm (CH 3); HMS
(70 eV): m/z (%): 259 [M+] (3), 242 (59), 159 (8), 129 (43), 100 (88);
HRMS calcd for C16H21NO2: 259.1572; found: 259.1576; IR (neat): n˜ =
3387, 1643, 1445 cmÀ1; Rf =0.5 (hexane/AcOEt 1:1); elemental analysis
calcd (%) for C16H21NO2: C 74.10, H 8.16, N 5.40; found: C 74.41, H
8.05, N 5.42.
General procedure for the synthesis of compound 3e: A solution of mer-
curic chloride (0.2 mmol) in THF (5 mL) was added to a suspension of
Sm (2.1 mmol) in THF (5 mL). This mixture was stirred for 10 min and
then a-hydroxy-b,g-unsaturated amide 2e (0.5 mmol) was added. The
mixture was cooled to À788C, and diiodomethane (2.0 mmol) was added
dropwise. The mixture was allowed to warm to RT and stirred for 2 h.
The reaction was then quenched with saturated K2CO3 and extracted
with ethyl ether. The organic layer was washed with brine three times,
dried over K2CO3, filtered and concentrated in a vacuum affording the
crude compound 3c, which was purified by flash column chromatography
on silica gel (hexane/AcOEt 10/1).
N,N-Diethyl-2-hydroxy-2-methyl-3-phenylbut-3-enamide (2d): 1H NMR
(200 MHz, CDCl3): d=7.44 7.18 (m, 5H), 5.55 (m, 2H), 5.40 (br, 1H),
3.68 3.42 (m, 2H), 3.38 2.81 (m, 2H), 1.65 (s, 3H), 1.04 (t, J=7.0 Hz,
3H), 0.65 ppm (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.7
(C), 150.8 (C), 139.6 (C), 127.7 (CH), 127.6 (CH), 127.3 (CH), 114.6
(CH2), 74.6 (C), 41.1 (CH2), 40.1 (CH2), 25.1 (CH3), 12.3 (CH3), 11.0 ppm
(CH3); HMS (70 eV): m/z (%): 247 [M+] (3), 230 (20), 147 (47), 100
(100), 77 (28); HRMS calcd for C15H21NO2: 247.1572; found: 247.1571;
IR (neat): n˜ =3346, 1620, 1446 cmÀ1; Rf =0.3 (hexane/AcOEt 3:1); ele-
mental analysis calcd (%) for C15H21NO2: C 72.84, H 8.56, N 5.66; found:
C 73.11, H 8.60, N 5.80.
(E)-N,N,3-Triethyl-2-hydroxy-2-methylpent-3-enamide (2e): 1H NMR
(300 MHz, CDCl3): d=5.68 (q, J=6.8 Hz, 1H), 5.29 (br, 1H), 3.57 3.41
(m, 2H), 3.39 3.23 (m, 2H), 2.19 2.09 (m, 1H), 1.95 1.83 (m, 1H), 1.71
(d, J=6.8 Hz, 3H), 1.51 (s, 3H), 1.15 (t, J=7.0 Hz, 3H), 1.11 (t, J=
7.0 Hz, 3H), 1.03 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=174.3 (C), 143.2 (C), 120.7 (CH), 76.2 (C), 41.8 (CH2), 41.0 (CH2),
23.9 (CH3), 20.9 (CH2), 13.9 (CH3), 13.4(CH 3), 13.3 (CH3), 12.2 ppm
(CH3); MS (70 eV): m/z (%): 213 [M+] (2), 196 (6), 144 (3), 113 (100),
100 (42); HRMS calcd for C12H23NO2: 213.1729; found: 213.1748; IR
(neat): n˜ =3384, 1620 cmÀ1; Rf =0.3 (hexane/AcOEt 3:1); elemental anal-
ysis calcd (%) for C12H23NO2: C 67.57, H 10.87, N 6,57; found; C 67.32,
H 10.80, N 6,72.
N,N-Diethyl-2-(1-ethyl-2-methylcyclopropyl)-2-hydroxypropanamide
(3e): 1H NMR (200 MHz, CDCl3): d=3.88 3.22 (m, 5H), 1.46 1.02 (m,
11H), 1.02 (s, 3H), 0.95 ppm (t, J=7.2 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d=175.4(C), 77.8 (C), 40.8 (CH 2), 40.5 (CH2), 30.2 (C), 23.1
(CH2), 22.8 (CH), 18.8 (CH3), 16.2 (CH2), 13.5 (CH3), 13.3 (CH3), 12.8
(CH3), 12.1 ppm (CH3); HMS (70 eV): m/z (%): 227 [M+] (<1), 198
(14), 144 (14), 127 (63), 100 (62); IR (neat): n˜ =3385, 1620 cmÀ1; Rf =0.3
(hexane/AcOEt :1); elemental analysis calcd (%) for C13H25NO2: C
68.53, H 11.08, N 6.16; found: C 68.70, H 11.19, N 6.27.
Acknowledgments
We thank II Plan Regional de InvestigaciÛn del Principado de Asturias
(PB-EXP01 11) and Ministerio de Ciencia y TecnologÌa (BQU2001
3807) for financial support. J. M.C. thanks Carmen Fernµndez-FlÛrez for
her time and E.B to Principado de Asturias for a predoctoral fellowship.
(E)-N,N-Diethyl-2-hydroxy-2-methyl-3-phenylpent-3-enamide
(2 f):
1H NMR (200 MHz, CDCl3): d=7.32 7.18 (m, 5H), 5.98 (q, J=6.9 Hz,
2449
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¹ 2004Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. M. ConcellÛn et al.
FULL PAPER
[17] Transformation of aromatic of a,b-epoxyamides into a,b-unsaturat-
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[18] A lower amount of SmI2 (< 0.2 equivalents) affords the correspond-
ing a-hydroxy-b,g-unsaturated amide unpurified with other com-
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[14] J. M. ConcellÛn, E. Bardales, Tetrahedron Lett. 2003, 44, 5323 5326.
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[16] SmI2 in THF was very rapidly generated, by reaction of diiodome-
thane with samarium powder in the presence of sonic waves: J. M.
ConcellÛn; H. RodrÌguez-Solla, E. Bardales, M. Huerta, Eur. J. Org.
Chem. 2003, 1775 1778.
Received: July 24, 2003
Revised: January 14, 2004 [F5375]
Published online: March 10, 2004
2450
¹ 2004Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2445 2450