Unusual reductive cleavage of 3-aryl-2,3-epoxyamides by using samarium diiodide. Synthesis of 3-aryl-3-deuterio-2-hydroxyamides with total regioselectivity

Article abstract of DOI:10.1016/S0040-4039(03)01201-2

Ring-opening of 3-aryl-2,3-epoxyamides 1 was achieved by using samarium diiodide and D₂O, yielding 3-aryl-3-deuterio-2-hydroxyamides 2 with total regioselectivity. The starting compounds 1 were easily prepared by reaction of the corresponding lithium or potassium enolates of α-chloroamides with aldehydes or ketones. When the reaction was carried out in the presence of H₂O instead of D₂O, the corresponding 3-aryl-2-hydroxyamides were isolated. The treatment of enantiopure 3-aryl-2,3-epoxyamides afforded optically active 3-aryl-2-hydroxyamides.

Full text of DOI:10.1016/S0040-4039(03)01201-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5323–5326
Unusual reductive cleavage of 3-aryl-2,3-epoxyamides by using
samarium diiodide. Synthesis of
3-aryl-3-deuterio-2-hydroxyamides with total regioselectivity
Jose´ M. Concello´n,a,* Eva Bardalesa and Cecilia Go´mezb
aDepartamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo, Julia´n Claver´ıa, 8,
33071 Oviedo, Spain
bDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, 03080 Alicante, Spain
Received 29 April 2003; revised 5 May 2003; accepted 9 May 2003
Abstract—Ring-opening of 3-aryl-2,3-epoxyamides 1 was achieved by using samarium diiodide and D2O, yielding 3-aryl-3-deu-
terio-2-hydroxyamides 2 with total regioselectivity. The starting compounds 1 were easily prepared by reaction of the correspond-
ing lithium or potassium enolates of a-chloroamides with aldehydes or ketones. When the reaction was carried out in the presence
of H2O instead of D2O, the corresponding 3-aryl-2-hydroxyamides were isolated. The treatment of enantiopure 3-aryl-2,3-
epoxyamides afforded optically active 3-aryl-2-hydroxyamides. © 2003 Elsevier Science Ltd. All rights reserved.
Racemic and optically active a,b-epoxycarbonyl com-
pounds, such as aldehydes, ketones and acid deriva-
tives, are versatile building blocks in organic synthesis,1
due to both carbonyl and epoxide moieties can be
subsequently functionalized and have been used as
starting compounds for the synthesis of natural
products.2
organic synthesis,9 whilst certain derivatives possess
anticancer properties.10
Recently, we have reported the transformation of a,b-
epoxyesters into a,b-unsaturated esters promoted by
SmI2,11 or into 2,3-dideuterioesters by successive treat-
ment with SmI2 and D2O,12 respectively. In this last
paper, treatment of aliphatic and aromatic a,b-
epoxyesters with SmI2 in the presence of D2O afforded
2-deuterio-3-hydroxyesters.
In particular, several methodologies3 have been
described to transform a,b-epoxycarbonyl compounds
into the corresponding b-hydroxycarbonyl compounds
(aldol-type products) through a reductive cleavage of
the CaꢀO bond of the oxirane ring. Probably the most
effective methodology makes use of SmI2, which in the
presence of a proton source promotes the reductive
cleavage affording 3-hydroxyketones4 or 3-hydroxy-
esters.5 However, to the best of our knowledge, only a
paper describing the transformation of a,b-epoxyacid
derivatives into the synthetically highly interesting a-
hydroxyacid derivatives has been described.6 In this
respect, methodologies to obtain a-hydroxycarbonyl
compounds by reduction of the CbꢀO bond of a,b-
epoxycarbonyl compounds would be synthetically
attractive, due to the difficult preparation of the latter
by other synthetic routes.7 In addition, a-hydroxyacid
derivatives are frequently encountered as parts of natu-
ral products,8 and also serve as useful intermediates in
Here we report the synthesis of 3-aryl-2-hydroxyamides
2 with total regioselectivity by a reductive cleavage of
the CbꢀO bond of 3-aryl-2,3-epoxyamides 1,13 pro-
moted by SmI2 in the presence of H2O. When the
reaction of aromatic compounds 1 was carried out with
D2O instead of H2O, the corresponding 3-aryl-3-deu-
terio-2-hydroxyamides 2 were obtained. When the reac-
tion of 3-alkyl-2,3-epoxyamides 3 was performed in the
presence of H2O or D2O, reductive cleavage of the
CaꢀO bond instead of CbꢀO of 3 took place and the
corresponding regioisomers 3-alkyl-3-hydroxyamides or
3-alkyl-2-deuterio-3-hydroxyamides
4 were isolated.
Finally, starting from enantiomerically enriched 3-aryl-
2,3-epoxyamides, this process provided an excellent
means to generate enantiomerically enriched 3-aryl-2-
hydroxyamides.
Disubstituted epoxyamides (1b and 1c) were prepared
by reaction of lithium enolate of chloroacetamide (gen-
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01201-2

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J. M. Concello´n et al. / Tetrahedron Letters 44 (2003) 5323–5326
erated by treatment of a-chloroacetamide with LDA at
−78°C) with benzaldehyde and further treatment with
sodium hydride.14 Trisubstituted epoxyamides (1d–j and
3) were obtained by reaction of the corresponding
potassium enolates of a-chloroamides (generated by
treatment of a-chloroamides with potassium hexa-
methyldisilazide at −78°C) with different aldehydes at
temperatures ranging from −78 to 25°C. Tetra-
substituted epoxyamides (1k and 1l) were obtained by
reaction of lithium enolate of chloropropanamide with
different ketones at temperatures ranging from −78 to
25°C.
aromatic ring, was unaffected by the presence of bulky
groups or H (R3,R4) on nitrogen (Table 1, compounds
2a,c,2g–2i) and can be performed starting from 3-aryl-
2,3-epoxyamides in which the oxirane ring is di, tri or
tetrasubstituted.19
The regiochemistry (>98%) of the opening of the oxi-
rane ring was established by analysis of 13C NMR
spectra and DEPT experiments of compounds 2d–j,
showing that the hydroxy group is bonded to a quater-
nary carbon atom. The structures of compounds 2a–c
and 2k–l were established based on analysis of their
mass spectrum. To corroborate the structures of 2a and
2l, a condensation of corresponding aldehyde or ketone
and the lithium enolate of acetamide or propanamide,
was carried out, respectively; 13C NMR spectra of these
aldol-type products were different to 13C NMR spectra
of 2a and 2l.
With the starting 3-aryl-2,3-epoxyamides 1 in hand, we
first investigated the reductive cleavage of 2,3-epoxy-
N,N-diisopropyl-3-[4-(methoxy)phenyl]-2-methylpro-
panamide 1g by using SmI215 in the presence of H2O, to
determine the optimum reaction conditions of this
transformation. The best results were obtained by treat-
ment of 1g with 5 equiv. of SmI2 (long or very long
reaction times were necessary by using less than 5
equiv. of SmI2), in the presence of H2O, for 5 h at
−78°C.16 These reaction conditions were applied to
different 3-aryl-2,3-epoxyamides 1 using D2O17 instead
of H2O, and 3-aryl-3-deuterio-2-hydroxyamides were
isolated with total regioselectivity (Scheme 1 and Table
1).18
Complete deuterium incorporation was determined by
mass spectroscopy, and was found to be > 98%.20 These
3-aryl-3-deuterio-2-hydroxyamides were isolated as a
mixture of diastereoisomers, roughly 1:1. Signals of the
1
diastereoisomers could not be detected in the H and
13C NMR spectra of compounds 2a–j. However, 13C
NMR spectrum of compound 2c O-acetylated shown
all signals corresponding to both diastereoisomers
(roughly 1:1).
The proposed methodology to obtain 3-aryl-3-deuterio-
2-hydroxyamides is general. Thus, the reaction was
carried out with electron rich or deficient groups at the
Several facts can be emphasized: (a) D2O is the cheap-
est deuteration reagent to obtain organic compounds
isotopically labeled with deuterium; (b) C-3 deuteration
of acid derivatives is difficult to achieve by using other
methodologies and (c) to the best of our knowledge, no
synthesis of 3-deuterio-2-hydroxyamides has been
reported.
When similar reaction conditions were applied to 3-
alkyl-2,3-epoxyamides 3 (Scheme 2), the opening of the
oxirane ring took place by cleavage of CaꢀO bond
(DEPT experiments, mass spectra), following the same
regiochemistry of the a,b-epoxyesters.5,12 Thus, 3-alkyl-
3-hydroxyamides (with H2O) or 3-alkyl-2-deuterio-3-
hydroxyamides (with D2O) were isolated, respectively
(Table 2).21
Scheme 1. Synthesis of 3-aryl-3-deuterio-2-hydroxyamides 2.
Table 1. Synthesis of 3-aryl-3-deuterio-2-hydroxyamides 2
2a
Ar
R1
R2
R3b
X
Yield (%)c
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Me
Et
H
H
H
Me
Et
i-Pr
Et
Et
Et
i-Pr
i-Pr
i-Pr
Et
Et
Et
H
D
D
D
D
D
H
D
D
D
D
H
71
60
80
64
Ideally, a proposed mechanism for this reaction should
also explain the opposite regiochemistry of the opening
of the oxirane ring in amides with respect to the esters.
In this sense, the synthesis of products 2 may be
explained (Scheme 3) by assuming the initial double
coordination of samarium with both oxygen atoms, the
carbonyl of the amide group and the oxirane ring. This
initial quelation is not possible with a,b-epoxyesters
Me
Bu
Me
Me
Me
Bu
Me
Me
Me
Ph
73d
50d
70d
73d
67d
69d
79
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
p-CNC6H4
Ph
2j
2k
2l
Ph
76
a All products were fully characterized by spectroscopic methods [IR,
NMR, MS and mp (2a,c,e, 2g–2j)].
b In all cases R3=R4, except compound 2a wherein R3=Me and
R4=H.
c Isolated yield after column chromatography based on compound 1.
d Isolated yield after vacuum distillation based on compound 1.
Scheme 2. Synthesis of 3-alkyl-2-deuterio-3-hydroxyamides 4.

J. M. Concello´n et al. / Tetrahedron Letters 44 (2003) 5323–5326
Table 2. Synthesis of 3-alkyl-2-deuterio-3-hydroxyamides 4
5325
4a
R1
R2
R3
R4
X
Yield (%)b
4a
4b
4c
C7H15
MeCH(Ph)
n-Bu
H
H
H
Me
Me
Ph
Et
Et
Et
H
D
D
63
61
64
a All products were fully characterized by spectroscopic methods [IR,
NMR, MS and mp (4c)].
Scheme 4. Synthesis of enantiomerically enriched 3-aryl-2-
hydroxyamides (2a).
b Isolated yield after column chromatography based on compound 3.
and (2R,3S)-2,3-epoxy-N-methyl-3-phenylpropanamide
(from Sharpless epoxidation of (E)-3-phenylprop-2-en-
1-ol,22 further oxidation23 and conversion into the
amide24) were transformed into enantiopure (2S)- or
(2R)-2-hydroxy-N-methyl-3-phenylpropanamide,
respectively (Scheme 4), with complete retention of
configuration at a-carbon atom.
Starting from the enantiomer (2R,3S) with a >99% ee,
the (2R)-hydroxyamide was obtained with a >99% ee,
determined by comparison of their [h] with those previ-
ously described.6 In the case of the other enantiomer, a
similar result was obtained. Thus, the combination of
the present method with the Sharpless process is consid-
ered to provide an efficient route to optically active
3-aryl-2-hydroxyamides.
In conclusion, an easy and general methodology has
been developed to synthesize aromatic 3-aryl-3-deu-
terio-2-hydroxyamides, 3-alkyl-2-deuterio-3-hydroxy-
amides or enantiopure 3-aryl-2-hydroxyamides with
total regioselectivity from the easily available 2,3-
epoxyamides, the reaction being promoted by samar-
ium diiodide. A mechanism has been proposed to
explain this reaction, as well as the different regio-
chemistries observed with respect a,b-epoxyesters.
Scheme 3. Mechanistic proposal for the synthesis of 3-aryl-3-
deuterio-2-hydroxyamides 2.
since the resonance structure II is more favored in
amides than esters (due to the electron-donating capac-
ity of the nitrogen). The coordination of samarium with
the oxirane ring produces a similar effect to that of a
Lewis acid, and can evolve according to two pathways:
(a) reduction of the CaꢀO or (b) reduction of the CbꢀO
bond. In the case of a,b-epoxyesters the reduction of
the CaꢀO bond is favored, the obtained radical being
efficiently stabilized by resonance, in contrast to a,b-
epoxyamides. In addition, the cleavage of the CbꢀO
bond in 3-aryl-2,3-epoxyamides is favored as a result of
a benzylic radical (stabilized by resonance) being
obtained. A very fast second reduction with another
equivalent of SmI2 affords the corresponding anion,
which is hydrolyzed by D2O to yield 3-aryl-3-deuterio-
2-hydroxyamides.
Acknowledgements
We thank II Plan Regional de Investigacio´n del Princi-
pado de Asturias (PB-EXP01-11) and Ministerio de
Ciencia y Tecnolog´ıa (BQU2001-3807) for financial
support. J.M.C. thanks Carmen Ferna´ndez-Flo´rez for
her time and E.B to Principado de Asturias for a
predoctoral fellowship. Thanks to Robin Walker for his
revision of the English.
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atmosphere, to
a stirred solution of aromatic a,b-
epoxyamide 1 (0.4 mmol) in THF (2 mL) at −78°C. The
mixture was stirred for 5 h at this temperature and then
quenched with aqueous HCl (0.1 M, 15 mL) and
extracted with CH2Cl2 (3×5 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in
vacuo to afford crude 3-aryl-2-hydroxyamides or 3-aryl-
3-deuterio-2-hydroxyamides 2, which were purified by
flash column chromatography on silica gel (hexane/
AcOEt 3:1) or vacuum distillation (see Table 1).
19. In the case of aromatic tetrasubstituted a,b-epoxyamides,
the reaction was carried out at −25°C during 3.5 h.
20. MS and HRMS spectra of the deuterated compounds 2,
show lack or a very weak peak of the M+ of the corre-
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of the no deuterated compound <1%.
21. General procedure for the synthesis of compounds 4: A
solution of SmI2 (2.3 mmol) and H2O (0.4 mL) or D2O
(0.4 mL) in THF (24 mL) was added under a nitrogen
atmosphere, to a stirred solution of 3 (0.4 mmol) in THF
(2 mL) at −25°C. The mixture was stirred for 2.5 h at this
temperature and then quenched with aqueous HCl (0.1
M, 15 mL). The same workup used for isolated com-
pounds 2 afforded crude 2-deuterio-3-hydroxyamides 4,
which were purified by flash column chromatography on
silica gel (hexane/AcOEt, 3:1).
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