Synthesis and transformations of alkyl N-(1-cyclohex-3-enyl)carbamates prepared from cyclohex-3-ene carboxylic acid via Curtius rearrangement

Article abstract of DOI:10.1016/j.tet.2004.11.037

The Curtius rearrangement of cyclohex-3-ene carboxylic acid using diphenylphosphoryl azide in the presence of triethylamime and ethanol, t-butanol or benzyl alcohol has been described. As a result the synthesis of ethyl, t-butyl or benzyl N-(1-cyclohex-3-enyl)carbamates has been achieved in one pot, in good chemical yield. A series of transformations of benzyl N-(1-cyclohex-3-enyl)carbamate, such as iodination and epoxidation, as well as opening of the corresponding ring epoxide, have been carried out leading to some useful oxygenated cyclohexylamimo building blocks.

Full text of DOI:10.1016/j.tet.2004.11.037

Tetrahedron 61 (2005) 1207–1219
Synthesis and transformations of alkyl
N-(1-cyclohex-3-enyl)carbamates prepared from cyclohex-3-ene
carboxylic acid via Curtius rearrangement
a,b
Elena Gomez-Sanchez and Jose Marco-Contelles
a,
*
´
´
´
aLaboratorio de Radicales Libres, IQOG (C.S.I.C.), C/Juan de la Cierva 3, 28006 Madrid, Spain
´ ´ ´
Departamento de Farmacologıa y Terapeutica, Facultad de Medicina, Instituto Teofilo Hernando, Universidad Autonoma de Madrid,
b
´
C/Arzobispo Morcillo, 4, 28029 Madrid, Spain
Received 21 September 2004; revised 10 November 2004; accepted 15 November 2004
Available online 16 December 2004
Abstract—The Curtius rearrangement of cyclohex-3-ene carboxylic acid using diphenylphosphoryl azide in the presence of triethylamime
and ethanol, t-butanol or benzyl alcohol has been described. As a result the synthesis of ethyl, t-butyl or benzyl N-(1-cyclohex-3-
enyl)carbamates has been achieved in one pot, in good chemical yield. A series of transformations of benzyl N-(1-cyclohex-3-
enyl)carbamate, such as iodination and epoxidation, as well as opening of the corresponding ring epoxide, have been carried out leading to
some useful oxygenated cyclohexylamimo building blocks.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
affording differently substituted cyclohexylamino deriva-
tives of potential synthetic interest.
exo-2-Substituted 7-azabicyclo[2.2.1] derivatives (A)
(Chart 1) are useful synthetic intermediates1 for the
synthesis of a number of natural products.2 Consequently,
a series of methodologies have been reported for the
preparation of this type of molecules.3 In this context, and in
connection with a current project in progress in our
laboratory, in this paper we report our initial results on
this subject, that have ended in a new synthetic protocol for
the synthesis of N-(1-cyclohex-3-enyl)carbamates (B, RZ
Et, t-Bu, Bn, Chart 1) from cyclohex-3-ene carboxylic acid
(1) via Curtius rearrangement;4 in addition, we have carried
out some additional transformations on these substrates
In our retrosynthetic analysis, compounds of type A should
be possibly obtained after double bond activation (halo-
genation, epoxidation, etc.) and heterocyclization reaction
on alkyl N-(1-cyclohex-3-enyl)carbamates (B, Chart 1). In
fact, carbamates (B) have been proposed as key inter-
mediates for the synthesis of the natural products, such as
clausenamide,5 and the related 4-(N-methyl-N trifluoro-
acetylamino)cyclohexene,6 has been transformed into
epibatidine.7
Carbamates B have been prepared by using different
Chart 1.
Keywords: Cyclohex-3-ene carboxylic acid; Curtius rearrangement; Diphenylphosphoryl azide; Alkyl N-(1-cyclohex-3-enyl)carbamates; Epoxides; Ring-
opening.
* Corresponding author. Tel.: C33 91 5622900; fax: C34 91 5644853; e-mail: iqoc21@iqog.csic.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.037

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1208
Scheme 1.
Scheme 2.
synthetic methodologies. For instance, carbamates of type B
(RZEt) (Chart 1) have been synthesized by photolysis of
cyclohexene in the presence of ethyl azidoformate,8a by
reaction of trans-1,2-dichlorohexane with ethyl azidoformi-
ate followed by reduction with zinc in ethanol8b or by
standard Curtius rearrangement on the acyl azide, obtained
from cyclohex-3-ene carboxylic acid via the acid chloride,
followed by reaction with sodium azide, in the presence of
ethanol.8c For carbamates of type B (RZt-Bu) (Chart 1), by
ring closing metathesis (RCM) reaction of 1-allyl-4-
pentenylamines9a and by palladium catalyzed reaction of
the allyl ester of cyclohex-3-ene carboxylic acid with
diphenylphosphoryl azide [(PhO)2P(O)N3, DPPA] in the
presence of sodium azide and t-BuOH.9b Finally, for
carbamates of type B (RZBn) (Chart 1), by RCM as
above9a and also by rearrangement of the adduct obtained in
the hetero Diels–Alder reaction of 1,3-cyclohexadiene and
N-sulfinyl,benzyl carbamate.10 Very surprisingly, to the best
of our knowledge, Curtius rearrangement of cyclohex-3-ene
carboxylic acid (1) in the original conditions as reported by
Yamada et al.11 with DPPA, in the presence of triethylamine
and the corresponding alcohol, only has been reported once
in literature patent10c,d for the synthesis of benzyl N-(1-
cyclohex-3-enyl)carbamate (Chart 1). This fact, coupled to
the simplicity of this method, prompted us to investigate the
general feasibility of this approach.
Next, several experiments were carried out in order to
improve these results.
In fact, when toluene was used as solvent in the presence of
ethanol (1.2 equiv), carbamate 2 and carbamoyl azide 3
were isolated in 51 and 32% yields, respectively, while only
traces of urea 4 could be detected. When Curtius reaction
shown in Scheme 1 was conducted in the presence of an
excess of DPPA (3.5 equiv) and triethylamine (3.9 equiv) in
a mixture of ethanol/DMF (1:1, in volume), the reaction was
more complex, giving carbamate 2 in 57% yield
accompanied by compounds 3 (18%) and 4 (14%), as well
as urea 6 (11%) (Scheme 2, Eq. 1). Interestingly, in these
conditions, but using t-butanol as co-solvent no carbamate 5
was detected, but products 3, 4 and 6 were isolated in 28, 62,
10% yields, respectively (Scheme 2, Eq. 2). The good yield
in the formation of carbamoylazide 4 in these experimental
conditions is worth of mention, as these are particularly
useful synthetic intermediates.12
Finally, and to our delight, when we applied the experi-
mental conditions shown in Scheme 1, but using benzylic
alcohol (1.0 equiv) and toluene as solvent, we obtained
N-benzyl carbamate 710 in 74% yield (Scheme 3) in a very
clean reaction, that we have scaled up without loss of
chemical yield.
2. Results and discussion
Under the standard conditions [DPPA (1.2 equiv), Et3N
(1.0 equiv)],11 compound 1 afforded carbamates 28 (54%)
and 59 (33%) (Scheme 1), using ethanol or t-butanol as
solvent, respectively. In these reactions, in addition to
compounds 2 and 5, amounts of other secondary com-
pounds, such as the carbamoyl azide (3) or the urea (4) were
detected and isolated (Scheme 1). These are commonly
formed by-products in this reaction, and the mechanism
involved in these processes has been discussed
extensively.11
Scheme 3.
All new (3, 4, 6) or known compounds (2, 5, 7) gave
analytical data and showed spectroscopic data (see Section
3) in good agreement with their structures or with the

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1209
1
reported data in literature.8–10 Particularly, in the H NMR
spectra of these compounds a new and very diagnostic
signal for H1 appears in the range d 4.02–3.78 as a multiplet.
This signal correlates with C1, observed in the range 46.3–
45.7 ppm, in the HMQC experiment. The carbamates,
carbamoyl azides and ureas also showed the typical bans
in the IR spectra for the carbonyl [(1696–1689 (st, NCO2R),
1703 (st, CON3), 1618 (NHCONH) cmK1] and the azido
(2135 cmK1) moieties.
The epoxidation of carbamate 7 with MCPBA in methylene
chloride gave epoxide 9 (Scheme 5, Eq. 1) as an inseparable
mixture of syn/anti isomers in a 2.9:1 ratio (determined by
GLC–MS analysis) in 91% yield. This result prompted us to
investigate the epoxidation reaction on the ethyl carbamate
2, and the analogous carbamoyl azide 3 and urea 4. Under
the same experimental conditions (see Section 3), com-
pound 2 gave epoxide 10 as a mixture of the syn and anti
isomers in lower yield 54%, but in a slightly better
diastereoselection (4:1) (Scheme 5, Eq. 2). Similarly,
compounds 3 and 4 afforded the expected compounds 11
(Scheme 5, Eq. 3) and 12 (Scheme 5, Eq. 4) have been
isolated in 55 and 52% yields, respectively, as almost
diastereomerically pure samples.
Being this protocol and this compound, the best in terms of
simplicity and chemical yields (Scheme 3), N-benzyl
carbamate 7 has been selected to carry out several
experiments in order to functionalize the alkene moiety,
looking for more advanced, functionalized, preferentially
halogenated or oxygenated intermediates, according to our
synthetic plan (see Chart 1).
From the structural and analytical point of view, these
compounds showed excellent data. In the 1H NMR spectra,
in particular, the signals for the vinylic protons have been
substituted by new signals, as singlets or multiplets, for
protons H1 and H2 in the range 3.20–3.13 ppm, correspond-
ing to the epoxide protons. Compounds 11 and 12, as well as
the major isomers in compounds 9 and 10, have been
tentatively assigned as the syn isomers, based on the well
established stereochemical trend observed during the
epoxidation of related 1-aminocyclohene derivatives, and
also by detailed comparison of their similar spectroscopic
data with those observed for the epoxide of (N-benzyl,N-
trifluoroacetyl)aminocyclohex-3-ene.6
With this idea in mind, first, we tested the iodination of the
double bond in order to prepare suitable activated precursors
for the subsequent aza-heterocyclization reaction (Chart 1).
As shown in Scheme 4, the reaction of compound 7 with
iodine in methylene chloride gave the bicyclic carbamate 8,
a compound that has been previously obtained in the
reaction of carbamate 5 (Scheme 1) with iodine in
the presence of potassium carbonate in ethyl ether.9a The
reported data for the analogous bromide derivative9a were in
good agreement with those observed for compound 8. This
result was interesting, but was not optimal for our purposes,
and accordingly, we reasoned that the epoxidation of the
double bond should provide possibly more useful
precursors.
With a high yielding and simple access to epoxides 9–12,
next we decided to investigate the opening of the epoxide
ring on these cyclohexylamino containing substrates, a
reaction that to the best of our knowledge has not been
previously investigated. Conversely, the analogous ring
opening of 1,2-epoxides on cis and trans-1,2-oxides of
4-(benzyloxy)cyclohexene, 4-[(benzyloxy)methyl]cyclo-
hexene and related compounds13,14 has been extensively
investigated, and proved useful for the synthesis of the
cyclohexyl moiety of several target molecules of interest.15
According to the trans-diaxial ring opening reaction (Fu¨rst–
Plattner rule16) the cis-1,2-oxide of 4-[(benzyloxy)methyl]-
cyclohexene, for instance, gives exclusively, nucleophilic
trans-attack at C-2,15 a result that is suitable for our
initial purposes leading to the synthesis of precursors for
7-azabicyclo[2.2.1]heptane derivatives (Chart 1). For the
exploratory experiments we have selected the inseparable
mixture (2.9:1) of epoxides syn/anti-9, and the hydrogen-
ation reaction as we speculated that after the hydrogenolysis
of the benzyloxycarbonyl group the resulting free amino
group would spontaneously cyclize to give the desired
intermediates.
Scheme 4.
The hydrogenation (H2, Pd/C 5%, 1 atm, rt) of epoxide 9
[(syn/anti 2.9:1)] gave a crude (13) that, after acetylation
and chromatography, provided a mixture of products, whose
spectroscopic and chromatographic analysis showed that it
was formed by three compounds (14A–C) in 70, 22.5 and
7.5% ratio, respectively (Scheme 6). The coupled MS/GLC
analysis gave the corresponding mass spectrum for each
component. Accordingly, we could assign 199 as the
molecular picks for 14A, and for 14B/C, 213, each one.
1
The H NMR analysis of the whole mixture showed no
N-benzyl and epoxide protons, appearing broad singlets for
Scheme 5.

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1210
Scheme 6.
NHCOCH3 at 5.62–5.25 ppm, multiplets and singlets for
H–C–OCOCH3 in the range 5.05–4.50 ppm, and 2.04/1.97
and 2.03/1.95 ppm, respectively; a broad multiplet between
4.00–3.78 ppm for HCNHCOR and, finally, we could
observe a series of three singlets (intensity) at 2.87 (31.6)
and 2.84 (19.9) ppm that correlated in the HMQC
experiment with signals at 30.2 and 27.0 ppm, respectively,
in the 13C NMR spectrum. Coherent with these data, in this
experiment we could also locate signals for carbonyl (not a
carbamate) function at 170.3/169.1 and 170.0/168.9 ppm, as
well as 23.5/21.3 and 23.4/21.2 ppm, which clearly suggest
the presence of an acetate and/or acetamide functional
moieties. To sum up, it is clear that the hydrogenation of
epoxides 9 has resulted in the reduction of the epoxide with
simultaneous hydrogenolysis of the N-benzyl carbamate to
yield a mixture of 3 or 4-(cis/trans)-aminocyclohexanols
(13);17 after acetylation major (cis/trans)-3 (or 4)-aceta-
midocyclohexyl acetate (14A) should have resulted (MC
199, C10H17NO3), while the two minor derivatives with
molecular picks equal to 213 are presumably N-methyl cis
or trans-3(or 4)-acetamidocyclohexyl acetates (14B/C,
C11H19NO3). Looking more carefully into the 13C NMR,
DEPT and HMQC spectra for the major isomer (14A) we
observed signals for H–C–OCOCH3 (68.8 ppm), H–C–
NHCOCH3 (46.8 ppm) and for two methylene groups, as
intense signals, at 28.4 and 27.5 ppm, a fact that suggests a
very symmetric compound, only possible in cis-4-aceta-
midocyclohexyl acetate (Scheme 6), obtained by reduction
of the major epoxide syn-9; this is also in agreement with the
bandwidth (WZ17.3 Hz)13 observed for H1 (4.97–
4.89 ppm) in the 1H NMR spectrum. As in the DEPT
experiment we also detected six significant (at 38.1, 32.2,
31.1, 29.6, 24.2, 21.2 ppm) and three minor (at 35.7, 29.7,
25.3 ppm) signals for the carbons of methylene groups, we
have hypothesized that the second product (22.5%) in the
mixture (14B) is the N-methyl known cis-3-acetamido-
cyclohexyl acetate.18,19 In agreement with this, the proton at
C1 joint to the acetoxy moiety appears at 4.80 ppm (as a
ddd) with vicinal coupling constants for two axial and one
equatorial protons (Scheme 6). Regarding the third
compound (14C) (7.5%) the spectroscopic data shown in
Scheme 6 agree for the cis-4-(N-methyl 9acetamidocyclo-
hexyl acetate, but we cannot rule out an alternative trans-3-
(N-methyl)acetamidocyclohexyl acetate structure. In
summary, we conclude that the hydrogenation of the
mixture 9 (syn/anti: 2.9/1) gave mixtures of 3- and
4-substituted aminocyclohexyl derivatives.
This unexpected result prompted us to investigate the
potassium carbonate/MeOH/H2O intramolecular epoxide
ring opening, a process that has been applied by Fletcher
et al. on trans-1,2-epoxide-(N-benzyl,N-trifluoroacetyl)-
aminocyclohexane for the synthesis of intermediates on
route to epibatidine.6b After 6 days at rt (see Section 3) we
isolated recovered pure syn-9 staring material, and two sets
of products. The first set consisted of an inseparable mixture
of compounds 15A/B in a 2:1 ratio, isolated in 32% yield;
the second set was formed by product 16 isolated in 27%
yield (Scheme 7). The full analysis of the mixture 15A/B
clearly showed us this was a mixture of trans-2-methoxy-1-
cyclohexanols obtained by intermolecular ring opening by
the methanol at the syn/anti-9 epoxides, respectively. In
fact, the stereospecific anti addition appears to be the rule
for the ring opening addition of oxiranes with nucleo-
philes.14 Major product (15A) should be the result of the
diaxial attack, in accordance with the Fu¨rst–Plattner rule,16
of methanol at C2 on syn-9 epoxide. Assuming that in
related trans 4-(or 5)(benzyloxy)-2-methoxy-1-cyclohexa-
nol derivatives,13a d H–C–OCH3[d H–C–OH, and that
conformer syn(A)-9 is more stable than conformer syn(B)-
9,13 the shapes for H1 (d 3.22–3.16, WZ24.5 Hz) and H2 (d
3.63–3.54, WZ28.5 Hz) suggest that in compound 15A two

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1211
Scheme 7.
conformers are in equilibrium, favoring the conformer with
the carbamate in pseudoaxial orientation (Scheme 7), giving
yield from 9), 18 (2%), 19 (3%) and 20 (18%, as a mixture
of isomers in a 2/1 ratio) (Scheme 8). After inspection of the
spectroscopic data for compounds 17A/B we conclude that
these compounds are the corresponding acetylated deriva-
tives of the mixture of alcohols 15A/B (Scheme 7), but in
this case the equilibrium of conformers must be significantly
shifted to the conformers with the acetoxy and the methoxy
groups in axial orientation, as it was deduced from the
values for the bandwidth for H1 and H2, in the range of
11–12 Hz. This fact could be a result of the absence of the
stabilizing hydrogen bonds present in the pair 15A/B, and
the unfavorable gauche interaction between the acetoxy and
the methoxy groups, absent in the conformer with these
groups in axial orientation that places also the sterically
demanding N-benzyl carbamate group in a more favorable
equatorial orientation. Accordingly, and as expected a
mixture of compounds 15A/B after acetylation afforded a
mixture of acetated identical to compounds 17A/B. To sum
up, these products should be the result of the initial attack of
methanol on the major conformer syn(A)-9 at carbon C2, or
in conformer anti-9 at carbon C1, respectively, following a
preferred trans-diaxial orientation. Conversely, minor
compounds 18 and 19 are possibly the result of methanol
attack on the major conformer syn(A)-9 at carbon C1, and
on conformer anti-9 at carbon C2 (Scheme 8); the chemical
shift and coupling constants for the protons bonded to the
C–OMe are in very agreement with this hypothesis (see
Scheme 8). Finally, product 20 was isolated a as a mixture
of two isomers, but the spectroscopic data only allowed us
to assign the structure shown in Scheme 8 for the major
isomer; in fact, in the 1H NMR spectrum we observed
signals for H1 and H2 corresponding for two protons joint to
carbons substituted with acetoxy groups and bandwidth
values for the bandwidth promedium between WHeq
Z
15.0 Hz, and WHaxZ37.5 Hz.13a Analogously, compound
15B should be the result of the diaxial attack of methanol at
C 1 on anti-9 epoxide, as shown by the observed shapes for
H1 (d 3.76–3.68, WZ24.5 Hz) and H2 (d 3.10–3.04, WZ
26.7 Hz). Precisely, and based on these data, we have ruled
out the nucleophilic attack of methanol on possible chelated
species,13 by the potassium counterion or by a simple O–H
bond, on the less stable conformer of syn(B)-9, that would
yield t-5-(N-benzyloxycarbonylamino)-t-2-methoxy-r-1-
cyclohexanol with the three substituents in pseudoequatorial
orientation, showing protons with higher bandwidths
(Scheme 7). Product 16 was isolated as a diastereomerically
pure compound, whose analytical and spectroscopic data are
in good agreement with a trans-1,2-diol derivative, possibly
obtained after epoxide ring opening by water on the chelated
conformer of isomer syn(B)-9 by an hydrogen bond
1
(Scheme 7). In fact, in the H NMR spectrum we could
locate H1, H2 and H4 with bandwidth in the high range of
around 37 Hz, what means that 16 is a compound in a highly
preferred conformation with these protons in axial
orientation.
To sum up, in this reaction no intramolecular epoxide ring
opening was observed, the only isolated products came from
the intermolecular epoxide ring opening by the solvents
used; in addition, the reaction was incomplete. Thus, we
decided to force the reaction conditions (refluxing for 20 h)
and the crude was acetylated. After work-up and chroma-
tography we have isolated and characterized compounds
17A/B (a mixture of isomers in a 3:1 ratio in 16% overall

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1212
Scheme 8.
around 13–18 Hz, what means that these protons are
oriented in equatorial, the acetoxy groups being axial, a
strong hydrogen bond between the NH on the carbamate and
the oxygen at the acetoxy at C2 stabilizing this conformer,
minimizing also the unfavorable gauche-interaction
between the acetoxy groups in the other conformer in
equilibrium. This product should be the result of the attack
of water to the syn(B)-9 conformer in a trans-diaxial
orientation. In fact, and as expected, the acetylation of
compound 16 (Scheme 7) gave a compound similar to the
major product 20, confirming this structural assignment. In
summary, the epoxide ring opening with methanol/water in
the presence of potassium carbonate of compound 9 resulted
in exclusive intermolecular reactions, following preferential
attack in diaxial orientation in chelated or non-chelated
intermediates.
b-hydroxynitrile derivatives 22 and 23 in 34% overall yield
(Scheme 9).
The structure of compounds 21A/B has been easily
established by their analytical data, as well as by simple
inspection of the IR spectrum (band at 2210 cmK1 for a a,b-
1
unsaturated nitrile). In the H NMR we observed vinylic
protons at 6.62 and 6.54 ppm spectrum, consistent with the
signals at 144.4/142.1 ppm, at 118.8/118.7 and 112.4/
110.3 ppm in the 13C NMR spectrum for the carbons in a
H–CaC(CN) functional moiety. Regarding the other
products, and according to the spectroscopic and analytical
data, major compound 22 is a b-hydroxynitrile resulting
from the attack on epoxide syn-9 following the diaxial
orientation in a chelated intermediate (Scheme 9) as we
could deduce by analysis of the coupling constants for H1
(2.42 ppm, ddd, JZ8.8, 11.1, 3.9 Hz) and H2 (3.86 ppm, br
t, JZ8.7 Hz). These assignments were confirmed in the
1H-13C HMQC and in the 1H–1H COSY experiments, as the
multiplet at 3.70–3.60 ppm, corresponding to a proton
bonded to a carbon a 47.3 ppm (C4) was coupled
exclusively to the multiplets at 1.43–1.23 ppm, correspond-
ing for H3 and 2 H5; accordingly, the proton (3.86 ppm, H2)
bonded to the carbon (69.1 ppm, C2), bearing the hydroxyl
group was coupled with the signals for H–C(CN)
(2.42 ppm) and with the signals at ppm (H3) at 2.32 and
at 1.43–1.23 ppm (H30). The structure of the minor
b-hydroxynitrile is 23 (Scheme 9), resulting after diaxial
In view of this, and pursuing with our initial project, then we
considered the direct incorporation of a carbon fragment by
nucleophilic attack to epoxide. In consequence, in the next
experiments we investigated similar reaction using
potassium cyanide in acetonitrile in the presence of lithium
perchlorate, a reaction system which is presumed to favor,
depending on the concentration, lithium-chelated partici-
pating reactive species.13 Under these conditions (see
Section 3), and starting from the mixture syn/anti-9 we
have isolated minor amounts of an inseparable mixture (1:1)
of a,b-unsaturated nitriles 21, in poor yield (8%), and the

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1213
Scheme 9.
attack on the minor conformer ‘non-chelated’ of major syn-
1
9. In agreement with this, in the H NMR spectrum of
clearly showed us that H5 was coupled with one of the
protons (H6) coupled to H1, only possible in product 23.
Obviously, we cannot rule out the possible formation of
compound 24, but we suggest that this product, not
observed, if formed, gives the a,b-unsaturated nitrile 21B,
after dehydration. In addition, the formation of compounds
21A/B are the result of cyanide mediated H–C–CN
abstraction followed by elimination of the b-hydroxy
compound 23 we could locate H1 (2.76–2.62) as a multiplet
with a high (WZ39 Hz) bandwidth. This also possible on
the major conformer of possible compound 24, obtained by
trans-diaxial attack on the minor anti-9 isomer (Scheme 9),
but we have excluded this possibility after careful inspection
1
of the H–1H COSY and the HMQC experiments, which
Scheme 10.

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1214
group with the final result of loss of water on compounds 22
and 23, respectively (Scheme 9).
cyanide and ITMS, processes that have afforded diverse
functionalized cyclohexylamino derivatives with moderate
selectivities and acceptable chemical yields.
Next we turned our attention to the reaction of epoxide 9
with trimethylsilyl iodide20 in order to achieve selective
hydrogenolysis of the carbamate looking for a free amino
derivative in which we could induce possibly intramolecular
ring opening of the epoxide. Under the usual conditions20
we observed a very complex reaction mixture, but after
careful chromatography we were able to isolated carbamate
7 (29%), identical to an authentic sample previously
prepared by us (see above), iodohydrins 25 (5%), 26
(12%), and a more polar product (27), which showed no
benzyl carbamate functional moiety in the 1H NMR
spectrum. The acetylation of this product as usual afforded
acetamide 28 (Scheme 10) in 60% overall yield from
epoxide 9. The structure of the less polar, minor iodohydrin
25, has been assigned by detailed spectroscopic analysis; in
fact, we could analyze the proton joint at the carbon bearing
the iodide atom at 3.84 ppm as a ddd, with vicinal coupling
constants (4.2, 9.6, 11.7 Hz) in agreement with a proton in
C1 in axial orientation, while in the major, diastereomeri-
cally pure, iodohydrin 26, the same proton appeared as a
multiplet with WZ22.2 Hz, coherent with a iodide atom
located at C2 in a product showing a mixture of chair
conformers (Scheme 10). For the same reasons, and as
shown in Scheme 10, we cannot discard the structure 29 for
this product, arising by trans-diaxial attack on the minor
anti-9 isomer; unfortunately, in this case the protons bonded
to the carbon bearing the N-benzyl carbamate and the
hydroxyl group overlap at 3.76–3.66 ppm, and the final
assignment is difficult; however, we think that the second,
major iodohydrin should be most probably 26, coming from
the major isomer syn-9 in a ‘non-chelated’ intermediate.13
In addition, in this reaction we have isolated a more polar
product (27), without the benzyl group, that after acetyl-
ation, afforded acetamide 28 (Scheme 10). In fact, in the 1H
NMR of compound 28 we have observed signals for four
vinylic protons in the range 6.47–5.43 ppm that correspond
to the signals at 125.0, 124.1, 122.1 and 108.7 ppm in the
13C NMR spectrum according to the HMQC experiment; in
addition, only an acetyl group has been located H1 (5.56–
5.50 ppm, multiplet) and two protons at high field
corresponding to 2 H6, as a broad singlet at 2.49 ppm.
These data fit perfectly in the 1-acetamido-2,4-cyclo-
hexadienyl structure for 28. In overall, the formation of
product 7 is possibly the result of the reaction of TMSI on
iodohydrins 25 and/or 26. The formation of product 27 is the
result of the N-benzyl deprotection on the iodohydrins 25
and/or 26; finally, it is expected that the basic medium
compound 27 suffers large dehydration, elimination of HI,
followed by acetylation, to give 28.
3. Experimental
3.1. General methods
Reactions were monitored by TLC using precoated silica gel
aluminum plates containing a fluorescent indicator (Merck,
5539). Anhydrous Na2SO4 was used to dry organic solutions
during work-ups and the removal of solvents was carried out
under vacuum with a rotary evaporator. Flash column
chromatography was performed using silica gel 60 (230–
400 mesh, Merck). 1H spectra were recorded with a Varian
VXR-300S spectrometer and 13C NMR spectra were
recorded with a Bruker WP-200-SY. Values with (*) can
be interchanged.
General method for the Curtius rearrangement. (A) A
solution of cyclohex-3-ene carboxylic acid (1), DPPA
(1.2 equiv) and triethylamine (1.0 equiv) in the correspond-
ing dry alcohol (ethanol or t-butanol) (0.16 M) were
refluxed until complete reaction (TLC analysis). The
reaction mixture was cooled, the solvent was removed,
the residue was dissolved in methylene chloride; then, the
organic phase was washed with 5% aqueous solution of
citric acid, water, aqueous saturated solution of sodium
bicarbonate, and brine. The organic phase was dried with
(Na2SO4), filtered, evaporated and the crude submitted to
chromatography to give the corresponding products. (B)
With toluene as solvent. As above, a solution of cyclohex-3-
ene carboxylic acid (1), DPPA (1.2 equiv) and triethylamine
(1.1 equiv) in dry toluene (0.13 M) was stirred at rt for
30 min, and were warmed at 60 8C for 30 min; then, the
alcohol (1.2 equiv) and the reaction was warmed at 60 8C
complete reaction (TLC analysis). (C) With DMF as
co-solvent. As above, a solution of cyclohex-3-ene
carboxylic acid (1), DPPA (3.5 equiv) and triethylamine
(3.9 equiv) in a mixture of the corresponding dry alcohol
(ethanol or t-butanol) and dry DMF (1:1 in volume) (0.13 M)
werewarmedat80 8C,untilcompletereaction(TLCanalysis).
General method for the epoxidation. To a solution of the
substrate in dry methylene chloride (0.11 M), under argon
and stirring, cooled in a water-ice bath, MCPBA (1.5 equiv)
was slowly added. Then, the mixture was warmed at rt
overnight. The precipitated solid was filtered, washed with
cold methylene chloride, and the organic phase was washed
with a 10% aqueous solution of sodium thiosulfite, 10%
aqueous solution of sodium bicarbonate, brine, and the
dried. After filtration, the solvent was evaporated, and the
residue purified by chromatography.
In summary, the Curtius rearrangement on cyclohex-3-ene
carboxylic acid is a simple and efficient method for the
synthesis of alkyl N-(1-cyclohex-3-enyl)carbamates, that
compares very favorably with other methodologies in terms
of simplicity and chemical yields. Some useful synthetic
transformations on the N-benzylcarbamate 7 have been also
reported, including the iodination and epoxidation reactions.
Finally, on the mixture of syn/anti-9 epoxides, we have
investigated the ring opening reaction with different reactive
systems, such as hydrogen, methanol/water, potassium
General method for acetylations. The product to be
acetylated was reacted with a mixture of Ac2O/pyridine
(1/1, in volume) at rt for the time stated in each case. When
the reaction was complete, the solvents were removed using
toluene, and the crude was submitted to chromatography.
3.1.1. Curtius rearrangement of cyclohex-3-ene car-
boxylic acid (1) with ethanol. (a) Following General

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1215
method for the Curtius rearrangement, a solution of
NHCON(CH3)2], 1534 cmK1
;
1H NMR (CDCl3,
cyclohex-3-ene carboxylic acid (1) (0.19 mL, 1.58 mmol),
DPPA (0.41 mL, 1.90 mmol, 1.2 equiv) and triethylamine
(0.24 mL, 1.74 mmol, 1.0 equiv) in dry ethanol (10 mL,
0.16 M) were refluxed 14 h. After work-up and chromato-
graphy (hexane/EtOAc, 5% to AcOEt) ethyl carbamate 2
(145.6 mg, 54%), carbamoylazide 3 (23.5 mg, 9%) and urea
4 (64 mg, 37%) were isolated.
300 MHz) d 5.68–5.57 (m, 2H, H4, H3), 4.33 [br s, 1H,
NHCON(CH3)2], 4.02–3.91 (m, 1H, H1), 2.87 [s, 6H,
NHCON(CH3)2], 2.39 (d, JZ17.2 Hz, 1H, H2), 2.11 (s, 2H,
H5), 1.92–1.81 (m, 2H, H6, H20), 1.55–1.49 (m, 1H, H60);
13C NMR (CDCl3, 75 MHz) d 158.0 [NHCON(CH3)2],
127.1 (C4), 124.9 (C3), 45.7 (C1), 36.2 [NHCON(CH3)2],
32.6 (C2), 28.9 (C6), 23.8 (C5); MS (CI): m/z 169 [MC1]C,
191 [MCNa]C, 337 [2MC1]C, 359 [2MCNa]C. Anal.
Calcd C9H16N2O: C, 64.25; H, 9.59; N, 16.65. Found: C,
64.41; H, 9.63; N, 16.42.
(b) Following General method for the Curtius rearrange-
ment with toluene as solvent a solution of cyclohex-3-ene
carboxylic acid (1) (0.19 mL, 1.58 mmol), DPPA (0.41 mL,
1.90 mmol, 1.2 equiv) and triethylamine (0.24 mL,
1.74 mmol, 1.0 equiv) in dry ethanol (10 mL) were refluxed
16 h. After work-up and chromatography (hexane/EtOAc,
10% to AcOEt) ethyl carbamate 28 (137.2 mg, 51%) and
carbamoylazide 3 (83.3 mg, 32%) were isolated.
3.1.2. Curtius rearrangement of cyclohex-3-ene car-
boxylic acid (1) with t-butanol. (a) Following General
method for the Curtius rearrangement, a solution of
cyclohex-3-ene carboxylic acid (1) (0.19 mL, 1.58 mmol),
DPPA (0.34 mL, 1.58 mmol, 1.2 equiv) and triethylamine
(0.22 mL, 1.58 mmol, 1.0 equiv) in dry t-butanol (10 mL,
0.16 M) were refluxed 48 h. After work-up and chromato-
graphy (hexane/EtOAc, 5% to AcOEt) t-butyl carbamate 59
(104 mg, 33%), carbamoylazide 3 (9.3 mg, 4%) and urea 4
(94 mg, 54%) were isolated. Compound 59: mp 52–55 8C;
IR (film) n 3427, 3316, 3021, 2929, 1696 [st, NHCO2-
C(CH3)3], 1677, 1531, 1364, 1048 cmK1; 1H NMR (CDCl3,
300 MHz) d 5.70–5.56 (m, 2H, H4, H3), 4.54 [br s, 1H,
NHCO2C(CH3)3], 3.78 (m, 1H, H1), 2.38 (d, JZ17.0 Hz,
1H, H2), 2.12 (br s, 2H, 2H5), 1.90–1.83 (m, 2H, H6, H20),
1.57–1.50 (m, 1H, H60), 1.45 [s, 9H, NHCO2C(CH3)3]; 13C
NMR (CDCl3, 75 MHz) d 155.4 [NHCO2C(CH3)3], 127.0
(C4), 124.6 (C3), 79.1 [NHCO2C(CH3)3], 45.7 (C1), 32.1
(C2), 28.5 [2 C, C6, NHCO2C(CH3)3, C6], 23.7 (C5); MS
(CI): m/z 142.1 [MK55]C, 198.2 [MC1]C, 220.2 [MC
Na]C, 417.5 [2MC23]C. Anal. Calcd C11H19NO2: C,
66.97; H, 9.71; N, 7.10. Found: C, 66.81; H, 9.82; N, 7.23.
(c) Following General method for the Curtius rearrange-
ment with DMF as co-solvent, a solution of cyclohex-3-ene
carboxylic acid (1) (0.19 mL, 1.58 mmol), DPPA (1.12 mL,
5.55 mmol, 3.5 equiv) and triethylamine (0.85 mL,
6.14 mmol, 3.9 equiv) in a mixture of dry ethanol/DMF
(6 mL/6 mL, 0.13 M) were warmed at 80 8C for 13 h. After
work-up and chromatography (hexane/EtOAc, 10% to
AcOEt) ethyl carbamate 28 (152 mg, 57%), carbamoylazide
3 (47 mg, 18%), and ureas 4 (24 mg, 14%) and 6 (30 mg,
11%) were isolated. Compound 28: oil; IR (film) n 3325,
2920, 1693 (st, NCO2CH2CH3), 1533, 1306, 1236,
1
1052 cmK1; H NMR (CDCl3, 300 MHz) d 5.64 (dm, JZ
10.2 Hz, 1H, H4), 5.63 (dm, JZ10.2 Hz, 1H, H3), 4.74 (br
s, 1H, NHCO2CH2CH3), 4.07 (q, JZ6.8 Hz, 2H, NHCO2-
CH2CH3), 3.79 (m, 1H, H1), 2.35 (d, JZ16.7 Hz, 1H, H2),
2.09 (br s, 2H, 2H5), 1.89–1.79 (m, 2H, H6, H20), 1.58–1.46
(m, 1H, H60), 1.20 (t, 3H, NHCO2CH2CH3); 13C NMR
(CDCl3, 75 MHz) d 155.9 (NHCO2CH2CH3), 126.8 (C4),
124.2 (C3), 60.4 (NHCO2CH2CH3), 45.9 (C1), 31.9 (C2),
28.2 (C6), 23.4 (C5), 14.5 (NHCO2CH2CH3); MS (CI): m/z
170 [MC1]C, 192 [MCNa]C, 339 [2MC1]C, 361 [2MC
Na]C. Anal. Calcd C9H15NO2: C, 63.88; H, 8.93; N, 8.28.
Found: C, 63.67; H, 8.74; N, 8.42. Compound 3: mp 69–
71 8C; IR (KBr) n 3430, 2135 (st, CON3), 1703 (st, CON3),
(b) Following General method for the Curtius rearrange-
ment with DMF as co-solvent, a solution of cyclohex-3-ene
carboxylic acid (1) (0.19 mL, 1.58 mmol), DPPA (1.12 mL,
5.55 mmol, 3.5 equiv) and triethylamine (0.85 mL,
6.14 mmol, 3.9 equiv) in a mixture of dry ethanol/DMF
(6 mL/6 mL, 0.13 M) were warmed at 80 8C for 13 h. After
work-up and chromatography (hexane/EtOAc, 10% to
AcOEt) carbamoylazide 3 (73 mg, 28%), and ureas 4
(108 mg, 62%) and 6 (27 mg, 10%) were isolated.
1
1675, 1544, 1230 cmK1; H NMR (CDCl3, 300 MHz) d
5.69 (dm, JZ10.1 Hz, 1H, H4), 5.60 (dm, JZ10.1 Hz, 1H,
H3), 5.08 (br s, 1H, NHCON3), 3.96 (m, 1H, H1), 2.40 (d,
JZ17.3 Hz, 1H, H2), 2.13 (br s, 2H, 2H5), 1.94–1.85 (m,
2H, H6, H20), 1.67 (m, 1H, H60); 13C NMR (CDCl3,
75 MHz) d 155.6 (NHCON3), 127.0 (C4), 123.8 (C3), 46.3
(C1), 31.4 (C2), 27.7 (C6), 23.1 (C5); MS (CI): m/z 167
[MC1]C, 189 [MCNa]C. Anal. Calcd C7H10N4O: C,
50.59; H, 6.07; N, 33.71. Found: C, 50.42; H, 6.11; N, 33.56.
Compound 4: mp 222–225 8C; IR (KBr) n 3427, 3322, 2937,
1618 (st, NHCONH), 1575, 1300 cmK1; 1H NMR (DMSO-
d6, 300 MHz) d 5.73 (d, JZ6.8 Hz, 2H, NHCONH), 5.63–
5.54 (m, 2!2H, H4, H3), 3.60 (m, 2!1H, H1), 2.19 (d, JZ
16.8 Hz, 2!1H, H2), 2.03 (br s, 2!2H, H5), 1.78–1.70 (m,
2!2H, H6, H20), 1.41–1.29 (m, 2!1H, H60); 13C NMR
(DMSO-d6, 75 MHz) d 156.9 (NHCONH), 126.6 (C4),
125.1 (C3), 44.1 (C1), 32.0 (C2), 28.6 (C6), 23.6 (C5); MS
(CI): m/z 221.2 [MC1]C, 243.0 [MCNa]C, 441.4 [2MC
Na]C. Anal. Calcd C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.68; H, 9.04; N, 12.65. Compound 6: mp 119–
121 8C; IR (KBr) n 3427, 3324, 2915, 1628 [st,
3.1.3. Curtius rearrangement of cyclohex-3-ene car-
boxylic acid (1) with benzyl alcohol. Following General
method for the Curtius rearrangement in toluene as solvent,
a solution of cyclohex-3-ene carboxylic acid (1) (2 g,
16.17 mmol), DPPA (4.1 mL, 19.40 mmol, 1.2 equiv),
triethylamine (2.48 mL, 17.79 mmol, 1.0 equiv) in dry
toluene (10 mL, 0.16 M) were stirred 30 min at rt, and at
reflux for 30 min more. Then, benzyl alcohol (2.0 mL,
19.40 mmol) was added and the mixture was refluxed 13 h.
After work-up and chromatography (hexane/EtOAc, 5%)
ethyl carbamate 710 (3.0 g, 74%) was isolated. Compound 7:
mp 64–67 8C; IR (KBr) n 3427, 3322, 2937, 1689 (st,
NCO2CH2C6H5), 1575, 1300 cmK1 1H NMR (CDCl3,
;
300 MHz) d 7.36–7.29 (m, 5H, HNCO2CH2C6H5), 5.67
(dm, JZ10.0 Hz, 1H, H4), 5.58 (dm, JZ10.0 Hz, 1H, H3),
5.09 (s, 2H, NCO2CH2C6H5), 4.80 (br s, 1H, HNCO2CH2-
C6H5), 3.87 (m, 1H, H1), 2.39 (d, JZ17.1 Hz, 1H, H2), 2.12
(br s, 2H, 2H5), 1.93–1.85 (m, 2H, H6, H20), 1.63–1.51 (m,

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1216
1H, H60); 13C NMR (CDCl3, 75 MHz) d 155.7 (HNCO2-
CH2C6H5), 136.5, 128.4, 128.1, 128.0 (HNCO2CH2C6H5),
126.9 (C4), 124.2 (C3), 66.6 (HNCO2CH2C6H5), 46.1 (C1),
31.8 (C2), 28.1 (C6), 23.3 (C5); MS (CI): m/z 232 [MC1]C,
254 [MCNa]C. Anal. Calcd C14H17NO2: C, 72.70; H, 7.41;
N, 6.06. Found: C, 72.55; H, 7.35; N, 6.22.
(m, 1H, H6), 1.92 (m, 1H, H60), 1.82 (dd, 1H, JZ7.2,
15.3 Hz, 1H, H30), 1.45 (m, 2H, 2H5), 1.18, (t, 3H,
HNCO2CH2CH3); 13C NMR (CDCl3, 75 MHz) (major syn
isomer) d 155.8 (HNCO2CH2CH3), 60.5 (HNCO2CH2CH3),
51.7, 51.6 (2 C, C1, C2) 44.6 (C4), 30.5 (C3), 24.7 (C6)*,
21.9 (C5)*, 14.5 (HNCO2CH2CH3); MS (CI): m/z 186 [MC
1]C, 208 [MCNa]C. Anal. Calcd C9H15NO3: C, 58.36; H,
8.16; N, 7.56. Found: C, 58.47; H, 8.01; N, 7.42.
3.1.4. Iodination of carbamate 7. To a solution of
compound 7 (79.7 mg, 0.34 mmol) in dry methylene
chloride (6 mL), under argon and at rt, I2 (131.2 mg,
0.517 mmol) was added. After 88 h, a 5% aqueous solution
of Na2S2O3 was added, and the mixture was extracted with
more CH2Cl2. The organic phase was washed with brine
dried, filtered and evaporated to give a crude, that was
submitted to chromatography eluting with hexane/AcOEt
mixtures, to give compound 8 (72.3 mg, 79%): amorphous
solid; IR (KBr) n 3427, 3234, 3108, 2947, 1732 (st, NCO2),
1696, 1417, 1272, 1100 cmK1; 1H NMR (CDCl3, 300 MHz)
d 6.49 (br s, 1H, HNCO2), 4.68 (s, 1H, HCOC]O), 4.62 (s,
1H, HCI), 3.62 (br s, 1H, HCNHCO2), 2.67 (d, JZ13.6 Hz,
1H), 2.29–2.16 (m, 1H), 2.01–1.92 (m, 3H), 1.75–1.67 (m,
1H); 13C NMR (CDCl3, 75 MHz) d 154.8 (NCO2), 76.6
(HCOC]O), 44.9 (HCNHCO2), 27.8, 27.4, 26.2, 24.8. MS
(CI): m/z 140.1 [MKI]C, 267.9 [MC1]C, 289.9 [MC
Na]C, 556.8 [2MCNa]C. Anal. Calcd C7H10INO2: C,
31.48; H, 3.77; N, 5.24. Found: C, 31.64; H, 3.52; N, 5.01.
3.1.7. Epoxidation of carbamoyl azide 3. Following the
General method for the epoxidation, carbamoyl azide 3
(213.6 mg, 1.28 mmol), in CH2Cl2 (6 mL), was treated with
MCPBA (432.1 mg, 1.93 mmol) for 5 h at rt. After work-up
and chromatography (hexane/EtOAc, 50%) epoxide 11
(134.4 mg, 55%) was isolated as an almost diastereomeri-
cally pure syn isomer: mp 108–111 8C; IR (KBr) n 3442,
3308, 3057, 2992, 2142 (st, CON3), 1676 (st, CON3), 1553,
1
1313, 1284, 1243 cmK1; H NMR (CDCl3, 300 MHz) d
4.93 (br s, 1H, NHCON3), 3.81 (m, 1H, H4), 3.20–3.15 (m,
2H, H1, H2), 2.39 (dd, JZ14.8,0 4.6 Hz, 1H, H3), 2.03 (m,
2H, 2H6), 1.82–1.60 (m, 1H, H3 ), 1.39–1.20 (m, 2H, 2H5);
13C NMR (CDCl3, 75 MHz) d 155.4 (NHCON3), 127.0
(C4), 51.5, 51.4 (C1, C2), 44.7 (C4), 29.8 (C3), 24.1 (C5),
21.3 (C6); MS (CI): m/z 140.1 [MKN3]C, 183.1 [MC1]C,
205.1 [MCNa]C. Anal. Calcd C7H10N4O2: C, 46.15; H,
5.53; N, 30.75. Found: C, 46.32; H, 5.70; N, 30.66.
3.1.5. Epoxidation of carbamate 7. Following the General
method for the epoxidation, carbamate 7 (500 mg,
2.16 mmol), in CH2Cl2 (10 mL), was treated with
MCPBA (729.7 mg, 3.24 mmol) for 2 h at rt. After work-
up and chromatography (hexane/EtOAc, 50%) epoxide 9
(486 mg, 91%) was isolated as a mixture of syn/anti isomers
in 2.9:1 ratio (GLC analysis): mp 63–68 8C; IR (KBr) n
3.1.8. Epoxidation of urea 4. Following the General
method for the epoxidation, urea 3 (90.9 mg, 0.41 mmol),
in MeOH (7 mL), was treated with MCPBA (277.4 mg,
1.24 mmol) for 2 h at rt. After work-up and chromatography
(hexane/EtOAc, 50%) epoxide 12 (54 mg, 52%) was
isolated as an almost diastereomerically pure syn isomer:
mp 8C; IR (KBr) n 3325, 3000, 2934, 1622 (st, NHCONH),
1574, 1429, 1306, 1084 cmK1; 1H NMR (CDCl3, 300 MHz)
d 4.60 (br s, 2H, NHCONH), 3.79 (m, 2!1H, H4), 3.18 (m,
2!1H, H1, H2), 2.20 (ddd, JZ15.3, 6.6, 3.0 Hz, 2!1H,
H3), 2.08 (dt, JZ15.6, 6.8 Hz, 2H, H6), 1.94 (m, 2!1H,
H60), 1.82 (dd, JZ15.3, 6.6 Hz, 2!1H, H30), 1.52–1.43 (m,
2!2H, H5); 13C NMR (CDCl3, 75 MHz) d 156.5
(NHCONH), 51.9 (2 C, C1, C2), 43.6 (C4), 30.9 (C3),
25.0 (C5)*, 21.9 (C6)*; MS (CI): m/z 253.1 [MC1]C, 275.0
[MCNa]C, 505.0 [2MC1]C, 527.0 [2MCNa]C. Anal.
Calcd C13H20N2O3: C, 61.88; H, 7.99; N, 11.10. Found: C,
61.63; H, 7.85; N, 11.22.
3313, 1686 (st, NCO2CH2C6H5), 1545 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 7.36–7.30 (m, 5H, HNCO2CH2C6H5),
5.12 (br s, 1H, HNCO2CH2C6H5), 5.07 (s, 2H, NCO2CH2-
C6H5), 3.72 (m, 1H, H4), 3.17 (br s, H1, H2, syn), 3.13 (m,
H1, H2, anti), 2.36 (dd, JZ14.9, 5.1 Hz, H3 anti), 2.22
(ddd, JZ15.4, 5.6, 2.6 Hz, H3 syn), 2.14 (t, JZ6.4 Hz, 1H,
H6 anti), 2.09 (t, JZ6.6 Hz, 1H, H6 syn0), 2.04–1.90 (m, H60
syn, anti), 1.84 (dd, JZ15.4, 6.9 Hz, H3 syn), 1.78–1.62 (m,
H30 anti), 1.55–1.42 (m, 2H, 2H5); 13C NMR (CDCl3,
75 MHz) d 155.4 (HNCO2CH2C6H5), 136.5, 128.4, 128.0,
127.9 (HNCO2CH2C6H5), 126.9 (C4), 124.2 (C3), 66.4
(HNCO2CH2C6H5), 52.0, 50.9 (C1, C2, anti), 51.6, 51.5
(C1, C2, syn), 44.7 (C4), 30.4 (C3), 24.6 (C6)*, 21.8 (C5)*;
MS (CI): m/z 248.1 [MC1]C, 270.0 [MCNa]C, 517.3
[2MCNa]C. Anal. Calcd C14H17NO3: C, 68.00; H, 6.93; N,
5.66. Found: C, 68.15; H, 7.05; N, 5.45.
3.1.9. Hydrogenation of epoxide 9. A solution of
compound 9 (251 mg, 1.01 mmol) in methanol (10 mL)
was hydrogenated at atmospheric pressure in the presence of
a catalytic amount of Pd/C 5% for 4 h 30 min at rt. The
catalyst was filtered over Celite-545, washed with methanol,
the solvent was evaporated, and the residue was submitted
to chromatography (hexane/AcOEt, 25%) to give un
separable mixture of compound 13 (122.5 mg), that was
submitted to standard acetylation (pyridine/Ac2O: 1 mL/
1 mL) at rt for 40 h. After work-up and chromatography
(hexane/AcOEt, 10%) afforded an inseparable mixture of
compounds 14 (15.9 mg). The analysis on GLC showed that
this mixture was formed by three compounds: (14A) rtZ
22.39 min; 70%; MS (EI): m/z 199 (MC), 139, 97, 80, 60, 43
(100); (14B) rtZ24.72 min; 22.5%; MS (EI) m/z 213 (MC),
153, 138, 112, 96, 80, 74, 70, 57, 43 (100); (14C) rtZ
25.25 min; 7.5; MS (EI): m/z 213 (MC),153, 138, 128, 112,
3.1.6. Epoxidation of carbamate 2. Following the General
method for the epoxidation, carbamate 2 (93.3 mg,
0.55 mmol), in CH2Cl2 (5 mL), was treated with MCPBA
(185.3 mg, 0.82 mmol) for 19 h at rt. After work-up and
chromatography (hexane/EtOAc, 50%) epoxide 10
(55.1 mg, 54%) was isolated as a mixture of syn/anti
isomers in 4:1 ratio (GLC analysis): oil; IR (film) n 3316,
3054, 2934, 1682 (HNCO2CH2CH3), 1544, 1341, 1279,
1049 cmK1 1H NMR (CDCl3, 300 MHz) (major syn
;
isomer) d 5.01 (br s, 1H, HNCO2CH2CH3), 4.04 (q, JZ
7.1 Hz, 2H, HNCO2CH2CH3), 3.65 (m, 1H, H4), 3.14 (s,
2H, H1, H2), 2.19 (ddd, JZ15.3, 5.9, 3.2 Hz, 1H, H3), 2.08

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E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1217
74, 70, 57, 43 (100): oil; IR (film) n 3291, 3065, 2942, 1734,
1649, 1547, 1247 cmK1; 1H and 13C NMR (see text).
1723, 1531, 1455, 1371, 1240, 1151, 1086 cmK1; 1H NMR
(CDCl3, 200 MHz) d 7.35–7.25 (m, 5H, NHCO2CH2C6H5),
5.28–5.04 (br s, NHCO2CH2C6H5, H1 minor isomer), 4.89–
4.86 (m, WZ11.7 Hz, H1 major isomer), 4.62 (br s, 1H,
NHCO2CH2C6H5), 3.84 (br s, 1H), 3.42–3.39 (m, WZ
11.6 Hz, H2 major isomer), 3.37 (s, OMe, minor isomer),
3.36 (s, OMe, major isomer), 3.30–3.24 (m, WZ12 Hz, H2
minor isomer), 2.04 (s, 3H, OCOCH3), 2.00–1.39 (m, 6H);
13C NMR (CDCl3, 75 MHz) d 170.0 (OCOCH3), 155.4
(NHCO2CH2C6H5), 136.4, 128.5, 128.1 (NHCO2CH2C6-
H5), 76.2 (C1 major isomer), 75.0 (C1, minor isomer), 69.8
(C2, major isomer), 69.3 (C2, minor isomer), 66.5 (NHCO2-
CH2C6H5), 45.4 (C5, minor isomer), 45.1 (C4, major
isomer), 32.5/32.2, 27.3/26.9, 24.5/24.1 (C3, C5, C6), 21.2
(OCOCH3); MS (CI): m/z 322.3 [MC1]C, 344.1 [MC
Na]C. Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N,
4.36. Found: C, 63.73; H, 7.44; N, 4.18. Compound 18: oil;
IR (film) n 3424, 3065, 2933, 1721, 1530, 1455, 1374, 1244,
1095, 1049 cmK1; 1H NMR (CDCl3, 200 MHz) d 7.35–7.25
(m, 5H, NHCO2CH2C6H5), 5.30–5.26 (m, 1H, H1), 5.09 (br
s, 2H, NHCO2CH2C6H5), 4.82 (br s, 1H, NHCO2CH2C6H5),
3.73 (br s, H5), 3.39 (s, OMe), 3.32 (dt, JZ3.2, 7.1 Hz, 1H,
H2), 2.07 (s, 3H, OCOCH3), 2.20–1.40 (m, 6H), 1.55–1.20
(m, 4H); MS (CI): m/z 322.3 [MC1]C, 344.1 [MCNa]C.
Compound 19: oil; IR (film) n 3430, 3340, 2931, 1731,
1691, 1540, 1454, 1374, 1246, 1102, 1060 cmK1; 1H NMR
(CDCl3, 200 MHz) d 7.35–7.25 (m, 5H, NHCO2CH2C6H5),
5.09 (br s, 2H, NHCO2CH2C6H5), 4.91–4.80 (br s, 2H,
NHCO2CH2C6H5, H1), 3.81–3.75 (m, H4), 3.38 (s, OMe),
3.27 (dt, JZ4.9 and 8.9 Hz, 1H, H2), 2.07 (s, 3H,
OCOCH3), 2.40–1.95 (m, 2H), 1.55–1.20 (m, 4H); MS
(CI): m/z 322.3 [MC1]C, 344.1 [MCNa]C. Compound 20:
oil; IR (film) n 3342, 3028, 2951, 1737, 1529, 1455, 1369,
1233, 1045 cmK1; 1H NMR (CDCl3, 200 MHz) d 7.44–7.32
(m, 5H, NHCO2CH2C6H5), 5.11 (s, 2H, NHCO2CH2C6H5),
5.04–4.97 (m, WZ14.8 Hz, H1, major isomer)*, 4.88–4.81
(m, WZ13.5 Hz, H2, major isomer)*, 4.70 (br s ancho, 1H,
NHCO2CH2C6H5), 3.90 (br s, H4, major isomer), 3.68 (br s,
minor isomer), 2.06 (s, 2!OCOCH3, major isomer), 2.04
(s, 2!OCOCH3, minor isomer), 2.00–1.50 (m, 6H); 13C
NMR (CDCl3, 50 MHz) d 170.4 (OCOCH3, minor isomer),
169.7 (OCOCH3, major isomer), 155.5 (NHCO2CH2C6H5,
major isomer), 154.8 (NHCO2CH2C6H5, minor isomer),
136.3, 128.5, 128.1 (NHCO2CH2C6H5), 72.7/71.3 (2 CH2,
minor isomer), 69.4 (2!C, C1, C2, major isomer), 66.7
(NHCO2CH2C6H5), 47.2 (CH, minor isomer), 45.4 (C4,
major isomer), 36.2, 30.7, 26.8 (3 CH2, minor isomer), 33.1,
27.2, 24.7 (C3, C5, C6), 21.0 (2!OCOCH3, major isomer),
20.9 (2!OCOCH3, minor isomer); MS (CI): m/z 350 [MC
1]C, 372 [MCNa]C. Anal. Calcd for C18H23NO6: C, 61.88;
H, 6.64; N, 4.01. Found: C, 61.65; H, 6.73; N, 4.14.
3.1.10. Reaction of epoxide 9 with MeOH/H2O in the
presence of K2CO3. (A) A solution of epoxide 9 (104.1 mg,
0.404 mmol) in methanol (2 mL) a solution of K2CO3
(143.7 mg, 1.04 mmol) in water (0.5 mL) was added. The
reaction was stirred at rt for 160 h. Then, the solvent was
removed and the residue taken in ethyl acetate, washed with
brine, dried, filtered, and evaporated to give crude that was
submitted to chromatography (hexane/EtOAc, 70% to
AcOEt–MeOH, 10%) to give unreacted pure syn-9
(27.2 mg), 15 [37.5 mg, 32% (44%), mixture of isomers in
a 2:1 ratio], 16 [32.9 mg, 27% (41%)] and two fractions
containing 8.3 mg and 6.4 mg, corresponding to isomers of
15 and 16, respectively, whose structures could not be
assigned. Compound 15: oil; IR (film) n 3326, 2933, 1695,
1
1533, 1455, 1234, 1090, 1043 cmK1; H NMR (CDCl3,
300 MHz) d 7.39–7.34 (m, 5H, NHCO2CH2C6H5), 5.11–
5.09 (m, 2H, NHCO2CH2C6H5), 4.76 (br s, 1H, NHCO2-
CH2C6H5), 3.97 (br s, 1H), 3.76–3.68 (m, WZ24.5 Hz, H2,
minor isomer), 3.63–3.54 (m, WZ28.5 Hz, H2, major
isomer), 3.39 (s, 3H, OCH3, minor isomer), 3.37 (s, 3H,
OCH3, major isomer), 3.22–3.16 (m, WZ24.5 Hz, H1,
major isomer), 3.10–3.04 (m, WZ26.7 Hz, H1, minor
isomer), 2.49 and 2.38 (2!br s, 1H), 2.15–1.89 (m, 2H),
1.73–1.40 (m, 3H); 13C NMR (CDCl3, 75 MHz) d 155.5
(NHCO2CH2C6H5), 136.4, 128.5, 128.2 (NHCO2CH2C6-
H5), 82.3 (C1, minor isomer), 80.7 (C1, major isomer), 71.5
(C2, major isomer), 69.5 (C2, minor isomer), 66.1 (NHCO2-
CH2C6H5), 56.9 (OCH3, major isomer), 56.8 (OCH3, minor
isomer), 46.2 (C4, major isomer), 45.9 (C5, minor isomer),
35.8, 31.9, 27.8, 27.6, 26.9 (CH2); MS (CI): m/z 280.0 [MC
1]C, 302.1 [MC23]C, 581.5 [2MC23]C, 248.1 [MK31]C,
236.2 [MK43]C 236.2. Anal. Calcd for C15H21NO4: C,
64.50; H, 7.58; N, 5.01. Found: C, 64.66; H, 7.81; N, 5.13.
Compound 16: amorphous solid; IR (KBr) n 3326, 3036,
2930, 1693, 1533, 1454, 1233, 1042 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 7.37–7.29 (m, 5H, NHCO2CH2C6H5),
5.08 (s, 2H, NHCO2CH2C6H5), 5.02 (br s, 1H, NHCO2-
CH2C6H5), 3.95–3.83 (m, WZ38.1 Hz, 1H, H4), 3.60–3.47
(m, WZ38.4 Hz,1H, H1)*, 3.44–3.31 (m WZ36.9 Hz,1H,
H2)*, 2.93–2.80 (br s, 2H, 2!OH), 2.08–1.26 (m, 6H, 2H3,
2H5, 2H6); 13C NMR (CDCl3, 75 MHz) d 155.7 (NHCO2-
CH2C6H5), 136.3, 128.5, 128.2 (NHCO2CH2C6H5), 73.6
(C1), 71.2 (C2), 66.7 (NHCO2CH2C6H5), 46.4 (C4), 36.3,
28.0, 27.3 (C3, C5, C6); MS (CI): m/z 266.0 [MC1]C,
288.0 [MCNa]C, 553.3 [2MCNa]C, 158.1 [MK107]C,
222.1 [MK43]C, 248.1 [MK17]. Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.54;
H, 7.03; N, 5.17.
(B) A solution of epoxide 9 (99.4 mg, 0.404 mmol) in
methanol (2 mL) was treated with a solution of K2CO3
(145.1 mg, 1.05 mmol) in water (0.5 mL) at w65 8C (bath
temperature) for 20 h. After work-up as above, the crude
was submitted to standard acetylation (Ac2O/pyridine:
2 mL/2 mL) for 24 h at rt. After work-up and chromato-
graphy (hexane/EtOAc, 50%) compounds 17 (21.3 mg, 16%
from 9, as a mixture of isomers in 3:1 ratio), 18 (3.1 mg, 2%
from 9), 19 (4.6 mg, 3% from 9) and 20 (26.5 mg, 18%, as a
mixture of two isomers in 2:1 ratio) were isolated.
Compound 17A/B: oil; IR (film) n 3335, 3057, 2940,
3.1.11. Reaction of epoxide 9 with potassium cyanide. To
a solution of epoxide 9 (123.3 mg, 0.5 mmol) in dry
acetonitrile (1 mL), under argon and stirring, KCN
(49 mg, 0.75 mmol) and LiClO4 (79.8 mg, 0.75 mmol)
were added. The mixture was warmed at 80 8C for 28 h,
cooled and diluted with ethyl ether, washed with brine,
dried, filtered and evaporated. The crude was submitted to
chromatography (hexane/EtOAc, 5% to 40%) to give
compounds 21 (10.2 mg, 8%, mixture of isomers in 1:1
ratio), 22 (13.8 mg), 22C23 (29.9 mg, 1/1 ratio) and 23
(3.5 mg) (total (22C23): 47.2 mg, 34%). Compound 21

´ ´
E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1218
(two isomers in 1:1 ratio): oil; IR (film) n 3334, 3028, 2925,
2210, 1694, 1525, 1259, 1230, 1049 cmK1 1H NMR
NHCO2CH2C6H5), 3.84 (ddd, JZ4.2, 9.6, 11.7 Hz, 1H,
CH–I) 3.68 (dt, JZ4.2, 9.9 Hz, CH–OH), 3.66–3.57 (m, 1H,
CH–NHCO2CH2C6H5), 2.47–2.27 (m, 2H, H3, H6), 2.10–
1.90 (m, 1H, H30), 1.82–1.77 (m, 1H, H4), 1.56 (br s, 1H,
OH), 1.26–1.06 (m, 2H, H60, H40); 13C NMR (CDCl3,
75 MHz)? d 155.8 (NHCO2CH2C6H5), 136.7, 128.9, 128.6,
128.5 (NHCO2CH2C6H5), 74.6 (CH–OH), 67.2 (NHCO2-
CH2C6H5), 48.4 (CH–NHCO2CH2C6H5), 39.6 (2 C, C2,
C6), 34.9 (C3), 34.4 (C4); MS (CI): m/z 359 [MK16]C,
332.0 [MK43]C, 248.3 [MK126.9]C, 376.0 [MC1]C,
398.0 [MCNa]C, 773.0 [2MCNa]C. Anal. Calcd for
C14H18INO3: C, 44.82; H, 4.84; N, 3.73. Found: C, 44.93;
H, 4.77; N, 3.62. Compound 26: oil; IR (film) n 3326, 3032,
;
(CDCl3, 300 MHz) d 7.40–7.30 (m, 5H, NHCO2CH2C6H5),
6.62/6.54 [s, s, H–CaC(CN)], 5.10 (s, 2H, NHCO2CH2C6-
H5), 4.72/3.88 (2!br s, 1H, NHCO2CH2C6H5), 2.62 (d, JZ
4.89 Hz, 1H), 2.36–2.35 (br s, 2H), 2.14–1.95 (m, 2H),
1.68–1.56 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 155.6
(NHCO2CH2C6H5), 144.4/142.1 [H–C]C(CN)], 136.2,
128.6, 128.3, 128.2 (NHCO2CH2C6H5), 118.8/118.7 [2 C,
H–C]C(CN)], 112.4/110.3 [2 C, H–C]C(CN)], 66.9 (2 C,
NHCO2CH2C6H5), 45.0, 44.8 (H–C–NHCO2CH2C6H5),
32.9/32.4 (CH2), 27.3/26.6 (CH2), 25.3/24.3 (CH2); MS
(CI): m/z 257.0 [MC1]C, 279.0 [MCNa]C. Anal. Calcd for
C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.33;
H, 618; N, 10.87. Compound 22: oil; IR (film) n 3338, 3028,
2950, 2243 (CN), 1695, 1532, 1453, 1317, 1258, 1224,
1069, 1044 cmK1; 1H NMR (CDCl3, 300 MHz) d 7.39–7.31
(m, 5H, NHCO2CH2C6H5), 5.09 (s, 2H, NHCO2CH2C6H5),
4.95 (br d, JZ5.7 Hz, 1H, NHCO2CH2C6H5), 3.86 (br t, JZ
8.8 Hz, 1H, CH–OH), 3.70–3.60 (m, WZ30 Hz, 1H, CH-
NHCO2CH2C6H5), 2.79 (br s, 1H, OH), 2.47–2.39 (ddd, JZ
3.9, 8.8, 11.1 Hz, 1H, CH–CN), 2.32 (br d, JZ12.30Hz, 1H,
H3), 2.20–2.10 (m, 1H, H6), 1.70–1.57 (m, 1H, H6 ), 1.42–
1.23 (m, 3H, H30, 2H5); 13C NMR (CDCl3, 75 MHz)? d
155.4 (NHCO2CH2C6H5), 136.2, 128.6, 128.2, 128.1
(NHCO2CH2C6H5), 120.5 (CN), 69.1 (CH–OH), 66.8
(NHCO2CH2C6H5), 47.3 (CH–NHCO2CH2C6H5), 39.4
(C3), 36.4 (CH–CN), 29.7 (C5), 24.5 (C6); MS (CI): m/z
275.0 [MC1]C, 297.0 [MCNa]C. Anal. Calcd for
C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C,
65.73; H, 6.82; N, 10.44. Compound 23: oil; IR (film) n
3338, 3028, 2932, 2243 (CN), 1694, 1532, 1454, 1324,
1253, 1080 cmK1; 1H NMR (CDCl3, 300 MHz) d 7.37–7.29
(m, 5H, NHCO2CH2C6H5), 5.03 (s, 2H, NHCO2CH2C6H5),
4.65 (br s), 3.87–3.75 (m, 2H, H2 –CH–OH–, H5
–HCNHCO2CH2C6H5–), 2.76–2.62 (m, WZ39 Hz, 1H,
H1 –H–C–CN–), 2.32 (br s, 1H, OH), 2.16 (br s, 1H, H4),
2.01–1.96 (m, 1H, H6), 1.93–1.86 (m, 1H, H40), 1.75–1.67
(m, 2H, 2H3), 1.58 (m, 1H, H60); 13C NMR (CDCl3,
75 MHz)? d 155.2 (NHCO2CH2C6H5), 136.1, 128.7, 128.2,
128.1 (NHCO2CH2C6H5), 120.5 (CN), 68.3 (CH–OH), 66.9
(NHCO2CH2C6H5), 45.3 (CH–NHCO2CH2C6H5), 32.6
(CH–CN), 30.3 (C4), 28.1 (C6), 27.0 (C3); MS (CI): m/z
275.0 [MC1]C, 297.0 [MCNa]C. Anal. Calcd for
C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C,
65.82; H, 6.53; N, 10.54.
2939, 1694, 1532, 1454, 1231, 1071 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 7.39–7.31 (m, 5H, NHCO2CH2C6H5),
5.02 (s, 2H, NHCO2CH2C6H5), 4.83 (br d, JZ6.6 Hz, 1H,
NHCO2CH2C6H5), 4.16–4.09 (m, WZ22.2 Hz, 1H, CH–I)
3.76–3.66 (m, 2H, CH–OH, CH–NHCO2CH2C6H5), 2.47–
2.27 (m, 1H, H3), 2.28 (br s, 1H, OH), 2.19–2.13 (m, 1H,
H30), 2.11–2.00 (m, 1H, H6)*, 1.81–1.58 (m, 2H, 2H4)*,
1.53–1.45 (m, 1H, H60)*; 13C NMR (CDCl3, 75 MHz)? d
156.0 (NHCO2CH2C6H5), 136.2, 128.5, 128.2 (NHCO2-
CH2C6H5), 74.0 (CH–OH), 66.8 (NHCO2CH2C6H5), 47.8
(CH–NHCO2CH2C6H5), 40.6 (C6), 35.8 (C2), 28.2 (C3)*,
27.7 (C4)*; MS (CI): m/z 376.0 [MC1]C, 398.0 [MC
Na]C, 773.0 [2MCNa]C. Anal. Calcd for C14H18INO3: C,
44.82; H, 4.84; N, 3.73. Found: C, 44.73; H, 4.91; N, 3.62.
Compound 28: amorphous solid; IR (KBr) n 3436, 2920,
1634, 1394, 1342, 1248 cmK1; 1H NMR (CDCl3, 200 MHz)
d 6.98 (br s, 1H, NHCOCH3), 6.47 (d, JZ7.5 Hz, 1H, H5),
5.98 (dd, JZ5.2, 9.3 Hz, 1H, H3), 5.79 (dd, JZ9.9,
15.6 Hz, 1 1H, H2), 5.56–5.50 (m, 1H, H1), 5.43 (t, JZ
6.6 Hz, 1H, H4), 2.49 (s, 2H, 2H6), 2.23 (s, 3H,
NHCOCH3); 13C NMR (CDCl3, 75 MHz) d 176.1
(NHCOCH3), 125.0 (C5), 124.1 (C2), 122.1 (C3), 108.7
(C4), 47.7 (C1), 38.7 (C6), 21.9 (NHCOCH3); MS (CI): m/z
138.0 [MC1]C, 160.0 [MCNa]C. Anal. Calcd for
C8H11NO: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.25;
H, 8.21; N, 10.01.
Acknowledgements
E.G.S. is a I3P-CSIC fellow. J.M.C. thanks Prof. Antonio
´
Garcıa Garcıa (Departamento de Farmacologıa
Terapeutica, Facultad de Medicina, UAM, Madrid, Spain)
´
´
y
´
for support and encouragement.
3.1.12. Reaction of epoxide 9 with trimethylsilyl iodide.
To a solution of epoxide 9 (142.8 mg, 0.58 mmol) in dry
acetonitrile (2 mL), under argon, TMSI (0.1 mL,
0.69 mmol) was added and the reaction was stirred at rt
for 44 h. Then, methanol was added, and the solvents were
removed. The crude was submitted to chromatography
(hexano/AcOEt, 30% to AcOEt) giving compounds 7
(39.9 mg, 29%), 25 (10.5 mg, 5%), 26 (26.4 mg, 12%),
and more polar product (27), isolated a viscous oil,
(60.5 mg) that was submitted to standard acetylation
(0.5 mL pyridine/0.5 mL Ac2O, rt, 15 h; chromatography:
hexane/AcOEt, 50%) to give product 28 (48.5 mg, 60%
from 9). Compound 25: 144–147 8C; IR (KBr) n 3467, 2927,
References and notes
´
1. Gonzalez, J.; Koontz, J. I.; Hodges, M.; Nilsson, K. R.; Nelly,
L. K.; Myers, W. H.; Sabat, M.; Harman, W. D. J. Am. Chem.
Soc. 1995, 117, 3405.
2. Broka, C. A. Med. Chem. Res. 1994, 4, 449.
3. Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
4. (a) Simth, P. A. S. Org. React. 1946, 3, 337. (b) Shiori, Y. In
Trost, B. M., Fleming, I., Eds.; Comprehensive Organic
Synthesis; Pergamon: Oxford, 1991; Vol. 6, p 795.
5. Yakura, T.; Matsumura, Y.; Ikeda, M. Synlett 1991, 343.
6. (a) Pfister, J. R.; Wymann, W. E.; Weissberg, R. M.; Strasberg,
1689, 1658, 1548, 1306, 1273, 1042 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 7.39–7.31 (m, 5H, NHCO2CH2C6H5),
5.01 (s, 2H, NHCO2CH2C6H5), 4.70 (br s, 1H,

´ ´
E. Gomez-Sanchez, J. Marco-Contelles / Tetrahedron 61 (2005) 1207–1219
1219
A. M. J. Pharm. Sci. 1985, 74, 208. (b) Fletcher, S. R.; Baker,
R.; Chambers, M. S.; Herbert, R. H.; Hobbs, S. C.; Thomas,
S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J. Org. Chem.
1994, 59, 1771. (c) Ramanaiah, K. C. V.; Zhu, N.; Klein-
Stevens, C.; Trudell, M. L. Org. Lett. 1999, 1, 1439.
7. Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475.
8. (a) Lwowski, W.; Mattingly, T. W. J. Am. Chem. Soc. 1965,
87, 1948. (b) Tardella, P. A.; Pellacani, L. Tetrahedron Lett.
1977, 4451. (c) Bastable, J. W.; Cooper, A. J. J. Chem. Soc.,
Perkin Trans. 1 1981, 1339.
Synth. Commun. 1996, 26, 4549. (d) Rawal, V. H.; Zhong,
H. M. Tetrahedron Lett. 1994, 35, 4947. (e) Affandi, H.;
Bayquen, A. V.; Read, R. W. Tetrahedron Lett. 1994, 35,
2729. (f) Reddy, P. S.; Yadagiri, P.; Lumin, S.; Shin, D.-S.;
Falck, J. R. Synth. Commun. 1988, 18, 545.
13. (a) Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. J. Org.
Chem. 1990, 55, 4265. (b) Chini, M.; Crotti, P.; Flippin, L. A.;
Macchia, F. J. Org. Chem. 1991, 56, 7043. (c) Chini, M.;
Crotti, P.; Flippin, L. A.; Macchia, F.; Pineschi, M. J. Org.
Chem. 1992, 57, 1405. (d) Crotti, P.; Di Bussolo, V.; Favero,
L.; Pineschi, M.; Marianucci, F.; Renzi, G.; Amici, G.; Roselli,
G. Tetrahedron 2000, 56, 7513.
9. (a) Maier, M. E.; Lapeva, T. Synlett 1998, 891. (b) Okumoto,
H.; Nishihara, S.; Yamamoto, S.; Hino, H.; Nozawa, A.;
Suzuki, A. Synlett 2000, 991.
14. Brewster, J. H. J. Am. Chem. Soc. 1956, 78, 4061.
15. Toyota, M.; Asoh, T.; Matsuura, M.; Fukumoto, K. J. Org.
Chem. 1996, 61, 8687.
10. (a) Bayer, A.; Gautun, O. R. Tetrahedron Lett. 2000, 41, 3743.
(b) Bayer, A.; Hansen, L. K.; Gautun, O. R. Tetrahedron:
Asymmetry 2002, 13, 2407.(c) Oku, T.; Sawada, K.; Kuroda,
A.; Kayakiri, N.; Urano, Y.; Sawada, Y.; Mizutani, T. PCT Int.
Appl. WO 2001030745, 2001.(d) Sawada, K.; Inoue, T.;
Sawada, Y.; Mizutani, T. PCT Int. Appl. WO 2001005770,
2001.
16. (a) Fu¨rst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275.
(b) Smith, J. G. Synthesis 1984, 629.
17. Fraser, R.; Swingle, R. B. Can. J. Chem. 1970, 48, 2065.
18. Sammes, P. G.; Thetford, D. J. Chem. Soc., Perkin Trans. 1
1989, 655.
19. Marinko, P.; Obreza, A.; Peterlin-Masic, L.; Krbavcic, A.;
Kikelj, D. J. Heterocycl. Chem. 2000, 37, 405.
11. (a) Shioiri, T.; Ninomiya, K.; Yamada, S.-i. J. Am. Chem. Soc.
1972, 94, 6203. (b) Ninomiya, K.; Shioiri, T.; Yamada, S.-i.
Tetrahedron 1974, 30, 2151.
20. (a) For a review; see: Olah, G. A.; Narang, S. C. Tetrahedron
1982, 38, 2225. (b) Jung, M. E.; Lyster, M. A. J. Chem. Soc.,
Chem. Commun. 1978, 315. (c) Lott, R. S.; Chauhan, V. S.;
Stammer, C. H. J. Chem. Soc., Chem. Commun. 1979, 495.
12. (a) Gumaste, V. K.; Deshmukh, A. R. A. S. Tetrahedron Lett.
2004, 45, 6571. (b) Marinescu, L.; Thinggaard, J.; Thomsen,
I. B.; Bols, M. J. Org. Chem. 2003, 68, 9453. (c) Froyen, P.