The aza-wharton reaction: Syntheses of cyclic allylic amines and vicinal hydroxyamines from the respective acylaziridines

Article abstract of DOI:10.1021/jo5029387

The Wharton reaction, initially described for acyl epoxides, has been studied using the structurally similar aziridines. By this reaction, a range of cyclic allylic amines and vicinal amino alcohols have been prepared stereoselectively and, in some cases, enantiomerically pure.

Full text of DOI:10.1021/jo5029387

Article
pubs.acs.org/joc
The Aza-Wharton Reaction: Syntheses of Cyclic Allylic Amines and
Vicinal Hydroxyamines from the Respective Acylaziridines
Saul Silva,† Paula Rodrigues,† Isabel Bento,† and Christopher D. Maycock*,†,‡
́
†Instituto de Tecnologia Química e Biolog
́
ica: Anton
́
́
io Xavier, Universidade Nova de Lisboa, Av. da Republica, 2780-157 Oeiras,
Portugal
‡Departamento de Química e Bioquímica, Faculdade de Cien
̂
cias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
S
* Supporting Information
ABSTRACT: The Wharton reaction, initially described for acyl epoxides, has been studied
using the structurally similar aziridines. By this reaction, a range of cyclic allylic amines and
vicinal amino alcohols have been prepared stereoselectively and, in some cases,
enantiomerically pure.
Table 1, and in each case, several conditions were applied. The
full range of conditions used is reported in the Supporting
Information.
INTRODUCTION
■
The original Wharton reaction1 comprises a reductive
rearrangement of α,β-epoxyketones into allylic alcohols using
hydrazine, and it has been used in several complex syntheses.2
An obvious extension of this process is the analogous reductive
rearrangement of cyclic acylaziridines (2-oxoazabicyclo[x.1.0]-
alkanes) to produce allylic amines, important ligands and
building blocks for organic chemistry.3 Little work on this
subject has been reported, one of the most notable being by
Yudin,4 who studied the reaction in linear benzoyl aziridines,
but the formation of pyrazoles as secondary products was
unavoidable. Another important work was carried out by
Jørgensen,5 who studied the reaction with a series of cyclic N-
tosylaziridines exclusively.
With para-substituted N-benzylaziridines it was possible to
see the effect of having a remote electron-withdrawing (1a) or
electron-donating (1b) group in the aromatic ring. The free
amine 2a was easily isolated in good yield, but the electron-rich
amine 2b was isolated as its acetamide since it was unstable and
darkened rapidly in the air. The facile air oxidation of electron-
rich benzylamines compared with electron-poor ones has
already been described.8 The acetamides of these products were
easier to purify and manipulate, but this made the NMR
characterization more difficult because of the presence of
signals due to amide rotamers. In the case of benzylaziridines,
there was no difference in yield under basic or acidic
conditions. For the preparation of 2b, basic conditions were
preferred since they permitted the subsequent acetylation of the
amino group in the same flask.
With cyclic acylaziridines6 containing a wide range of N-
substituents in hand, the goal of the work reported here was to
study the Wharton reaction (Scheme 1) on these substrates, in
this way demonstrating the scope of this reaction for the
preparation of cyclic allylic amines.
N-Benzyl-, N-aryl-, N-allyl-, and N-alkylaziridines (1a−f)9
(Scheme 1, n = 2) were tested, and the N-alkylaziridines, for
example 1d and 1e, were the ones that gave the best results.
Acylaziridines with powerful electron-withdrawing groups (1g
and 1h) were found to be some of the worst substrates.
Nevertheless the versatility of the Wharton reaction was
demonstrated. It was not possible to prepare aniline 2f under
the acidic conditions, since the only product isolated was
methoxyaniline, formed apparently by elimination.
Scheme 1. Aziridination and the Wharton Reaction
Substrates having a five-membered ring (1j and 1k) (Scheme
1, n = 1) were also studied and afforded good yields of the
corresponding allylic amines. Interestingly it was not possible to
isolate acetamide 2j because the amide group was eliminated,
probably through a pericyclic mechanism (Scheme 2), and the
RESULTS AND DISCUSSION
■
Several acylaziridines (Scheme 1) were subjected to the
Wharton conditions in order to study the effect of the groups
attached to the nitrogen atom. Two methods were used to carry
out the reaction: the classical1 acidic conditions and the more
recently studied7 basic conditions. Although the reaction was
much faster under acidic conditions, the yields in some cases
were greater under basic ones. The results are summarized in
Received: December 29, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo5029387
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Table 1. Synthesis of Allylic Amines by the Wharton Reaction10
a
b
c
N2H4·H2O, AcOH, MeOH. (1) N2H4, Et3N, MeCN; (2) Ac2O, Et3N. N2H4, Et3N, MeCN.
enantioselective organocatalytic aziridination of the corre-
sponding cyclohexenone. The preparation of 2i and 2j
represents a good alternative for the synthesis of optically
pure allylic amines. Enantiomerically pure α-alkylbenzylamines
are readily available, making the process cheap and easy.
α-Amino alcohols are important synthetic targets since they
are present in diverse products of interest such as natural
products and synthetic drugs.11 They are also important for
catalysis, acting as ligands and auxiliaries in enantioselective
reactions.12
The major products obtained by aziridination of protected or
free 4-hydroxy-2-iodocyclohex-2-enone using primary amines
were the cis-hydroxyazidirines 1l−n. On the other hand, when
the aziridination was carried out with tosylamide, the major
aziridination product was the trans isomer 1o. Applying the
Wharton conditions to aziridines 1l−n produced cis-amino
alcohols 2l−n,13 and similarly, trans-amino alcohol 2o could be
prepared in good yield from aziridine 1o (Table 2).
Scheme 2. Possible Mechanism for Amide Elimination from
Acetylated 2j
only product obtained was N-(1-phenylethyl)acetamide.
Toluenesulfonamide 2k was isolated without elimination of
tosylamide, further consolidating the proposed mechanism for
the elimination of acetamide from acetylated 2j.
The enantiomerically pure amines 2i and 2j were prepared
from the respective enantiopure aziridines (1i,j). (1R,6R)-1i
and (1S,5S)-1j were obtained by separation of the two
diastereoisomers formed by aziridination using enantiomerically
pure (+)-R-α-methylbenzylamine. Their absolute configura-
tions were determined by X-ray diffraction, and the structures
obtained are reported in the Supporting Information.
Cyclopentene cis-amino alcohols 2p and 2q were also
prepared, and it was possible to isolate acetamide 2p without
Optically active tosylamide 2g was previously prepared by
Jørgensen using an aza-Wharton reaction5 on 1g formed by
B
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Table 2. Synthesis of Amino Alcohols by the Wharton Reaction
a
b
(1) N2H4, Et3N, MeCN; (2) Ac2O, Et3N. N2H4·H2O, AcOH, MeOH.
elimination of the amide group. This observation also supports
the pericyclic mechanism for the unsubstituted cyclopentane
(Scheme 2), since the substitution at position 4 of the ring is cis
to the acetamido group. The cis-substituted cycloheptene 2r
was also formed in good yield from alcohol 1r. The protected
aminodiol 2s was produced enantiomerically pure in a
reasonable yield from aziridine 1s.14
EXPERIMENTAL SECTION
■
General. All chemicals used were of reagent grade. All solvents
were dried by established methods.17 Flash chromatography was
performed on Kieselgel 60, particle size 0.032−0.063 mm. Preparative
TLC employed silica gel Merck 60 GF254. Analytical TLC used
aluminum-backed silica gel Merck 60 F254. Infrared (IR) spectra were
obtained using a commercial FT-IR spectrophotometer, and peak
positions are given in cm−1. Specific rotations were measured using an
automatic polarimeter and are reported as follows: [α]TD (c = g/100
mL; solvent), where T is the temperature in °C. Melting points were
determined with a capillary apparatus and are uncorrected. HRMS
spectra were recorded on a commercial apparatus (ESI source). NMR
spectra were obtained on a commercial instrument at 400 MHz (1H
NMR) or 100 MHz (13C NMR) using CDCl3 as the solvent. Chemical
shifts (δ) are reported in parts per million relative to TMS, and
coupling constants (J) are reported in hertz. The chemical shift
assignments of all compounds were carried out with the help of 2D
NMR experiments such as COSY, HMQC, and HMBC.
X-ray Crystallography. Single-crystal X-ray data for compounds
1i (C14H17NO) and 1j (C13H15NO) were collected on a
diffractometer with graphite-monochromatized Mo Kα radiation (λ
= 0.71069 Å). The selected crystals of each compound were positioned
40 mm from the CCD detector and exposed for 10 s per frame. Data
reduction of each data set was carried out with a multiscan absorption
correction (SADABS). The structures were solved with SHELXS18 by
direct methods and refined on F2 using full-matrix least-squares with
CONCLUSION
■
The aza-Wharton reaction using a range of azabicyclic
compounds has been studied and shown to be a viable method
for the production of cyclic allylic amines. N-Alkylated
azabicyclo[4.1.0] compounds were found to be the best
substrates for this reaction. For the azabicyclo[3.1.0]
compounds, the N-tosyl substrate was found to be the best.
The choice between acidic or basic conditions depended upon
the N-substituent, and clear trends were not observed. The
potential for the rapid stereoselective production of cyclic
amino alcohols by this method is noteworthy. Molecules with
this type of functionality have the potential for use as chelating
agents for metal-catalyzed reactions, as organocatalysts, and as
intermediates for the synthesis of compounds such as
aminocyclitols15 and sialic acid mimics such as oseltamivir.16
C
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SHELXL18 included in the WINGX version 1.70.01 package of
programs.19 All non-hydrogen atoms were refined with anisotropic
thermal parameters. All hydrogen atoms were placed in agreement
with the electron density difference maps.
General Procedure for the Synthesis of Aziridines 1a−s. In a
flask under argon, a mixture of iodoenone (1.35 mmol), anhydrous
cesium carbonate (480 mg, 1.1 equiv), 1,10-phenanthroline (240 mg,
1.0 equiv), primary amine (1.5 equiv), and dry dichloromethane (10
mL) was stirred at room temperature. After complete reaction (TLC,
about 4 h), the reaction mixture was diluted with dichloromethane (10
mL) and washed with water (10 mL). The organic layer was dried with
magnesium sulfate and evaporated to dryness. Purification by flash
column chromatography afforded the pure aziridine. Small changes to
the procedure in individual experiments are reported in the
corresponding data paragraphs below.
obtained as a colorless oil after purification by flash column
chromatography, eluting with hexane/ethyl acetate (9:1).
1H NMR δ: 2.47−2.37 (2H, m, H-3, H-1′); 2.26 (1H, dt, 2J = 11.5;
J1′,2′ = 7.2; H-1′); 2.14 (1H, dt, J6,1 = 5.4; J6,5 = 2.6; H-6); 2.08 (1H,
dtd, 2J = 13.3; J5,4 = 4.5; J5,6 = 2.1; H-5); 2.01−1.92 (2H, m, H-3, H-4);
1.90 (1H, d, J1,6 = 5.9; H-1); 1.77−1.68 (1H, m, H-5); 1.62−1.49 (3H,
m, H-4, H-2′); 1.36−1.24 (10H, m, H-3′−H-7′); 0.88 (3H, t, J8′,7′
=
6.7; H-8′). 13C NMR δ: 208.1 (C-2); 60.6 (C-1′); 46.3 (C-1); 43.9
(C-6); 37.0 (C-3); 31.8, 29.7, 29.2, 27.3, 22.6 (C-3′−C-7′); 29.5 (C-
2); 23.3 (C-5); 18.9 (C-4); 14.0 (C-8′). IR (NaCl): 1709 (CO st.).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H26NO 224.2009;
found 224.2009. Rf = 0.65 (hexane/ethyl acetate 8:2).
( )-7-(4-Methoxyphenyl)-7-azabicyclo[4.1.0]heptan-2-one (1f).
By means of the general procedure, with a reaction time of 17 h,
109 mg (37% yield) of the pure product was obtained as a white solid
after purification by flash column chromatography, eluting with
hexane/ethyl acetate (1:1).
( )-7-[(4-Fluorophenyl)methyl]-7-azabicyclo[4.1.0]heptan-2-one
(1a). By means of the general procedure, 264 mg (89% yield) of the
pure product was obtained as a colorless oil after purification by flash
column chromatography, eluting with hexane/ethyl acetate (9:1).
1H NMR δ: 7.28 (2H, dd, JAr(o),Ar(m) = 8.5; JAr(o),F = 5.5; Ar(o)); 7.01
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.7; Ar(m)); 3.70 (1H, d, 2 J = 13.6; CH2
3
3
1H NMR δ: 6.92 (2H, d, J = 8.9; Ar(o)); 6.78 (2H, d, J = 8.9;
Ar(m)); 3.75 (3H, s, −OMe); 2.85−2.81 (1H, m, H-6); 2.00 (1H, d,
J1,6 = 6.0; H-1); 2.58−2.51 (1H, m, H-3); 2.34−2.28 (1H, m, H-5);
2.13−2.01 (2H, m, H-3, H-4); 1.93−1.84 (1H, m, H-5); 1.78−1.65
(1H, m, H-4). 13C NMR δ: 206.6 (C-2); 155.6 (Ar(p) (C−OMe));
145.9 (Ar Cq); 121.1 (Ar(o)); 114.4 (Ar(m)); 55.6 (−OMe); 46.7 (C-
1); 43.1 (C-6); 37.1 (C-3); 23.4 (C-5); 18.3 (C-4). IR (NaCl): 1704
(CO st.); 1240 (C−O−C st.). Mp = 63−65 °C. Anal. Calcd for
C13H15NO2: C 71.87; H 6.96; N 6.45. Found: C 71.89; H 6.83; N
6.60. Rf = 0.62 (hexane/ethyl acetate 2:1).
2
−Ar); 3.37 (1H, d, J = 13.6; CH2 −Ar); 2.50−2.45 (1H, m, H-3);
2.32−2.29 (1H, m, H-6); 2.11 (1H, d, J1,6 = 5.9; H-1); 2.07−1.98 (3H,
m, H-3, H-4, H-5); 1.79−1.71 (1H, m, H-5); 1.64−1.57 (1H, m, H-4).
13C NMR δ: 207.4 (C-2); 162.0 (d, 1 JC,F = 245; Ar(p) (C−F)); 134.2
4
3
2
(d, JC,F = 3; Ar Cq); 129.1 (d, JC,F = 8; Ar(o)); 115.3 (d, JC,F = 21;
Ar(m)); 62.6 (CH2−Ar); 46.3 (C-1); 43.7 (C-6); 37.1 (C-3); 23.2 (C-
5); 18.7 (C-4). Rf = 0.33 (hexane/ethyl acetate 8:2).
( )-7-[(4-Methylphenyl)sulfonyl]-7-azabicyclo[4.1.0]heptan-2-
one (1g). The general procedure was followed except that 1,10-
phenanthroline was not added and 3 equiv of tosylamide was used
instead of the normal 1.5 equiv. After purification by flash column
chromatography, eluting with hexane/ethyl acetate (8:2), 244 mg
(68% yield) of pure 1g was obtained as a white solid.
( )-7-[(4-Methoxyphenyl)methyl]-7-azabicyclo[4.1.0]heptan-2-
one (1b). By means of the general procedure, 272 mg (87% yield) of
the pure product was obtained as a colorless oil after purification by
flash column chromatography, eluting with hexane/ethyl acetate (9:1).
3
3
1H NMR δ: 7.23 (2H, d, J = 8.6; Ar(o)); 6.86 (2H, d, J = 8.6;
Ar(m)); 3.80 (3H, s, −OMe); 3.71 (1H, d, 2J = 13.4; CH2−Ar); 3.32
(1H, d, 2J = 13.4; CH2−Ar); 2.50−2.44 (1H, m, H-3); 2.32−2.29 (1H,
m, H-6); 2.10 (1H, d, J1,6 = 6.0; H-1); 2.09−1.96 (3H, m, H-3, H-4, H-
5); 1.77−1.70 (1H, m, H-5); 1.62−1.57 (1H, m, H-4). 13C NMR δ:
207.7 (C-2); 158.8 (Ar(p) (C−OMe)); 130.6 (Ar Cq); 128.9 (Ar(o));
113.8 (Ar(m)); 62.8 (CH2−Ar); 55.3 (−OMe); 46.3 (C-1); 43.7 (C-
6); 37.1 (C-3); 23.2 (C-5); 18.8 (C-4). Rf = 0.30 (hexane/ethyl acetate
8:2).
2
2
1H NMR δ: 7.81 (2H, d, J = 8.0; Ar( o)); 7.35 (2H, d, J = 8.0;
Ar(m)); 3.47−3.44 (1H, m, H-6); 3.15 (1H, d, J1,6 = 6.4; H-6); 2.46−
2.39 (4H, m, H-3, Me Ts); 2.20−2.15 (1H, m, H-5); 2.07−1.99 (1H,
m, H-3); 1.95−1.81 (2H, m, H-4, H-5); 1.70−1.64 (1H, m, H-4). 13C
NMR δ: 201.3 (C-2); 145.0 (Ar C−SO2 Ts); 134.4 (Ar(p)); 129.9
(Ar(m)); 127.9 (Ar(o)); 43.9 (C-6); 40.9 (C-1); 37.0 (C-3); 21.7 (C-
5); 21.6 (Me Ts); 17.0 (C-4). IR (NaCl): 1718 (CO st.); 1161
(SO2 st.). Mp = 73−73.5 °C. Anal. Calcd for C13H15NO3S: C 58.85; H
5.70; N 5.28; S 12.09. Found: C 58.94; H 5.73; N 5.17; S 11.89. Rf =
0.55 (hexane/ethyl acetate 6:4).
( )-7-(Prop-2-en-1-yl)-7-azabicyclo[4.1.0]heptan-2-one (1c). By
means of the general procedure, 202 mg (99% yield) of the pure
product was obtained as a colorless oil after purification by flash
column chromatography, eluting with hexane/ethyl acetate (9:1).
1H NMR δ: 5.89 (1H, ddt, J2′,3′ = 16.7; J2′,3′ = 10.6; J2′,1′ = 5.4; H-
2′); 5.23 (1H, d, J3′,2′ = 17.2; H-3′); 5.14 (1H, d, J3′,2′ = 10.4; H-3′);
3.10 (1H, dd, 2J = 14.4; J1′,2′ = 5.1; H-1′); 2.90 (1H, dd, 2J = 14.4; J1′,2′
( )-7-Acetyl-7-azabicyclo[4.1.0]heptan-2-one (1h). The general
procedure was used, but instead of a primary amine, the reaction
mixture was continuously saturated with ammonia gas for 4 h. Argon
was then passed through the solution to eliminate excess ammonia.
Acetic anhydride (2 equiv) was added at 0 °C, and the reaction
mixture was left to stir for an additional hour at room temperature.
The reaction mixture was treated as described in the typical procedure,
and 108 mg (52% yield) of the pure product was obtained as a white
solid after purification by flash column chromatography, eluting with
hexane/ethyl acetate (2:1).
= 5.5; H-1′); 2.51−2.41 (1H, m, H-3); 2.21 (1H, dt, J6,1 = 5.9; J6,5
=
2.9; H-6); 2.15−2.08 (1H, m, H-5); 2.05−1.92 (3H, m, H-2, H-3, H-
4); 1.80−1.72 (1H, m, H-5); 1.68−1.56 (1H, m, H-4). 13C NMR δ:
207.6 (C-2); 134.5 (C-2′); 130.6 (C-3′); 62.1 (C-1′); 46.0 (C-1); 43.6
(C-6); 37.0 (C-3); 23.2 (C-5); 18.8 (C-4). IR (NaCl): 1705 (CO
st.). Rf = 0.54 (hexane/ethyl acetate 8:2).
1H NMR δ: 3.17 (1H, dt, J6,1 = 5.6; J6,5 = 2.8; H-6); 2.90 (1H, d, J1,6
= 5.6; H-1); 2.51 (1H, dt, 2J = 17.7; J3,4 = 4.1; H-3); 2.26 (1H, dq, 2J =
13.9; J5,4 = J5,6 = 3.2; H-5); 2.17 (3H, s, CH3 Ac); 2.09 (1H, ddd, 2J =
17.6; J3,4 = 11.4; J3,4 = 5.9; H-3); 2.01−1.80 (2H, m, H-4, H-5); 1.74−
1.66 (1H, m, H-4). 13C NMR δ: 203.5 (C-2); 181.3 (CO Ac); 42.0
(C-1); 39.6 (C-6); 37.1 (C-3); 23.5 (CH3 Ac); 22.8 (C-5); 17.0 (C-4).
IR (NaCl): 1712 (CO st.). Mp = 41−42 °C. Anal. Calcd for
C8H11NO2: C 62.73; H 7.24; N 9.14. Found: C 62.84; H 7.19; N 8.77.
Rf = 0.45 (hexane/ethyl acetate 1:1).
( )-7-[(1R)-1-Phenylethyl]-7-azabicyclo[4.1.0]heptan-2-one (1i).
By means of the general procedure, two diastereoisomers were
obtained and separated by flash column chromatography, eluting with
dichloromethane/hexane (1:1), affording 140 mg (48% yield) of pure
(1S,6S)-1i as a colorless oil and 136 mg (47% yield) of pure (1R,6R)-
1i as a white solid.
( )-7-Butyl-7-azabicyclo[4.1.0]heptan-2-one (1d). By means of
the general procedure, 206 mg (91% yield) of the pure product was
obtained as a colorless oil after purification by flash column
chromatography, eluting with hexane/ethyl acetate (9:1).
1H NMR δ: 2.47−2.37 (2H, m, H-3, H-1′); 2.29 (1H, dt, 2J = 11.5;
J1′,2′ = 7.1; H-1′); 2.21 (1H, dt, J6,1 = 5.5; J6,5 = 2.7; H-6); 2.08 (1H,
dtd, 2J = 13.4; J5,4 = 4.5; J5,6 = 2.2; H-5); 2.01−1.92 (2H, m, H-3, H-4);
1.90 (1H, d, J1,6 = 5.9; H-1); 1.77−1.69 (1H, m, H-5); 1.63−1.49 (3H,
m, H-4, H-2′); 1.41−1.31 (2H, m, H-3′); 0.91 (3H, t, J4′,3′ = 7.3; H-
4′). 13C NMR δ: 208.1 (C-2); 60.2 (C-1′); 46.3 (C-1); 43.8 (C-6);
37.0 (C-3); 31.8 (C-2′); 23.3 (C-5); 20.4 (C-3′); 18.9 (C-4); 14.0 (C-
4′). IR (NaCl): 1707 (CO st.). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C10H18NO 168.1383; found 168.1376. Rf = 0.62 (hexane/
ethyl acetate 8:2).
( )-7-Octyl-7-azabicyclo[4.1.0]heptan-2-one (1e). By means of
the general procedure, 257 mg (100% yield) of the pure product was
(−)-(1S,6S)-7-[(1R)-1-Phenylethyl]-7-azabicyclo[4.1.0]heptan-2-
one [(1S,6S)-1i]. 1H NMR δ: 7.31−7.19 (5H, m, Ar); 2.70 (1H, q, 3J =
D
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6.5; CH−Ar); 2.50 (1H, dt, 2J = 17.0; J3,4 = 5.1; H-3); 2.37−2.34 (1H,
m, H-6); 2.17−2.04 (2H, m, H-4, H-5); 2.01−1.93 (2H, m, H-1, H-3);
1H NMR δ: 7.38 (2H, dd, JAr(o),Ar(m) = 8.8; JAr(o),F = 5.6; Ar(o)); 6.99
(2H, t, JAr(m),Ar(o) = J
= 8.8; Ar(m)); 4.12 (1H, ddd, J5,4 = 10.8;
Ar(m),F
3
1.85−1.77 (1H, m, H-5); 1.67−1.56 (1H, m, H-4); 1.41 (3H, d, J =
J5,4 = 5.2; J5,6 = 1.6; H-5); 3.91 (1H, d, 2J = 14.0; CH2−Ar); 3.26 (1H,
2 2
6.5; Me). 13C NMR δ: 207.6 (C-2); 143.8 (Ar Cq); 128.4 (Ar(m));
127.1 (Ar(p)); 126.4 (Ar(o)); 68.8 (CH−Ar); 46.2 (C-1); 44.0 (C-6);
37.0 (C-3); 23.9 (Me); 23.7 (C-5); 19.5 (C-4). IR (NaCl): 1702 (C
O st.). [α]2D0 = −10 (c = 1.6; CH2Cl2). Anal. Calcd for C14H17NO: C
78.10; H 7.96; N 6.51. Found: C 78.24; H 8.16; N 6.45. Rf = 0.68
(dichloromethane).
d, J = 14.0; CH2−Ar); 2.43 (1H, ddd, J = 18.0; J3,4 = 5.4; J3,4 = 2.0;
H-3); 2.29 (1H, br d, J6,1 = 6.0; H-6); 2.25−2.22 (2H, m, H-1, H-4);
2
2.07 (1H, ddd, J = 18.4; J3,4 = 12.4; J3,4 = 6.0; H-3); 1.67−1.60 (1H,
t
m, H-4); 0.86 (9H, s, Bu TBDMS); 0.08 (3H, s, Me TBDMS); 0.04
(3H, s, Me TBDMS). 13C NMR δ: 205.4 (C-2); 162.0 (d, 1JC,F = 243;
Ar(p) (C−F)); 133.9 (d, 4JC,F = 3; Ar Cq); 129.1 (d, 3JC,F = 8; Ar(o));
115.1 (d, 2JC,F = 21; Ar(m)); 67.8 (C-5); 62.1 (CH2−Ar); 48.1 (C-6);
(+)-(1R,6R)-7-[(1R)-1-Phenylethyl]-7-azabicyclo[4.1.0]heptan-2-
one [(1R,6R)-1i]. 1H NMR δ: 7.36 (2H, d, 3J = 6.9; Ar( o)); 7.33 (2H,
t, 3J = 7.8; Ar(m)); 7.26 (1H, t, 3J = 6.9; Ar(p)); 2.68 (1H, q, 3J = 6.5;
CH−Ar); 2.55−2.48 (1H, m, H-3); 2.20 (1H, dt, J6,1 = 5.9; J6,5 = 2.7;
H-6); 2.11 (1H, d, J1,6 = 6.0, H-1); 2.09−1.91 (3H, m, H-3, H-4, H-5);
1.67−1.56 (2H, m, H-4, H-5); 1.39 (3H, d, 3J = 6.5; Me). 13C NMR δ:
207.8 (C-2); 144.5 (Ar Cq); 128.4 (Ar(m)); 127.1 (Ar(p)); 126.4
(Ar(o)); 69.1 (CH−Ar); 46.4 (C-1); 42.9 (C-6); 37.2 (C-3); 23.7
46.8 (C-1); 35.3 (C-3); 25.8 (C-4); 25.7 (3 × Me tBu); 18.0 (Cq Bu);
t
−4.7 (Me TBDMS); −4.8 (Me TBDMS). IR (NaCl): 1711 (CO
st.). Anal. Calcd for C19H28FNO2Si: C 65.29; H 8.07; N 4.01. Found:
C 65.29; H 7.90; N 3.92. Rf = 0.43 (hexane/ethyl acetate 9:1).
( )-(1S,5S,6R)-7-[(4-Fluorophenyl)methyl]-5-hydroxy-7-aza-
bicyclo[4.1.0]heptan-2-one (1m). By means of the general procedure,
236 mg (74% yield) of the pure product was obtained as a white solid
after purification by flash column chromatography, eluting with
hexane/ethyl acetate (2:1).
(Me); 23.1 (C-5); 18.6 (C-4). IR (NaCl): 1702 (CO st.). [α]D20
=
+79 (c = 1.3; CH2Cl2). Mp = 62.5−63.5 °C. Anal. Calcd for
C14H17NO: C 78.10; H 7.96; N 6.51. Found: C 78.04; H 8.05; N 6.67.
Rf = 0.56 (CH2Cl2).
1H NMR δ: 7.31 (2H, dd, JAr(o),Ar(m) = 8.3; JAr(o),F = 5.5; Ar(o)); 7.04
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.6; Ar(m)); 4.15−4.09 (1H, m, H-5);
2
2
3.73 (1H, d, J = 13.2; CH2−Ar); 3.39 (1H, d, J = 13.2; CH2−Ar);
2.58 (1H, dd, J6,1 = 5.7; J6,5 = 3.5; H-6); 2.55−2.47 (1H, m, H-3); 2.31
(1H, d, J1,6 = 5.9; H-1); 2.10−1.95 (3H, m, H-3, H-4, OH); 1.85−1.76
( )-6-[(1R)-1-Phenylethyl]-6-azabicyclo[3.1.0]hexan-2-one (1j).
By means of the general procedure, two diastereoisomers were
obtained and separated by flash column chromatography, eluting with
hexane/ethyl acetate (9:1). This afforded 95 mg (35% yield) of pure
(1R,5R)-1j as a white solid and 122 mg (45% yield) of pure (1S,5S)-1j
as a colorless oil.
(1H, m, H-4). 13C NMR δ: 207.8 (C-2); 162.3 (d, JC,F = 246; Ar(p)
1
(C−F)); 133.6 (d, 4JC,F = 3; Ar Cq); 129.7 (d, 3JC,F = 8; Ar(o)); 115.6
2
(d, JC,F = 21; Ar(m)); 64.8 (C-5); 62.6 (CH2−Ar); 48.1 (C-6); 47.6
(C-1); 34.0 (C-3); 29.3 (C-4). IR (NaCl): 3390 (br, OH st.); 1698
(CO st.). Mp = 69.5−71 °C. Anal. Calcd for C13H14FNO2: C 66.37;
H 5.95; N 6.00. Found: C 66.40; H 5.97; N 6.02. Rf = 0.63 (hexane/
ethyl acetate 1:1).
(−)-(1S,5S)-6-[(1R)-1-Phenylethyl]-6-azabicyclo[3.1.0]hexan-2-
one [(1S,5S)-1j]. 1H NMR δ: 7.30−7.20 (5H, m, Ar); 2.75 (1H, t, J5,1
= J5,4 = 3.5; H-5); (1H, q, 3 J = 6.5; CH−Ar); 2.44−2.22 (2H, m, H-3,
H-4); 2.06 (1H, d, J1,5 = 4.1; H-1); 2.04−1.93 (2H, m, H-3, H-4); 1.46
(3H, d, 3J = 6.5; Me). 13C NMR δ: 212.1 (C-2); 143.6 (Ar Cq); 128.4
(Ar(m)); 127.2 (Ar(p)); 126.4 (Ar(o)); 67.1 (CH−Ar); 46.6 (C-1);
46.4 (C-5); 33.0 (C-3); 24.4 (C-4); 23.9 (Me). IR (NaCl): 1735 (C
O st.). [α]2D0 = −13 (c = 0.6; CH2Cl2). Anal. Calcd for C13H15NO: C
77.58; H 7.51; N 6.96. Found: C 77.70; H 7.19; N 6.57. Rf = 0.36
(hexane/ethyl acetate 8:2).
(−)-(1S,5S,6R)-5-Hydroxy-7-(prop-2-en-1-yl)-7-azabicyclo[4.1.0]-
heptan-2-one (1n). By means of the general procedure, 198 mg (88%
yield) of the pure product was obtained as a colorless oil after
purification by flash column chromatography, eluting with hexane/
ethyl acetate (1:1).
1H NMR δ: 5.91 (1H, ddt, J2′,3′ = 17.0; J2′,3′ = 10.4; J2′,1′ = 5.9; H-
2′); 5.26 (1H, dq, J3′,2′ = 17.2; 2J = J3′,1′ = 1.5; H-3′); 5.19 (1H, dq, J2′,3′
= 10.3; 2J = J2′,1′ = 1.2; H-3′); 4.17−4.14 (1H, m, H-5); 3.11 (1H, dd,
2J = 13.8; J1′,2′ = 5.8; H-1′); 2.99 (1H, dd, 2J = 13.8; J1′,2′ = 5.9; H-1′);
(+)-(1R,5R)-6-[(1R)-1-Phenylethyl]-6-azabicyclo[3.1.0]hexan-2-
one [(1R,5R)-1j]. 1H NMR δ: 7.39 (2H, d, 3J = 6.8; Ar( o)); 7.34 (2H,
t, 3J = 7.4; Ar(m)); 7.27 (1H, t, 3J = 7.0; Ar(p)); 2.66 (1H, q, 3J = 6.5;
CH−Ar); 2.57 (1H, t, J5,1 = J5,4 = 3.7; H-5); 2.38 (1H, dt, 2J = 17.9; J3,4
= 9.0; H-3); 2.25 (1H, d, J1,5 = 4.1, H-1); 2.08 (1H, ddd, 2J = 13.0; J4,3
2.56−2.47 (2H, m, H-6, H-3); 2.41 (1H, s br, OH); 2.19 (1H, d, J1,6
=
5.9; H-1); 2.09−1.96 (2H, m, H-3, H-4); 1.86−1.77 (1H, m, H-4). 13C
NMR δ: 206.2 (C-2); 133.9 (C-2′); 117.9 (C-3′); 64.5 (C-5); 62.1
(C-1′); 48.1 (C-6); 47.4 (C-1); 33.8 (C-3); 29.7 (C-4). IR: 3400 (OH
st.); 1694 (CO st.). [α]D20 = −118 (c = 1.0; DCM). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C9H14NO2 168.1019; found 168.1015.
Rf = 0.31 (hexane/ethyl acetate 1:1).
2
= 9.1; J4,3 = 1.0; H-4); 1.97 (1H, dd, J = 17.9; J3,4 = 9.7; H-3); 1.85
2
3
(1H, dtd, J = 12.9; J4,3 = 9.3; J4,5 = 2.4; H-4); 1.41 (3H, d, J = 6.5;
Me). 13C NMR δ: 212.5 (C-2); 144.2 (Ar Cq); 128.5 (Ar(m)); 127.2
(Ar(p)); 126.5 (Ar(o)); 67.1 (CH−Ar); 47.4 (C-1); 45.4 (C-5); 33.1
(C-3); 24.1 (C-4); 23.5 (Me). IR (NaCl): 1733 (CO st.). [α]D20
=
+41 (c = 1.4; CH2Cl2). Mp = 74−75 °C. Anal. Calcd for C13H15NO: C
77.58; H 7.51; N 6.96. Found: C 77.40; H 7.29; N 6.84. Rf = 0.49
(hexane/ethyl acetate 8:2).
( )-(1R,5S,6S)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(4-methyl-
phenyl)sulfonyl]-7-azabicyclo[4.1.0]heptan-2-one (1o). By means of
the same procedure as for 1g, 386 mg (85% yield) of the pure product
was obtained as a white solid after purification by flash column
chromatography, eluting with hexane/ethyl acetate (9:1).
( )-6-[(4-Methylphenyl)sulfonyl]-6-azabicyclo[3.1.0]hexan-2-one
(1k). By means of the experimental procedure used for 1g, 185 mg
(85% yield) of the pure product was obtained as a white solid after
purification by flash column chromatography, eluting with hexane/
ethyl acetate (2:1).
2
2
1H NMR δ: 7.80 (2H, d, J = 8.0; Ar(o)); 7.36 (2H, d, J = 8.0;
Ar(m)); 4.38 (1H, q, J5,4 = J5,6 = 3.1; H-5); 3.34 (1H, ddd, J6,1 = 6.4;
J6,5 = 2.8; J = 1.2; H-6); 3.17 (1H, d, J1,6 = 6.4; H-1); 2.45 (3H, s, Me
2
2
1H NMR δ: 7.82 (2H, d, J = 8.4, Ar( o)), 7.36 (2H, d, J = 8.0;
Ar(m)); 3.79−3.77 (1H, m, H-5); 3.26 (1H, d, J1,5 = 4.8; H-1); 2.46
(3H, s, Me Ts); 2.33−2.21 (2H, m, H-3, H-4); 2.16−2.04 (2H, m, H-
3, H-4). 13C NMR δ: 206.8 (C-2); 145.2 (Ar C−SO2 Ts); 134.4
(Ar(p)); 129.9 (Ar(m)); 127.9 (Ar(o)); 45.4 (C-1); 44.2 (C-5); 31.8
(C-3); 23.1 (C-4); 21.6 (Me Ts). IR (NaCl): 1753 (CO st.); 1157
(SO2 st.). Mp = 110.5−111 °C. Anal. Calcd for C12H13NO3S: C 57.35;
H 5.21; N 5.57; S 12.76. Found: C 57.53; H 5.29; N 5.45; S 12.42. Rf
= 0.59 (hexane/ethyl acetate 1:1).
2
Ts); 2.38 (1H, ddd, J = 18.2; J3,4 = 12.2; J3,4 = 6.2; H-3); 2.20 (1H,
2
ddd, J = 18.4; J3,4 = 5.2; J3,4 = 3.2; H-3); 2.07−1.99 (1H, m, H-4);
t
1.71−1.63 (1H, m, H-4); 0.89 (9H, s, Bu TBDMS); 0.13 (3H, s, Me
TBDMS); 0.09 (3H, s, Me TBDMS). 13C NMR δ: 200.8 (C-2); 145.2
(Ar C−SO2 Ts); 134.0 (Ar(p)); 129.9 (Ar(m)); 127.9 (Ar(o)); 63.6
t
(C-5); 43.7 (C-1); 43.5 (C-6); 31.9 (C-3); 25.6 (3 × Me Bu); 35.4
(C-4); 21.6 (Me Ts); 17.9 (Cq tBu); −4.8 (Me TBDMS); −4.9 (Me
TBDMS). IR (NaCl): 1722 (CO st.); 1163 (SO2 st.). Mp = 98.5−
99 °C. Anal. Calcd for C19H29NO4SSi: C 57.69; H 7.39; N 3.54; S
8.11. Found: C 57.90; H 7.54; N 3.58; S 7.90. Rf = 0.39 (hexane/ethyl
acetate 8:2).
( )-(1S,5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(4-fluoro-
phenyl)methyl]-7-azabicyclo[4.1.0]heptan-2-one (1l). By means of
the general procedure, 370 mg (78% yield) of the pure product was
obtained as a colorless oil after purification by flash column
chromatography, eluting with hexane/ethyl acetate (95:5).
( )-(1S,4S,5R)-4-[(tert-Butyldimethylsilyl)oxy]-6-[(4-fluoro-
phenyl)methyl]-6-azabicyclo[3.1.0]hexan-2-one (1p). By means of
the general procedure, 374 mg (83% yield) of the pure product was
E
DOI: 10.1021/jo5029387
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
obtained as a colorless oil after purification by flash column
chromatography, eluting with hexane/ethyl acetate (9:1).
raphy (flash column or preparative plates) afforded the pure allylic
amine or amide. Small changes to the procedure are reported below.
( )-N-[(4-Fluorophenyl)methyl]cyclohex-2-en-1-amine (2a). By
means of the general procedure under acidic conditions, 78 mg
(83% yield) of the pure product was obtained as a yellow oil after
purification by flash column chromatography, eluting with chloro-
form/methanol (9:1).
1H NMR δ: 7.43 (2H, dd, JAr(o),Ar(m) = 8.7; JAr(o),F = 5.5; Ar(o)); 7.04
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.7; Ar(m)); 4.39 (1H, td, J4,3 = 8.0; J4,5
=
2
2
3.2; H-4); 3.94 (1H, d, J = 14.1; CH2−Ar); 3.18 (1H, d, J = 14.1;
CH2−Ar); 2.74 (1H, t, J5,1 = J5,4 = 3.7; H-5); 2.47 (1H, dd, 2J = 16.8;
J3,4 = 8.0; H-3); 2.37 (1H, d, J1,5 = 4.2; H-1); 2.22 (1H, dd, 2J = 16.8;
J3,4 = 8.0; H-3); 0.90 (9H, s, tBu TBDMS); 0.07 (3H, s, Me TBDMS);
1H NMR δ: 7.31 (2H, dd, JAr(o),Ar(m) = 10.1; JAr(o),F = 7.0; Ar(o));
7.00 (2H, t, JAr(m),Ar(o) = JAr(m),F = 8.7; Ar(m)); 5.79−5.75 (1H, m, H-
0.06 (3H, s, Me TBDMS). 13C NMR δ: 206.9 (C-2); 162.0 (d, 1JC,F
=
2
4
3
3); 5.73−5.70 (1H, m, H-2); 3.80 (1H, d, J = 12.7; CH2−Ar); 3.76
245; Ar(p) (C−F)); 133.7 (d, JC,F = 3; Ar Cq); 128.9 (d, JC,F = 8;
(1H, d, 2J = 12.7; CH2−Ar); 3.23−3.19 (1H, m, H-1); 2.03−1.96 (2H,
m, H-4); 1.93−1.86 (1H, m, H-6); 1.78−1.71 (1H, m, H-5); 1.66 (1H,
Ar(o)); 115.2 (d, 2JC,F = 21; Ar(m)); 68.2 (C-4); 60.1 (CH2−Ar); 50.3
(C-5); 48.6 (C-1); 41.6 (C-3); 25.7 (3 × Me Bu); 18.1 (Cq tBu);
t
br s, NH); 1.60−1.44 (2H, m, H-5, H-6). 13C NMR δ: 161.9 (d, 1JC,F
=
−4.7 (Me TBDMS); −4.8 (Me TBDMS). IR (NaCl): 1745 (CO
st.). Anal. Calcd for C18H26FNO2Si: C 64.44; H 7.81; N 4.18. Found:
C 64.48; H 8.00; N 4.10. Rf = 0.57 (hexane/ethyl acetate 8:2).
( )-(1S,4S,5R)-6-[(4-Fluorophenyl)methyl]-4-hydroxy-6-aza-
bicyclo[3.1.0]hexan-2-one (1q). By means of the general procedure,
180 mg (60% yield) of the pure product was obtained as a white solid
after purification by flash column chromatography, eluting with
hexane/ethyl acetate (1:1).
4
3
244; Ar(p) (C−F)); 136.3 (d, JC,F = 3; Ar Cq); 129.7 (d, JC,F = 8;
2
Ar(o)); 129.6 (C-2); 129.2 (C-3); 115.1 (d, JC,F = 21; Ar(m)); 52.4
(C-1); 50.2 (CH2−Ar); 29.4 (C-6); 25.3 (C-4); 20.2 (C-5). HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C13H17FN 206.1345; found
206.1340. Rf = 0.69 (chloroform/methanol 8:2).
( )-N-(Cyclohex-2-en-1-yl)-N-[(4-methoxyphenyl)methyl]-
acetamide (2b). After completion of the Wharton reaction under
basic conditions (14 h), triethylamine (3 equiv) and acetic anhydride
(5 equiv) were added at 0 °C. The reaction mixture was stirred at
room temperature for an additional 2 h. After treatment as described
in the general procedure, 67 mg (60% yield) of the pure product was
obtained as a colorless oil upon purification by preparative TLC,
eluting with hexane/ethyl acetate (1:1).
1H NMR δ: 7.32 (2H, dd, JAr(o),Ar(m) = 8.4; JAr(o),F = 5.5; Ar(o)); 7.04
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.6; Ar(m)); 4.36 (1H, td, J4,3 = 8.2; J4,5
=
2
2
3.2; H-4); 3.62 (1H, d, J = 13.4; CH2−Ar); 3.46 (1H, d, J = 13.4;
CH2−Ar); 2.96 (1H, t, J5,1 = J5,4 = 3.8; H-5); 2.47 (1H, d, J1,5 = 4.2; H-
1); 2.41 (1H, dd, 2J = 17.9; J3,4 = 8.4; H-3); 2.23 (1H, dd, 2J = 17.9; J3,4
= 6.9; H-3); 2.27−2.18 (1H, br s, OH). 13C NMR δ: 206.7 (C-2);
162.3 (d, 1JC,F = 246; Ar(p) (C−F)); 133.4 (d, 4JC,F = 3; Ar Cq); 129.5
Major rotamer: 1H NMR δ: 7.11 (2H, d, 2J = 8.7; Ar(o)); 6.88 (2H,
2
3
2
d, J = 8.7; Ar(m)); 5.88−5.84 (1H, m, H-3); 5.48−5.42 (1H, m, H-
(d, JC,F = 8; Ar(o)); 115.6 (d, JC,F = 21; Ar(m)); 67.4 (C-4); 60.6
(CH2−Ar); 50.0 (C-1); 49.7 (C-5); 42.0 (C-3). IR (NaCl): 3400 (OH
st.); 1745 (CO st.). Mp = 105−105.5 °C. Anal. Calcd for
C12H12FNO2: C 65.15; H 5.47; N 6.33. Found: C 65.24; H 5.55; N
6.24. Rf = 0.31 (hexane/ethyl acetate 1:1).
2
2); 5.36−5.31 (1H, m, H-1); 4.47 (1H, d, J = 17.6; CH2−Ar); 4.39
2
(1H, d, J = 17.6; CH2−Ar); 3.80 (3H, s, −OMe); 1.99 (3H, s, CH3
Ac); 1.97−1.91 (2H, m, H-4); 1.83−1.56 (3H, m, H-5, H-6); 1.44−
1.37 (1H, m, H-6). 13C NMR δ: 172.0 (Ac (CO)); 158.6 (Ar(p)
(C−OMe)); 131.9 (C-3); 130.6 (Ar Cq); 128.0 (C-2); 126.8 (Ar(o));
114.1 (Ar(m)); 55.3 (−OMe); 51.3 (CH2−Ar); 47.5 (C-1); 27.7 (C-
6); 24.6 (C-4); 22.5 (CH3 Ac); 21.4 (C-5). IR (NaCl): 1639 (CO
st.). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H22NO2
260.1651; found 260.1645. Rf = 0.49 (hexane/ethyl acetate 1:1).
( )-N-(Cyclohex-2-en-1-yl)-N-(prop-2-en-1-yl)acetamide (2c). By
means of the procedure used for 2b, 65 mg (84% yield) of the pure
product was obtained as a colorless oil after purification by preparative
TLC, eluting with hexane/ethyl acetate (1:1).
( )-(1S,6S,7R)-8-[(4-Fluorophenyl)methyl]-6-hydroxy-8-aza-
bicyclo[5.1.0]octan-2-one (1r). By means of the general procedure,
201 mg (60% yield) of the pure product was obtained as a colorless oil
after purification by flash column chromatography, eluting with
hexane/ethyl acetate (1:1).
1H NMR δ: 7.33 (2H, dd, JAr(o),Ar(m) = 8.6; JAr(o),F = 5.5; Ar(o)); 7.04
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.7; Ar(m)); 3.86 (1H, br d, J = 9.8; H-4);
2
2
3.69 (1H, d, J = 13.2; CH2−Ar); 3.39 (1H, d, J = 13.2; CH2−Ar);
2.77 (1H, ddd, 2J = 13.7; J3,4 = 11.1; J3,4 = 2.9; H-3); 2.33 (1H, dd, J7,1
= 7.5; J7,6 = 1.2; H-7); 2.30 (1H, d, J1,7 = 7.5; H-1); 2.25−2.20 (1H, m,
H-3); 1.96−1.78 (3H, m, H-4, H-5); 1.46 (1H, br s, OH); 1.28−1.15
1
Major rotamer: H NMR δ: 5.92−5.76 (2H, m, H-3, H-2′); 5.43
(1H, br d, J2,3 = 10.1; H-2); 5.29−5.06 (3H, m, H-1, H-3′); 3.95 (2H,
m, H-1′); 2.07 (3H, CH3 Ac); 2.06−1.97 (2H, m, H-4); 1.91−1.60
(3H, m, H-5, H-6); 1.42 (1H, tdd, J = 12.4; J = 9.7; J = 2.9; H-6). 13C
NMR δ: 171.4 (Ac (CO)); 135.5 (C-2′); 131.7 (C-3); 128.1 (C-2);
116.0 (C-3′); 50.9 (C-1); 46.8 (C-1′); 27.6 (C-6); 24.6 (C-4); 22.1
(CH3 Ac); 21.4 (C-5). IR (NaCl): 1643; 1631 (CO st.). HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H18NO 180.1383; found
180.1384. Rf = 0.48 (hexane/ethyl acetate 1:1).
1
(1H, m, H-4). 13C NMR δ: 210.6 (C-2); 162.2 (d, JC,F = 246; Ar(p)
(C−F)); 134.0 (d, 4JC,F = 3; Ar Cq); 129.6 (d, 3JC,F = 8; Ar(o)); 115.5
2
(d, JC,F = 21; Ar(m)); 71.6 (C-6); 63.4 (CH2−Ar); 49.7 (C-1); 49.1
(C-7); 41.4 (C-3); 34.2 (C-5); 22.3 (C-4). IR (NaCl): 3400 (OH st.);
1687 (CO st.). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H17FNO2 250.1238; found 250.1240. Rf = 0.57 (hexane/ethyl
acetate 1:2).
( )-N-Butyl-N-(cyclohex-2-en-1-yl)acetamide (2d). By means of
the procedure used for 2b, 80 mg (94% yield) of the pure product was
obtained as a colorless oil after purification by preparative TLC,
eluting with hexane/ethyl acetate (1:1).
General Procedure for the Wharton Reaction of Aziridines
1a−s. Acidic Conditions. A solution of aziridine (0.46 mmol),
monohydrated hydrazine (44 μL, 2 equiv), and acetic acid (52 μL, 2
equiv) in distilled methanol (20 mL) was stirred at room temperature.
After complete reaction (TLC, around 2 h), the reaction mixture was
quenched with a saturated aqueous solution of sodium carbonate (10
mL), and the aqueous layer was extracted with ethyl acetate (3 × 15
mL). The organic layer was dried with anhydrous sodium sulfate and
evaporated to dryness. Purification by chromatography (flash column
or preparative plates) afforded the pure allylic amine or amide. Small
changes to the procedure are reported below.
Basic Conditions. In a flask under argon, a mixture of hydrazine
hydrochloride (170 mg, 3 equiv), triethylamine (170 mg, 3 equiv), and
dry acetonitrile (2 mL) was sonicated for 2 h at room temperature. A
solution of aziridine (0.43 mmol) in dry acetonitrile (1 mL) was
added, and the reaction mixture was stirred at room temperature. After
complete reaction (TLC, around 14 h), the reaction mixture was
quenched with water (5 mL), and the aqueous layer was extracted with
ethyl acetate (3 × 5 mL). The organic layer was dried with anhydrous
sodium sulfate and evaporated to dryness. Purification by chromatog-
Two rotamers: 1H NMR δ: 5.92−5.84 (1H, m, H-3); 5.51 (0.5H, br
d, J2,3 = 10.1; H-2); 5.44 (0.5H, br d, J2,3 = 10.2; H-2); 5.18−5.12
(0.5H, m, H-1); 4.31−4.26 (0.5H, m, H-1); 3.21−3.04 (2H, m, H-1′);
2.11 (3H, CH3 Ac); 2.06−2.00 (2H, m, H-4); 1.91−1.75 (2H, m, H-5,
H-6); 1.72−1.44 (4H, m, H-5, H-6, H-2′); 1.31 (1H, sext, 3J = 7.7; H-
3′); 1.29 (1H, sext, 3J = 7.7; H-3′); 0.94 (1.5H, t, 3J = 7.3; H-4′); 0.90
3
(1.5H, t, J = 7.3; H-4′). 13C NMR δ: 170.7, 170.2 (Ac (CO));
131.3, 130.9 (C-3); 128.8, 128.4 (C-2); 55.8, 51.0 (C-1); 44.9, 43.1
(C-1′); 33.5, 31.6 (C-2′); 28.7, 27.6 (C-6); 24.6, 24.4 (C-4); 22.2, 21.9
(CH3 Ac); 21.7, 21.6 (C-5); 20.6, 20.4 (C-3′); 13.9, 13.7 (C-4′). IR
(NaCl): 1639 (CO st.). HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C12H22NO 196.1696; found 196.1688. Rf = 0.31 (hexane/ethyl
acetate 2:1).
( )-N-Octylcyclohex-2-en-1-amine (2e). By means of the general
procedure under acidic conditions, 90 mg (93% yield) of the pure
product was obtained as a yellow oil after purification by flash column
F
DOI: 10.1021/jo5029387
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
chromatography, eluting with dichloromethane/methanol (95:5), Rf =
0.24 (dichloromethane/methanol 9:1).
66.80; N 3.71; H 8.54. Found: C 66.68; N 3.65; H 8.22. Rf = 0.56
(hexane/ethyl acetate 7:3).
( )-(1S,2R)-2-{[(4-Fluorophenyl)methyl]amino}cyclohex-3-en-1-
ol (2m). By means of the general procedure under acidic conditions,
62 mg (61% yield) of the pure product was obtained as a pale-yellow
solid after purification by flash column chromatography, eluting with
ethyl acetate.
( )-N-(Cyclohex-2-en-1-yl)-4-methoxyaniline (2f). By means of
the general procedure under basic conditions, 47 mg (54% yield) of
the pure product was obtained as a yellow oil following purification by
preparative TLC, eluting with hexane/ethyl acetate (8:2), Rf = 0.72
(hexane/ethyl acetate 8:2).
( )-N-(Cyclohex-2-en-1-yl)-4-methylbenzene-1-sulfonamide
(2g). By means of the general procedure under acidic conditions, 57
mg (49% yield) of the pure product was obtained as a white solid after
purification by preparative TLC, eluting with hexane/ethyl acetate
(6:4), Rf = 0.72 (hexane/ethyl acetate 6:4).
( )-N-(Cyclohex-2-en-1-yl)acetamide (2h). By means of the
general procedure under acidic conditions, 26 mg (40% yield) of the
pure product was obtained as a white solid after purification by
preparative TLC, eluting with hexane/ethyl acetate (1:2), Rf = 0.35
(hexane/ethyl acetate 1:2).
1H NMR δ: 7.34 (2H, dd, JAr(o),Ar(m) = 8.6; JAr(o),F = 5.5; Ar(o)); 7.04
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.7; Ar(m)); 5.84 (1H, dtd, J4,3 = 10.0; J =
3.7; J = 1.7; H-4); 5.62 (1H, ddt, J3,4 = 10.0; J = 3.6; J = 2.0; H-3); 4.14
(2H, br s, NH, OH); 3.93 (1H, d, 2J = 13.0; CH2−Ar); 3.88 (1H, d, 2J
= 13.1; CH2−Ar); 3.88−3.85 (1H, m, H-1); 3.22−3.19 (1H, m, H-2);
2.21−2.11 (1H, m, H-5); 2.04−1.95 (1H, m, H-5); 1.69 (2H, q, J6,1
=
1
J6,5 = 6.2; H-6). 13C NMR δ: 162.1 (d, JC,F = 245; Ar(p) (C−F));
4
3
135.6 (d, JC,F = 3; Ar Cq); 130.1 (C-4); 129.8 (d, JC,F = 8; Ar(o));
126.4 (C-3); 115.4 (d, 2JC,F = 21; Ar(m)); 65.5 (C-1); 55.2 (C-2); 51.2
(CH2−Ar); 27.0 (C-6); 22.7 (C-5). IR (NaCl): 3400 (OH, NH st.).
Mp = 72.5−73 °C. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H17FNO 222.1294; found 222.1289. Rf = 0.33 (ethyl acetate).
(−)-N-[(1R,6S)-6-Hydroxycyclohex-2-en-1-yl]-N-(prop-2-en-1-yl)-
acetamide (2n). By means of the same procedure as used for 2b, 71
mg (84% yield) of the pure product was obtained as a colorless oil
after purification by preparative TLC, eluting with hexane/ethyl
acetate (1:2).
(+)-(1R)-N-[(1R)-1-Phenylethyl]cyclohex-2-en-1-amine (2i). By
means of the general procedure under acidic conditions, 54 mg
(58% yield) of the pure product was obtained as a pale-yellow oil after
purification by flash column chromatography, eluting with hexane/
ethyl acetate (1:2).
2
2
1H NMR δ: 7.35 (2H, d, J = 7.6; Ar(o)); 7.32 (2H, t, J = 7.6;
2
Ar(m)); 7.23 (1H, t, J = 7.7; Ar(p)); 5.82 (1H, d, J2,3 = 10.4; H-2);
5.73 (1H, d, J3,2 = 10.3; H-3); 4.02 (1H, q, J = 6.6; CH−Ar); 3.02−
1H NMR δ: 5.99−5.95 (1H, m, H-3); 5.83 (1H, ddt, J2′,3′ = 16.2;
J2′,3′ = 10.7; J2′,1′ = 5.1; H-2′); 5.54 (1H, br d, J2,3 = 9.4; H-2); 5.23
(1H, br d, J3′,2′ = 11.1; H-3′); 5.19 (1H, br d, J3′,2′ = 18.0; H-3′); 4.98
(1H, br s, H-1); 4.16−4.10 (1H, m, H-6); 4.03 (2H, s, H-1′); 2.56
(1H, br s, OH); 2.37−2.01 (2H, m, H-4); 2.14 (3H, s, Ac (CH3));
1.83−1.77 (1H, m, H-5); 1.72−1.63 (1H, m, H-5). 13C NMR δ: 174.6
(Ac (CO)); 134.9 (C-2′); 132.3 (C-3); 123.7 (C-2); 116.2 (C-3′);
69.7 (C-6); 54.9 (C-1); 49.8 (C-1′); 26.5 (C-5); 22.7 (C-4); 22.3 (Ac
(CH3)). IR (NaCl): 1624 (CO st.). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C11H18NO2 196.1332; found 196.1325. [α]2D0 = −52 (c =
0.2; CH2Cl2). Rf = 0.38 (hexane/ethyl acetate 1:2).
3
2.98 (1H, m, H-1); 2.27 (1H, br s, NH); 2.03−1.87 (2H, m, H-4);
1.79−1.64 (2H, m, H-5, H-6); 1.51−1.38 (2H, m, H-4, H-5); 1.35
(3H, d, 3J = 6.6; Me). 13C NMR δ: 145.8 (Ar Cq); 129.4 (C-2); 128.7
(C-3); 128.4 (Ar(m)); 126.9 (Ar(p)); 126.7 (Ar(o)); 55.0 (CH−Ar);
50.2 (C-1); 30.5 (C-6); 25.3 (C-4); 24.7 (Me); 20.5 (C-5). [α]D20
=
+160 (c = 0.8; CH2Cl2). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H20N 202.1596; found 202.1590. Rf = 0.38 (ethyl acetate).
(+)-(1S)-N-[(1R)-1-Phenylethyl]cyclopent-2-en-1-amine (2j). By
means of the general procedure under basic conditions, 36 mg (44%
yield) of the pure product was obtained as a pale-yellow oil after
purification by flash column chromatography, eluting with hexane/
ethyl acetate (1:2).
( )-N-{(1S,6S)-6-[(tert-Butyldimethylsilyl)oxy]cyclohex-2-en-1-yl}-
4-methylbenzene-1-sulfonamide (2o). By means of the general
procedure under acidic conditions, 117 mg (67% yield) of the pure
product was obtained as a colorless oil after purification by preparative
TLC, eluting with hexane/ethyl acetate (8:2).
2
2
1H NMR δ: 7.35 (2H, d, J = 6.5; Ar(o)); 7.32 (2H, t, J = 7.4;
Ar(m)); 7.23 (1H, t, 2J = 6.8; Ar(p)); 5.78 (1H, dq, J2,3 = 5.6; J2,1 = J2,4
= 2.0; H-2); 5.61 (1H, dq, J3,2 = 5.6; J3,1 = J3,4 = 1.9; H-3); 3.89 (1H, q,
3J = 6.6; CH−Ar); 3.68−3.63 (1H, m, H-1); 2.46−2.36 (1H, m, H-4);
1H NMR δ: 7.73 (2H, d, 2J = 8.2; Ar(o) Ts); 7.27 (2H, d, 2J = 8.1;
Ar(m) Ts); 5.77−5.72 (1H, m, H-3); 5.29 (1H, dm, J2,3 = 9.9; H-2);
4.52 (1H, d, JNH,1 = 6.5; NH); 3.83−3.80 (1H, m, H-6); 3.48−3.44
2.25−2.09 (2H, m, H-4, H-5); 1.63−1.52 (2H, m, H-5, NH); 1.36
(3H, d, 3J = 6.6; Me). 13C NMR δ: 145.7 (Ar Cq); 133.6 (C-3); 132.3
(C-2); 128.4 (Ar(m)); 126.93 (Ar(p)); 126.86 (Ar(o)); 62.0 (C-1);
56.2 (CH−Ar); 31.1, 31.0 (C-4, C-5); 24.7 (Me). [α]2D0 = +50 (c = 0.5;
CH2Cl2). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H18N
188.1439; found 188.1434. Rf = 0.37 (ethyl acetate).
( )-N-(Cyclopent-2-en-1-yl)-4-methylbenzene-1-sulfonamide
(2k). By means of the general procedure under acidic conditions, 71
mg (65% yield) of the pure product was obtained as a white solid after
purification by preparative TLC, eluting with hexane/ethyl acetate
(2:1), Rf = 0.66 (hexane/ethyl acetate 2:1).
2
(1H, m, H-1); 2.43 (3H, s, Me Ts); 2.14 (1H, dm, J = 18.1; H-4);
2
1.93 (1H, dm, J = 18.2; H-4); 1.74−1.57 (2H, m, H-5); 0.84 (9H, s,
tBu TBDMS); 0.05 (3H, s, CH3 TBDMS); 0.04 (3H, s, CH3
TBDMS). 13C NMR δ: 143.4 (Ar C−SO2 Ts); 137.7 (Ar(p) Ts);
131.2 (C-3); 129.7 (Ar(m) Ts); 127.1 (Ar(o) Ts); 124.0 (C-2); 70.2
t
(C-6); 54.8 (C-1); 26.8 (C-5); 25.7 (3 × Me Bu); 21.7 (C-4); 21.5
(Me Ts); 18.0 (Cq tBu); −4.7 (Me TBDMS); −4.8 (Me TBDMS).
Anal. Calcd for C19H31NO3SSi: C 59.80; N 3.67; H 8.19; S 8.40.
Found: C 59.80; N 3.58; H 8.26; S 8.21. Rf = 0.53 (hexane/ethyl
acetate 8:2).
( )-N-{(1R,6S)-6-[(tert-Butyldimethylsilyl)oxy]cyclohex-2-en-1-yl}-
N-[(4-fluorophenyl)methyl]acetamide (2l). By means of the same
procedure as used for 2b, 75 mg (46% yield) of the pure product was
obtained as a colorless oil after purification by preparative TLC,
eluting with hexane/ethyl acetate (7:3).
( )-N-{(1R,5S)-5-[(tert-Butyldimethylsilyl)oxy]cyclopent-2-en-1-
yl}-N-[(4-fluorophenyl)methyl]acetamide (2p). By means of the
procedure used for 2b, 45 mg (29% yield) of the pure product was
obtained as a colorless oil after purification by preparative TLC,
eluting with hexane/ethyl acetate (7:3).
1H NMR δ: 7.14 (2H, dd, JAr(o),Ar(m) = 8.5; JAr(o),F = 5.4; Ar(o)); 7.02
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.5; Ar(m)); 5.80−5.75 (1H, m, H-3);
5.26−5.22 (2H, m, H-2, H-1); 4.68 (1H, d, 2J = 18.3, CH2−Ar); 4.49
(1H, d, 2J = 18.3, CH2−Ar); 4.39−4.35 (1H, m, H-6); 2.33−2.25 (1H,
1H NMR δ: 7.16 (2H, dd, JAr(o),Ar(m) = 8.6; JAr(o),F = 5.4; Ar(o)); 7.04
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.6; Ar(m)); 5.83−5.79 (1H, m, H-3);
5.55−5.52 (1H, m, H-1); 5.45−5.42 (1H, m, H-2); 4.64 (1H, td, J5,1
=
J5,4 = 6.4; J5,4 = 2.3; H-5); 4.53 (1H, d, 2J = 17.5; CH2−Ar); 4.38 (1H,
d, 2J = 18.1; CH2−Ar); 2.62 (1H, dm, 2J = 17.3; H-4); 2.28 (1H, dm,
2
m, H-4); 1.94 (3H, s, Ac (CH3)); 1.88 (1H, dm, J = 18.3; H-4);
t
2J = 17.2; H-4); 1.99 (3H, s, Ac (CH3)); 0.91 (9H, s, Bu TBDMS);
t
1.77−1.74 (2H, m, H-5); 0.93 (9H, s, Bu TBDMS); 0.07 (3H, s, Me
TBDMS); 0.04 (3H, s, Me TBDMS). 13C NMR δ: 172.1 (Ac (C
0.08 (3H, s, Me TBDMS); 0.05 (3H, s, Me TBDMS). 13C NMR δ:
1
O)); 161.7 (d, 1JC,F = 245; Ar(p) (C−F)); 135.3 (d, 4JC,F = 3; Ar Cq);
171.9 (Ac (CO)); 161.8 (d, JC,F = 245; Ar(p) (C−F)); 135.0 (d,
4JC,F = 3; Ar Cq); 132.4 (C-3); 127.9 (C-2); 127.1 (d, 3JC,F = 8; Ar(o));
115.6 (d, 2JC,F = 21; Ar(m)); 71.2 (C-5); 62.9 (C-1); 49.9 (CH2−Ar);
131.6 (C-3); 126.9 (d, 3JC,F = 8; Ar(o)); 123.3 (C-2); 115.6 (d, 2JC,F
=
21; Ar(m)); 66.8 (C-6); 55.2 (C-1); 50.4 (CH2−Ar); 28.8 (C-5); 25.9
t
(3 × Me tBu); 22.4 (Ac (CH3)); 20.1 (C-1); 17.9 (Cq Bu); −4.8 (Me
t
41.8 (C-4); 25.8 (3 × Me tBu); 22.2 (Ac (CH3)); 17.9 (Cq Bu); −4.9
TBDMS); −4.9 (Me TBDMS). Anal. Calcd for C21H32FNO2Si: C
(Me TBDMS); −5.1 (Me TBDMS). Anal. Calcd for C20H30FNO2Si:
G
DOI: 10.1021/jo5029387
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C 66.08; N 3.85; H 8.32. Found: C 66.30; N 3.80; H 8.49. Rf = 0.50
(hexane/ethyl acetate 7:3).
( )-(1S,2R)-2-{[(4-Fluorophenyl)methyl]amino}cyclopent-3-en-1-
ol (2q). By means of the general procedure under acidic conditions, 39
mg (41% yield) of the pure product was obtained as a yellow solid
after purification by flash column chromatography, eluting with
chloroform/methanol (95:5).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
S.S. and P.R. thank the Fundaca
■
̧
o para a Cien
̂
cia e Tecnologia
̃
for Grants SFRH/BD/84309/2012 and SFRH/BD/27423/
2006. This work was supported by FCT through Grant PEst-
OE/EQB/LA0004/2011 and Projects PTDC/QUI-QUI/
104056/2008 and POCI/QUI/62794/2004. The NMR spec-
trometers are part of The National NMR Facility, supported by
1H NMR δ: 7.32−7.26 (2H, m, Ar(o)); 7.02 (2H, t, JAr(m),Ar(o)
=
JAr(m),F = 8.3; Ar( m)); 5.84−5.81 (1H, m, H-3); 5.62−5.59 (1H, m, H-
4); 4.22−4.18 (1H, m, H-1); 3.82 (2H, s, CH2−Ar); 3.70−3.67 (1H,
m, H-2); 2.81 (2H, br s, NH, OH); 2.55 (1H, dd, 2J = 17.3; J = 3.9; H-
2
1
5); 2.34 (1H, d, J = 17.2; H-5). 13C NMR δ: 162.1 (d, JC,F = 245;
Fundaca̧ o para a Ciencia e a Tecnologia (RECI/BBB-BQB/
0230/2012). We thank the Analytical Services Unit (ASU) at
ITQB for providing CHNS elemental analyses.
̂
̃
Ar(p) (C−F)); 135.5 (d, 4JC,F = 3; Ar Cq); 132.0 (C-3); 130.5 (C-4);
3
2
129.7 (d, JC,F = 8; Ar(o)); 115.4 (d, JC,F = 21; Ar(m)); 68.6 (C-1);
65.5 (C-2); 52.2 (CH2−Ar); 40.9 (C-5). IR (NaCl): 3300 (OH, NH
st.). Mp = 41.5−42 °C. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C12H15FNO 208.1138; found 208.1132. Rf = 0.44 (chloroform/
methanol 9:1).
REFERENCES
■
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ol (2r). By means of the general procedure under acidic conditions, 83
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after purification by flash column chromatography, eluting with
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(9) The corresponding free amine of 2c oxidized rapidly and that of
2d was very volatile. Therefore, these products were isolated as their
acetamides.
(10) Basic and acidic conditions were tried, and the best results are
reported in the table.
(11) (a) Klingler, F. D. Acc. Chem. Res. 2007, 40, 1367. (b) Bergmeier,
S. C. Tetrahedron 2000, 56, 2561.
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1H NMR δ: 7.30 (2H, dd, JAr(o),Ar(m) = 8.6; JAr(o),F = 5.5; Ar(o)); 7.01
(2H, t, JAr(m),Ar(o) = JAr(m),F = 8.7; Ar(m)); 5.96 (1H, dddd, J4,3 = 11.3;
J4,5 = 7.3; J4,5 = 5.7; J4,2 = 1.7; H-4); 5.50 (1H, br dd, J3,4 = 10.9; J3,2
=
4.4; H-3); 3.91−3.88 (1H, m, H-1); 3.85 (1H, d, 2J = 13.1; CH2−Ar);
3.77 (1H, d, 2J = 13.1; CH2−Ar); 3.47−3.45 (1H, m, H-2); 2.30−2.15
2
(2H, br s, OH, NH); 2.18 (1H, dtd, J = 15.3; J5,4 = J5,6 = 7.6; J5,6
=
2.9; H-5); 2.11−2.06 (1H, m, H-5); 2.02 (1H, dtd, 2J = 14.1; J = 7.0; J
= 3.0; H-7); 1.77 (1H, ddt, 2J = 14.1; J = 10.5; J = 3.3; H-7); 1.61 (1H,
dtt, 2J = 13.6; J = 10.3; J = 3.1; H-6); 1.49 (1H, ddt, 2J = 14.1; J = 7.1; J
1
= 3.5; H-6). 13C NMR δ: 162.0 (d, JC,F = 245; Ar(p) (C−F)); 135.7
3
(Ar Cq); 133.5 (C-4); 131.1 (C-3); 129.8 (d, JC,F = 8; Ar(o)); 115.3
2
(d, JC,F = 21; Ar(m)); 69.5 (C-1); 61.2 (C-2); 50.9 (CH2−Ar); 35.4
(C-5); 28.6 (C-7); 21.0 (C-6). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C14H19FNO 236.1445; found 236.1441. Rf = 0.64
(chloroform/methanol 9:1).
(+)-(3aS,4R,7aR)-N-[(4-Methoxyphenyl)methyl]-2,2-dimethyl-
3a,4,7,7a-tetrahydro-2H-1,3-benzodioxol-4-amine (2s). By means of
the general procedure under acidic conditions, 83 mg (68% yield) of
the pure product was obtained as a yellow oil after purification by flash
column chromatography, eluting with chloroform/methanol (95:5).
1H NMR δ: 7.26 (2H, d, 2J = 8.6 Hz; Ar(o)); 6.86 (2H, d, 2J = 8.6;
Ar(m)); 5.82−5.74 (2H, m, H-5, H-6); 4.32 (1H, td, J7a,3a = J7a,7 = 6.8;
J7a,7 = 5.3; H-7a); 4.00 (1H, t, J3a,7a = J3a,4 = 6.5; H-3a); 3.88 (1H, d, 2J
2
= 13.1; CH2−Ar); 3.81 (1H, d, J = 13.2; CH2−Ar); 3.79 (3H, s,
(16) (a) Johnson, D. S.; Li, J. J. In The Art of Drug Synthesis; Johnson,
D. S., Li, J. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2006; p 95.
(b) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
(17) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals; Butterworth-Heinemann: Oxford, U.K., 2003.
(18) Sheldrick, G. Acta Crystallogr., Sect. A 2008, 64, 112.
(19) Farrugia, L. J. Appl. Crystallogr. 1999, 32, 837.
−OMe); 3.25−3.23 (1H, m, H-4); 2.62 (1H, ddd, 2J = 16.0; J7,7a = 6.7;
J7,6 = 5.0; H-7); 2.21−2.13 (1H, m, H-7); 1.86 (1H, s, NH); 1.41 (3H,
s, Me); 1.35 (3H, s, Me). 13C NMR δ: 158.7 (Ar(p) (C−OMe));
132.4 (Ar Cq); 129.9 (C-6); 129.4 (Ar(o)); 125.7 (C-5); 113.8
(Ar(m)); 108.2 (C-2); 79.2 (C-3a); 72.6 (C-7a); 57.0 (C-4); 55.3
(−OMe); 51.0 (CH2−Ar); 28.7 (C-7); 27.5 (Me); 25.2 (Me). [α]D20
=
+45 (c = 0.5; CH2Cl2). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H24NO3 290.1756; found 290.1751. Rf = 0.71 (chloroform/
methanol 9:1).
ASSOCIATED CONTENT
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* Supporting Information
1
Copies of H and 13C NMR spectra of all products, X-ray
structures and crystallographic information files for compounds
(1R,6R)-1i and (1R,5R)-1j, and a table summarizing the results
of other Wharton reactions with compounds 1a−k. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: maycock@itqb.unl.pt.
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DOI: 10.1021/jo5029387
J. Org. Chem. XXXX, XXX, XXX−XXX