Synthesis of 2,4-, 3,4- and 2,3,4-substituted pyrrolidines by cyclization of neutral C-centered α-aminoalkyl radicals

Article abstract of DOI:10.1016/S0040-4020(02)00754-8

The effect of substitution at C-3 or C-4 of the 2-azahex-5-enyl chain has been studied in the SmI₂-promoted cyclizations of neutral α-aminoalkyl radicals generated from N-(α-benzotriazolyl)alkenylamines. 2,4-, 3,4- and 2,3,4-substituted pyrroli

Full text of DOI:10.1016/S0040-4020(02)00754-8

Tetrahedron 58 (2002) 6837–6842
Synthesis of 2,4-, 3,4- and 2,3,4-substituted pyrrolidines by
cyclization of neutral C-centered a-aminoalkyl radicals
*
´ ´ ´
Fernando Bustos, Jose M. Gorgojo, Ruben Suero and Jose M. Aurrecoechea
´ ´ ´
Departamento de Quımica Organica II, Facultad de Ciencias, Universidad del Paıs Vasco, Apartado 644, 48080 Bilbao, Spain
Received 4 April 2002; revised 7 June 2002; accepted 28 June 2002
Abstract—The effect of substitution at C-3 or C-4 of the 2-azahex-5-enyl chain has been studied in the SmI2-promoted cyclizations of
neutral a-aminoalkyl radicals generated from N-(a-benzotriazolyl)alkenylamines. 2,4-, 3,4- and 2,3,4-substituted pyrrolidines are obtained
in this manner in uniformly high yields but with stereoselectivities which depend markedly on the substitution pattern. Thus, a methyl
substituent at C-4 (hex-5-enyl numbering) effectively controls the stereochemistry over three contiguous stereogenic centers whereas
substituents at C-3 are found to exert a very poor control. Stereochemical results are rationalized according to the existing models for radical
ring-closures. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
generated by reduction of iminium cations formed by in situ
dissociation of adducts 2 in solution.8 It was of interest to
extend this methodology to substrates containing substi-
tution at the 3- or 4-positions of the 2-azahex-5-enyl system
(R2, R3–H) as this would provide a ready access to
pyrrolidines with a wider range of substitution patterns.9–16
In our previous work it was also noticed that the cyclizations
of 1-alkyl-substituted radicals 3 (R¼alkyl; R2¼R3¼H;
Y¼EWG) took place with useful levels of cis-selectivity,6a
in agreement with the Beckwith–Houk model17 for radical
ring-closures. Therefore, the presence of substituents at C-3
or C-4 of 3 would also allow a more complete assessment of
the stereochemical impact brought about by the presence of
a neutral N-alkyl-substituted 2-aza moiety in the cycliza-
tions of substituted hex-5-enyl radicals. This paper
describes our results in this area.
The pyrrolidine ring system is found in a vast variety of
compounds displaying an impressive range of biological
activities. Thus, the incorporation of different substitution
patterns and motives into the basic heterocyclic structure
common to such activities has potential in the discovery of
new substances with useful pharmacological properties.1–5
Recently, we have reported that a variety of 2,3-disubsti-
tuted pyrrolidines 4 (R2¼R3¼H) are available from simple
acyclic precursors in a two-step procedure involving
condensation of amines 1 with an aldehyde and benzo-
triazole, followed by SmI2-promoted reductive cyclization
of the so-formed adducts 2 (Scheme 1).6 This cyclization
proceeds through the intermediacy of a-amino radicals7 3
2. Results and discussion
2.1. Synthesis of 2,4-disubstituted pyrrolidines
Appropriate secondary amine substrates 1a–d were selected
for this study (Schemes 2 and 3). Since we had previously
found that electron-deficient alkenes gave best results both
in terms of yield and diastereoselectivity of cyclization,6
amines 1a–d all contain an electron-withdrawing sub-
stituent at the alkene terminus. Amine 1a was conveniently
prepared from N-benzylidenebenzylamine (5) by addition of
a zinc dienolate derived from ethyl 4-bromocrotonate (6),18,
19
whereas a similar addition to benzotriazoles 7 provided
Scheme 1.
tertiary allylamines 8b,c that were easily deallylated20 to
give the desired 1b and 1c, as described elsewhere21
(Scheme 2). Amine 1d, designed to also exemplify the
formation of bicyclic products, was prepared from the
Keywords: radical cyclizations; pyrrolidines; samarium.
*
Corresponding author. Tel.: þ34-946-01-2578; fax: þ34-944-64-8500;
e-mail: qopaufem@lg.ehu.es
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00754-8

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F. Bustos et al. / Tetrahedron 58 (2002) 6837–6842
stereoselectivity. No attempt was made at the stereo-
chemical elucidation of the individual isomers.
2.2. Synthesis of 3,4- and 2,3,4-substituted pyrrolidines
An appropriate methyl-substituted amine 1e, bearing an
electron-deficient olefin, was prepared from the Michael
adduct 1123 by DIBAL-H reduction of Boc-protected 12,
followed by Wittig olefination of the resulting aldehyde and
N-deprotection (Scheme 5).
Scheme 2.
Scheme 5.
Treatment of the benzotriazole adduct 2e derived from 1e
and formaldehyde with SmI2 and t-BuOH, under the
conditions described above, afforded a good yield of the
expected 3,4-disubstituted pyrrolidine 4e (Scheme 6). In
contrast to the formation of 2,4-disubstituted pyrrolidines,
this time cyclization took place with more useful levels of
diastereoselectivity, with the trans-isomer being the major
one obtained (87:13 dr). This stereochemical assignment
was based on the observation of upfield shifts on the carbon
resonances of C-3, C-4 and the exocyclic CH2 at C-3,6,24,25
as well as on the CH3 protons at C-4, for the minor isomer
when compared with the major one. Similarly, amine 1e was
condensed with benzotriazole and butyraldehyde to afford
an adduct 2f, which was then treated with SmI2 and t-BuOH
to give trisubstituted pyrrolidine 4f in 67% yield with good
stereoselectivity. The stereochemistry of the major product
was determined with the aid of NOE experiments that
showed a ,10% enhancement in the resonances of H-3
upon saturation of H-2, consistent with a 2,3-cis relation-
ship. The 3,4-trans relationship was established after the
observation of small NOE’s between H-3 and H-4 (1–3%)
and a comparatively greater enhancement (,10%) of the
H-3 signal upon saturation of the (C-4)-methyl resonance.
Scheme 3.
known aldehyde 922 by Wittig olefination and N-deprotec-
tion (Scheme 3).
Amines 1a–d were treated with N-(hydroxymethyl)benzo-
triazole (BtCH2OH, the equivalent of formaldehyde and
˚
benzotriazole) in the presence of 4 A molecular sieves to
give N-(benzotriazolylmethyl)amines 2a–d, that were
directly used in the subsequent cyclization reactions in a
crude form (Scheme 4). Thus, following our reported
procedure,6a benzotriazole adducts 2a–c were treated with
excess SmI2/t-BuOH from 2788C to room temperature to
give in all cases high yields (two steps from amines 1a–c) of
the expected pyrrolidines 4a–c, that were obtained as
diastereomeric mixtures with little selectivity (Scheme 4).
The geometrical constraints imposed by the cyclic nature of
the substrate 1d had no effect on the stereochemical
outcome of the reaction. Thus, under the same conditions,
bicyclic amine 4d was also obtained with very low
Scheme 6.
2.3. Stereochemistry
The lack of stereoselectivity observed in the formation of
2,4-disubstituted pyrrolidines is in line with that found in
cyclizations of related dialkylaminomethyl radicals
generated by photoinduced electron transfer (PET).26,27
Therefore, the introduction of a 2-aza moiety appears to
Scheme 4.

F. Bustos et al. / Tetrahedron 58 (2002) 6837–6842
6839
have an adverse effect on the stereochemical outcome of the
otherwise selective 3-alkylhex-5-enyl radical.17 The amino-
methyl radical has been studied in some detail and it is
shown to have a delocalized structure with partial double
bond character between the N atom and the C atom formally
bearing the unpaired electron.28–30 Calculations31 per-
formed on a model radical 3 (R¼R3¼H, R1¼R2¼CH3,
Y¼CN) indicate that these structural features are also
reflected in the TS for cyclization of the 2-azahex-5-enyl
radical. Thus, in the chair- and boat-like transition structures
14a–d the N-methyl substituent occupies a position where it
allows some interaction between the unpaired electron and
the N lone pair, while the latter is oriented away from the
double bond undergoing addition to minimize electron
repulsion. The calculated energies are very similar for cis
and trans TS’s, in agreement with the observed low isomer
ratios.32a A gauche-type interaction between the methyl
group at C-3 (hex-5-enyl radical numbering) and the
N-methyl substituent in cis-chair 14a and trans-boat 14d,
absent in cis-boat 14b and trans-chair 14c, could be
responsible for the lack of a well defined stereopreference
in these reactions.
effects of the 4-Me and 1-alkyl substitutions (hex-5-enyl
radical numbering) appear to reinforce each other, making
this reaction a convenient stereoselective entry into 2,3,4-
trisubstituted pyrrolidines.
3. Conclusions
The reduction of N-(a-benzotriazolyl)alkenylamines pro-
vides a useful entry into 2,4-, 3,4- and 2,3,4-substituted
pyrrolidines through the intermediacy of 2-azahex-5-enyl
radicals. A substituent at C-4 of the 2-azahex-5-enyl chain
effectively controls the stereochemistry of cyclization
making this a potentially useful method for formation of
2,3,4-trisubstituted pyrrolidines. In contrast, substituents at
C-3 afford very poor stereoinduction.
4. Experimental
4.1. General methods
All reactions involving air- and moisture sensitive materials
were performed under an atmosphere of dry Ar. Tetra-
hydrofuran (THF) and toluene were freshly distilled from
sodium/benzophenone and, for reactions with SmI2, THF
was deoxygenated prior to use. Acetonitrile and dichloro-
methane were freshly distilled from CaH2. SmI2 (ca. 0.1 M
in THF) was prepared from Sm and diiodomethane using a
literature procedure.33 Flash chromatography34 was per-
In contrast, similar calculations performed on model radical
3 (R¼R2¼H, R1¼R3¼CH3, Y¼CN) predict a much better
stereoselectivity in the formation of 3,4-substituted pyr-
rolidines (Fig. 1), as confirmed experimentally.32b In both
calculations and experiment, the extent and sense of
stereoselectivity are in agreement with expectations based
on the Beckwith–Houk model,17 that predicts a preferred
trans-4,5 relationship (hex-5-enyl radical numbering)
through a chair-like transition structure 15c. Also, the
observed diastereomeric ratios are in the range found for the
parent 4-methylhex-5-enyl radical.17d Therefore, in this
radical the introduction of a 2-aza unit appears to have no
major consequences on the stereochemistry of cyclization. It
is remarkable that upon introduction of an alkyl substituent
at C-1 of the 2-aza-4-methylhex-5-enyl chain the cycliza-
tion maintained the same high level of stereoselectivity.
Thus, in the formation of 4f, out of four possible isomers one
amounts to 90% of the diastereomeric mixture. Interest-
ingly, under the same reaction conditions, the related cis-
2,3-dialkyl pyrrolidines are formed in diastereomeric ratios
in the range 86:14–91:9.6a Therefore, the stereochemical
1
formed on silica gel (230–400 mesh). Routine H and 13C
NMR spectra were obtained at 250 and 62.9 MHz,
respectively, using CDCl3 as solvent and internal reference
1
(d 7.26 for H and d 77.0 for 13C). IR data include only
characteristic absorptions. Mass spectra were obtained at
70 eV. GC-MS analysis were performed at 70–2808C
(208C/min) with a stationary phase of methylphenylsilicone
(0.25 mm, 30 m£0.25 mm).
4.2. Synthesis of 2,4-disubstituted pyrrolidines
4.2.1. Ethyl (E )-6-aza-5,7-diphenylhept-2-enoate (1a).
Ethyl (E)-4-bromobut-2-enoate (3.85 mL, 28.0 mmol) was
added dropwise to a stirred mixture of N-benzylidene-
benzylamine (2.68 g, 13.8 mmol), Zn (3.66 g, 56.0 mmol),
Yb(OTf)3 (1.71 g, 2.76 mmol) and Me3SiCl (1.78 mL,
14.0 mmol) in acetonitrile (80 mL) at 08C. The mixture
was allowed to warm to room temperature, stirred for 12 h
and poured into 32% aq. ammonia (150 mL). The layers
were separated and the aqueous layer was extracted with
EtOAc (3£200 mL). The combined organic extracts were
dried (Na2SO4) and filtered over Celite. The crude after
evaporation was purified by flash chromatography (85:15
hexanes/EtOAc) to yield 1a (1.57 g, 37%) as an orange-
tinted oil: 1H NMR d 1.27 (t, J¼7.1 Hz, 3H, CH3), 1.66 (br
s, 1H, NH), 2.53–2.60 (m, 2H, H-4), 3.54 and 3.67 (AB
system, J¼13.2 Hz, 2H, PhCH2), 3.79 (t, J¼6.8 Hz, 1H,
H-5), 4.16 (q, J¼7.1 Hz, 2H, OCH2), 5.82 (dt, J¼15.7,
1.4 Hz, 1H, H-2), 6.87 (dt, J¼15.7, 7.4 Hz, 1H, H-3), 7.21–
7.40 (m, 10H, Ar); 13C NMR d 14.2, 41.1, 51.2, 60.1, 61.1
(C-5), 123.5 (C-2), 126.9, 127.0, 127.3, 128.0, 128.3, 128.5,
140.2, 142.8, 145.4 (C-3), 166.2 (CvO); IR (neat) n 3320
(N–H), 1720 (CvO), 1650 (CvC) cm21; LRMS (EI) m/z
Figure 1. Relative PM3-UHF transition structure energies (kcal/mol) for
cyclizations of model radicals 3 (R¼H, R1¼Me, Y¼CN, R2 or R3¼Me).

6840
F. Bustos et al. / Tetrahedron 58 (2002) 6837–6842
197 (17), 196 (base), 194 (2), 129 (2), 92 (5), 91 (59);
HRMS calcd for C20H23NO2 309.1729, found 309.1716.
flash chromatography (silica gel saturated with Et3N, 99:1
hexanes/Et3N) to yield 4c (75%, 55:45 dr). Data for the
diastereomeric mixture: 1H NMR d 0.93 (t, J¼6.9 Hz, 3H),
1.12–1.85 (m, 9H), 2.14–2.52 (m, 5H), 2.59–2.63 and
3.03–3.16 (2m, 2H), 4.00–4.13 (m, 3H), 7.19–7.31 (m,
5H); 13C NMR d 14.1, 14.4, 19.2, 19.3, 31.7 (C-4), 32.1
(C-4), 36.1, 36.4, 36.8, 37.5, 39.2, 40.7, 57.7, 58.4, 59.0,
59.9, 60.0, 60.2, 63.3 (C-2), 64.2 (C-2), 126.5, 126.6, 127.9,
128.0, 128.4, 128.7, 139.3, 139.7, 172.5 (CvO), 172.9
(CvO); IR (neat)n 1740 (CvO) cm21; LRMS (EI) m/z 289
(M, 22), 288 (base), 258 (2), 246 (4), 162 (7), 91 (29);
HRMS calcd for C18H27NO2 289.2042, found 289.1989.
4.2.2. 1-Benzyl-4-(ethoxycarbonylmethyl)-2-phenylpyr-
rolidine (4a). Representative procedure for formation
of adducts 2 and SmI2-promoted cyclization. A mixture
of 1a (1.17 g, 3.79 mmol), N-(hydroxymethyl)benzotriazole
˚
(576 mg, 3.79 mmol) and molecular sieves (4 A, 1.90 g) in
benzene (6 mL) was stirred at rt for 12 h. The resulting
mixture was filtered over Celite and evaporated to dryness
to yield the crude adduct 2a (1.73 g). The resulting residue
and t-BuOH (0.72 mL, 7.6 mmol) were dissolved in THF
(91 mL) and added dropwise to a solution of SmI2 (ca.
0.1 M in THF, 114 mL, 11.4 mmol) at 2788C. The mixture
was stirred at 2788C for an additional 30 min and allowed
to warm to room temperature. After further stirring for 2 h
the reaction mixture was quenched with a mixture of sat.
K2CO3 (100 mL) and water (100 mL). After separation, the
aqueous layer was extracted with EtOAc (3£200 mL), the
combined organic extracts were washed with a mixture of
water (100 mL) and brine (100 mL), dried (Na2SO4) and
evaporated to give a crude product that was purified by flash
chromatography (silica gel saturated with Et3N, 99:1
hexanes/Et3N) to yield 4a (968 mg, 79%, 64:36 dr) as an
4.2.5. Ethyl (Z )-4-[N-(tert-butoxycarbonyl)piperidin-2-
yl]prop-2-enoate (10Z ) and ethyl (E )-4-[N-(tert-butoxy-
carbonyl)piperidin-2-yl]prop-2-enoate (10E ). To a sol-
ution of 922 (6.81 g, 30.0 mmol) in CH2Cl2 (120 mL) at 08C
was added (ethoxycarbonylmethylene)triphenylphosphor-
ane (12.1 g, 33.0 mmol). The mixture was allowed to warm
to rt and further stirred for 3.5 h. The solvent was removed
in vacuo and the crude product was purified by flash
chromatography (86:14 hexanes/EtOAc) to yield in order of
elution 10Z (0.519 g, 6%) and 10E (7.68 g, 86%) as oils.
Data for 10Z: 1H NMR d 1.23 (t, J¼7.1 Hz, 3H, CH2CH3),
1.27–1.64 (m, 15H), 1.38 (s, t-Bu, included in m at 1.27–
1.64), 2.71–2.84 (m, 2H), 3.04–3.18 (m, 1H), 3.87–3.92
(br s, 1H), 4.11 (q, J¼7.1 Hz, 2H, CO2CH2), 4.28–4.42 (br
s, 1H), 5.75 (dt, J¼11.5, 1.6 Hz, 1H, H-30), 6.16 (dt, J¼11.5,
7.5 Hz, 1H, H-20); 13C NMR d 14.1, 18.9, 25.4, 28.3, 28.05,
29.4, 38.8 (br, C-6), 49.9 (br, C-2), 59.7, 79.1, 120.8 (C-3 ),
147.0 (C-20), 154.9 (NCO), 166.3 (CvO); IR (neat) n 1725
(CvO), 1695 (CvO), 1.650 (CvC) cm21; LRMS (EI) m/z
224 (29), 198 (13), 184 (75), 152 (40), 129 (39), 128 (base),
114 (16), 84 (18); HRMS calcd for C16H27NO4 297.1940,
found 297.1926. Data for 10E: 1H NMR d 1.25 (t,
J¼7.1 Hz, 3H, CH2CH3), 1.32–1.67 (m, 15H), 1.42 (s,
t-Bu, included in m at 1.32–1.67), 2.24–2.35 (m, 1H),
2.51–2.78 (m, 2H), 3.96–4.01 (m, 1H), 4.15 (q, J¼7.1 Hz,
2H, CO2CH2), 4.36 (br s W1/2¼18.6 Hz, 1H), 5.81 (dt,
J¼15.5, 1.4 Hz, 1H, H-30), 6.86 (dt, J¼15.5, 7.7 Hz, 1H,
H-20); 13C NMR d 14.2, 18.8, 25.3, 28.3,0 33.0, 38.7 (br,
C-6), 49.5 (br, C-2), 60.2, 79.4, 123.1 (C-3 ), 145.6 (C-20),
154.8 (NCO), 166.2 (CvO); IR (neat) n 1725 (CvO), 1690
(CvO), 1655 (CvC) cm21; LRMS (EI) m/z 224 (26), 198
(11), 184 (43), 152 (28), 129 (30), 128 (86), 114 (21), 84
(base); HRMS calcd for C16H27NO4, 297.1940, found
297.1929.
1
oil. Data for the diastereomeric mixture: H NMR d 1.22
and 1.23 (2t, J¼7.1 Hz, 3H), 1.39–1.50 and 1.85–2.10 (2m,
2H), 2.37–2.77 (m, 4H), 2.84 (dd, J¼9.3, 2.3 Hz) and 3.31
(dd, J¼9.1, 7.0 Hz) (total 1H), 3.05 (d, J¼13.4 Hz, 1H,
PhCH ), 3.44–3.52 (m, 1H), 3.85 (d, J¼13.5 Hz, 1H,
PhCH ), 4.09 and 4.10 (2q, J¼7.1 Hz, 2H, OCH2), 7.19–
7.51 (m, 10H, Ar); 13C NMR d 14.1, 32.2 (C-4), 32.4 (C-4),
39.5, 41.0, 41.3, 42.3, 57.5, 57.8, 58.3, 59.6, 60.1, 60.2, 68.4
(C-2), 69.6 (C-2), 126.6, 126.7, 127.0, 128.4, 128.4, 128.5,
139.2, 139.5, 143.1, 143.5, 172.5 (CvO), 172.9 (CvO); IR
(neat) n 1735 (CvO) cm21; LRMS (EI) m/z 323 (M, 39),
322 (28), 278 (23), 246 (85), 232 (83), 118 (20), 91 (base);
HRMS calcd for C21H25NO2 323.1885, found 323.1879.
4.2.3. 1-Benzyl-4-(ethoxycarbonylmethyl)-2-(pyridin-3-
yl)pyrrolidine (4b). Prepared from 1b21 using the pro-
cedure described above for 4a. The crude product was
purified by flash chromatography (silica gel saturated with
Et3N, 90:8:2 hexanes/EtOAc/Et3N) to yield 4b (66%, 65:35
dr). Data for the diastereomeric mixture: 1H NMR d 1.17–
1.25 (m, 3H, CH2CH3), 1.37–1.48 (m, 1H, isomer A),
1.97–2.01 (m, 1H), 2.36–2.86 (m, 5H), 3.10 (d, J¼13.2 Hz,
1H, PhCH ), 3.27–3.33 (m, 1H, isomer B), 3.48–3.53 (m,
1H), 3.77 (d, J¼13.2 Hz, 1H, PhCH ), 4.08 (m, 2H,
CH3CH2), 7.26 (br s, W1/2¼16.7 Hz, 6H), 7.81 (d,
J¼7.7 Hz, 1H, H-40), 8.49 (br s, W1/2¼8.3 Hz, 1H, H-20),
8.64 (br s, W1/2¼8.3 Hz, 1H, H-60); 13C NMR d 14.1, 32.3,
32.6, 39.1, 40.8, 41.2, 42.2, 57.5, 57.8, 58.3, 59.6, 60.2,
65.8, 67.0, 123.6, 126.8, 126.8, 128.1, 128.2, 128.4, 134.8,
134.9, 138.4, 138.7, 138.9, 139.0, 148.6, 148.7, 149.5, 172.3
(CvO), 172.6 (CvO); IR (neat) n 1740 (CvO),
1580 cm21; LRMS (EI) m/z 324 (M, 26), 323 (16), 279
(24), 246 (67), 236 (21), 233 (base), 219 (10), 119 (20), 91
(50); HRMS calcd for C20H24N2O2 324.1838, found
324.1835.
4.2.6. Ethyl (E )-4-(piperidin-2-yl)prop-2-enoate (1d).
Trifluoroacetic acid (2.60 mL) was added dropwise to a
solution of 10E (594 mg, 2.00 mmol) in CH2Cl2 (14.8 mL)
at 08C. The mixture was then stirred at rt for 3 h and
evaporated. The residue was dissolved in EtOAc (40 mL),
washed with sat. K2CO3 (40 mL), dried (Na2SO4) and
evaporated to dryness, to yield 1d (382 mg, 97%): 1H NMR
d 1.07–1.48 (m, 6H), 1.26 (t, 7.1H, CH2CH3, included in m
at 1.07–1.48), 1.56–1.79 (m, 3H), 2.04 (br s,
W1/2¼19.8 Hz, 1H, NH), 2.14–2.34 (m, 2H), 2.55–2.66
(m, 2H), 3.01–3.07 (m, 1H), 4.16 (q, J¼0 7.4 Hz, 2H,
CO2CH2), 5.86 (dt, J¼15.7, 1.4 Hz, 1H, H-3 ), 6.83–6.95
(m, 1H, H-20); 13C NMR d 14.2, 24.6, 26.0, 32.7, 40.1, 047.0,
55.6 (C-2), 60.3, 123.6 (C-30), 145.8 (C-20), 166.4 (C-4 ); IR
4.2.4. 1-Benzyl-4-(ethoxycarbonylmethyl)-2-propylpyr-
rolidine (4c). Prepared from 1c21 using the procedure
described above for 4a. The crude product was purified by
(neat) n 3400 (N–H), 1720 (CvO), 1655 (CvC) cm21
;

F. Bustos et al. / Tetrahedron 58 (2002) 6837–6842
6841
LRMS (EI) m/z 235 (base), 197 (M, 3), 184 (22), 84 (20);
HRMS calcd for C11H19NO2 197.1416, found 197.1406.
15 min a mixture of ethanol–water (1:1, 0.96 mL) was
added, followed by solid Na2SO4·10H2O (0.63 g). The
mixture was allowed to warm to rt, stirred for 3.5 h, filtered
over Celite and evaporated. The residue was dissolved in
CH2Cl2 (31 mL) and (ethoxycarbonylmethylene)triphenyl-
phosphorane (3.20 g, 9.30 mmol) was added. The mixture
was stirred at rt for 12 h and evaporated. The crude product
was purified by flash chromatography (silica gel saturated
with Et3N, 98:2 hexanes/Et3N) to yield 13 (1.31 g, 64% for
two steps from 12) as an oil: 1H NMR d 0.95–1.01 (m, 3H,
C4–CH3), 1.25 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.40 and 1.47
(2s, 9H, t-Bu), 2.57–2.70 (m, 1H, H-4), 3.01 (dd, J¼14.6,
5.8 Hz) and 3.17–3.26 (m) (total 2H), 4.38–4.44 (m, 2H,
OCH2CH3), 5.69–5.79 (m, 1H, H-2), 6.76–6.89 (m, 1H,
H-3), 7.18–7.32 (m, 5H, Ar-H ); 13C NMR d 13.6, 16.4,
27.6, 35.3 (C-4), 35.6 (C-4), 49.5, 50.5, 50.8, 59.3, 79.0,
120.4 (C-2), 126.5, 127.0, 127.8, 137.5, 137.6, 150.7 (C-3),
154.9 (NCO), 165.4 (CO2Et).
4.2.7. 2-(Ethoxycarbonylmethyl)indolizidine (4d). Pre-
pared from 1d using the procedure described above for 4a.
The crude product was purified by flash chromatography
(silica gel saturated with Et3N, 92:6:2 hexanes/EtOAc/
Et3N) to yield the two diastereoisomers of 4d (330 mg and
164 mg, total yield 58%). Data for the less polar isomer: 1H
NMR d 1.00–1.26 (m) and 1.23 (t, J¼7.1 Hz, CH2CH3)
(total 6H), 1.48–1.64 (m, 2H), 1.74–1.85 (m, 3H), 1.92 (td,
J¼10.9, 4.1 Hz, 1H), 2.02–2.12 (m, 1H), 2.30–2.50 (m,
4H), 2.76 (d, J¼8.1 Hz, 1H), 3.00 (dt, J¼10.8, 3.1 Hz, 1H),
4.10 (q, J¼7.1 Hz, 2H, CH3CH2); 13C NMR d 14.2, 24.2,
25.3, 30.8, 31.0 (C-2), 38.4, 41.2, 52.9, 59.8, 60.0, 64.6
(C-8a), 173.0 (CvO); IR (neat) n 1740 (CvO) cm21
;
LRMS (EI) m/z 211 (M, 22), 210 (base), 209 (19), 182 (23),
180 (6), 166 (14), 137 (11), 136 (54), 124 (18); HRMS calcd
for C12H21NO2 211.1572, found 211.1567. Data for the
more polar isomer: 1H NMR d 1.03–1.18 (m, 1H), 1.12 (t,
J¼7.1 Hz, 3H, CH2CH3), 1.35–1.74 (m, 9H), 1.82 (td,
J¼11.1, 3.5 Hz, 1H), 2.14–2.30 (m, 2H), 2.38–2.56 (m,
1H), 2.89–2.95 (m, 1H), 3.16 (dd, J¼9.1, 7.5 Hz, 1H), 3.99
(q, J¼7.1 Hz, 2H, CH3CH2); 13C NMR d 14.0, 24.2, 25.1,
30.7, 30.8, 37.0 (C-2), 39.8, 52.7, 60.0, 61.0, 63.0 (C-8a),
172.4 (CvO); IR (neat) n 1740 (CvO) cm21; LRMS (EI)
m/z 211 (M, 39), 210 (base), 209 (17), 182 (61), 180 (25),
166 (27), 138 (27), 136 (28), 124 (50); HRMS calcd for
C12H21NO2 211.1572, found 211.1564.
4.3.3. Ethyl 6-aza-7-phenyl-4-methylhept-2-enoate (1e).
The procedure described above for 1d was followed starting
from 13 to yield 1e (100%): 1H NMR d 1.07 (d, J¼6.3 Hz,
3H, C4–CH3), 1.28 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.32–
1.54 (m, 1H, NH), 2.49–2.63 (m, 3H), 3.77 (s, 2H, H-7),
4.18 (q, J¼7.1 Hz, 2H, OCH2CH3), 5.85 (dd, J¼15.6,
1.0 Hz, 1H, H-2), 6.87 (dd, J¼15.6, 7.3 Hz, 1H, H-3), 7.21–
7.34 (m, 5H, H-Ar); 13C NMR d 14.2, 17.4, 36.9 (C-4), 53.8,
54.2, 60.2, 121.0 (C-2), 126.9, 140.0, 152.4 (C-3), 166.6
(CO2Et); LRMS (EI) m/z 121 (8), 120 (90), 106 (6), 92 (8),
91 (base), 65 (5); HRMS calcd for C15H21NO2 247.1572,
found 247.1578.
4.3. Synthesis of 3,4- and 2,3,4-substituted pyrrolidines
4.3.1. Ethyl 4-aza-4-(tert-butoxycarbonyl)-5-phenyl-2-
methylpentanoate (12). To a solution of benzylamine
(1.23 mL, 11.2 mmol) in ethanol (9 mL) was added ethyl
methacrylate (7.00 mL, 56.0 mmol) and H2O (4.00 mL,
224 mmol), and the mixture was stirred for 4 days at rt. The
solvent was removed in vacuo and the residue (1123) was
dissolved in EtOAc (5 mL). To this solution at 08C was
added dropwise ditert-butyl dicarbonate (2.20 mL,
9.40 mmol) and the mixture was stirred at rt for 16 h. The
solution was washed with HCl (1 M, 15 mL), sat. NaHCO3
(15 mL) and brine (15 mL), and dried (Na2SO4). The crude
after evaporation was purified by flash chromatography
(silica gel saturated with Et3N, 96:4 hexanes/Et3N) to yield
12 (2.41 g, 80%, rotamer mixture) as an oil: 1H NMR d 1.11
(d, J¼5.6 Hz, 3H, C2–CH3), 1.25 (t, J¼7.1 Hz, 3H,
OCH2CH3), 1.42 and 1.50 (2s, 9H, t-Bu), 2.81–2.91 (m,
1H, H-2), 3.24–3.37 (m, 2H), 4.05–4.15 (m, 2H,
OCH2CH3), 4.32 (d, J¼15.5 Hz, 1H, H-5), 4.51 and 4.62
(2d, J¼15.5 Hz, 1H, H-5), 7.21–7.35 (m, 5H, ArH); 13C
NMR d 14.1, 15.0, 28.3, 38.8 (C-2), 39.0 (C-2), 49.4, 49.9,
50.4, 51.5, 60.4, 79.9, 127.0, 127.6, 128.4, 138.0, 138.3,
155.6 (NCO), 155.8 (NCO), 175.2 (CO2Et), 175.4 (CO2Et);
IR (neat) n 1740 (CvO), 1700 (CvO) cm21; LRMS (EI)
m/z 321 (M, 2), 265 (42), 221 (13), 220 (64), 164 (15), 120
(81), 106 (57), 91 (base); HRMS calcd for C18H27NO4
321.1940, found 321.1930.
4.3.4. N-Benzyl-3-(ethoxycarbonylmethyl)-4-methylpyr-
rolidine (4e). The procedure described above for 4a was
followed starting from 1e. The crude product was purified
by flash chromatography (silica gel saturated with Et3N,
99:1 hexanes/Et3N) to yield 4e (78 mg, 66%, 87:13
1
trans/cis ) as an oil: H NMR d 0.90 (d, J¼7.1 Hz, C4–
CH3, cis isomer) and 1.03 (d, J¼6.7 Hz, C4–CH3, trans
isomer) (total 3H), 1.24 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.85
(quint, J¼6.9 Hz, trans isomer), 1.93–2.19 (m, 2H), 2.23–
2.51 (m, 3H), 2.61–2.70 (m, cis isomer), 2.73–2.84 (m,
trans isomer) and 2.94–3.04 (m, cis isomer) (total 2H), 3.54
and 3.62 (2d, J¼13.1 Hz, 2H, PhCH2), 4.10 (q, J¼7.1 Hz,
2H, OCH2CH3), 7.19–7.31 (m, 5H, Ar); 13C NMR d 14.1,
14.7, 18.9, 33.7 (C-3 or C-4, cis isomer), 34.6 (C3–C H2, cis
isomer), 36.5 (C-3 or C-4, cis isomer), 38.6 (C-3 or C-4,
trans isomer), 39.1 (C3–CH2, trans isomer), 42.1 (C-3 or
C-4, trans isomer), 59.5, 59.8, 60.0, 60.3, 60.5, 61.7, 126.6,
128.0, 128.5, 139.1, 172.8 (CvO); IR (neat) n 1740
(CvO) cm21; LRMS (EI) m/z 261 (M, 26), 260 (33), 232
(12), 230 (6), 216 (25), 186 (13), 184 (18), 173 (24), 170
(63), 105 (base); HRMS calcd for C16H23NO2 261.1729,
found 261.1718.
4.3.5. N-Benzyl-3-(ethoxycarbonylmethyl)-4-methyl-2-
propylpyrrolidine (4f). A mixture of 1e (114 mg,
0.50 mmol), benzotriazole (60 mg, 0.51 mmol), butyralde-
˚
hyde (0.04 mL, 0.50 mmol) and molecular sieves (4 A,
4.3.2. Ethyl 6-aza-6-(tert-butoxycarbonyl)-7-phenyl-4-
methylhept-2-enoate (13). To a solution of 12 (2.40 g,
7.50 mmol) in toluene (21 mL) at 2788C was added
dropwise DIBALH (1.0 M, 9.75 mL, 9.75 mmol). After
240 mg) in benzene (1.0 mL) was stirred at rt for 18 h. The
resulting mixture was filtered over Celite and evaporated to
yield 2f (123 mg). This crude adduct and t-BuOH (0.10 mL,
1.0 mmol) were dissolved in THF (12 mL) and added

6842
F. Bustos et al. / Tetrahedron 58 (2002) 6837–6842
10. Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Synlett 1997,
275–276.
dropwise to a solution of SmI2 (ca. 0.1 M in THF, 15 mL,
1.5 mmol) at 2788C. The mixture was stirred at 2788C for
an additional 30 min and allowed to warm to room
temperature. After further stirring for 2 h the reaction
mixture was quenched with a mixture of sat. K2CO3
(25 mL) and water (25 mL). After separation, the aqueous
layer was extracted with EtOAc (3£30 mL). The combined
organic extracts were washed with a mixture of water
(25 mL) and brine (25 mL), dried (Na2SO4) and evaporated
to give a crude product that was purified by flash
chromatography (silica gel saturated with Et3N, 99:1
hexanes/Et3N) to yield 4f (102 mg, 67%), as an oil (a
90:4:3:3 diastereomeric mixture, as determined by 13C
NMR). Data for the major isomer: 1H NMR d 0.94 (apparent
t, J¼6.4 Hz, 6H), 1.27 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.33–
1.52 (m, 4H), 1.71–1.86 (m, 2H, H-4 and H-5), 2.05–2.16
(m, 1H, H-3), 2.39 (d, J¼7.7 Hz, 2H, C3–CH2), 2.61–2.69
(m, 1H, H-2), 3.00–3.06 (m, 1H, H-5), 3.19 (d, J¼12.9 Hz,
1H, PhCH ), 4.02 (d, J¼12.9 Hz, 1H, PhCH ), 4.14 (q,
J¼7.1 Hz, 2H, OCH2CH3), 7.20–7.31 (m, 5H, Ar); 13C
NMR d 14.2, 14.6, 18.8, 19.7, 32.4, 34.6, 36.4, 44.6, 59.6,
60.2, 61.8, 65.1 (C-2), 126.6, 128.1, 128.6, 128.7, 140.0,
173.7 (CvO); IR (neat) n 1740 (CvO) cm21; GC-MS:
tR¼12.8 min, LRMS (EI) m/z 260 (M2Pr, 24), 91 (base);
tR¼13.1 min, LRMS (EI) m/z 260 (M2Pr, base), 91 (83),
tR¼13.4 min, LRMS (EI) m/z 260 (M2Pr, 61), 91 (base).
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