Synthesis of functionalized cyclic enamines from lithium alkylphenyl sulfones and N-carbo-tert-butoxy lactams

Article abstract of DOI:10.1002/jhet.5570380104

Alkylphenyl sulfones 3 are appropriate synthons for the synthesis of 2-phenylsulfonyl alkylidene pyrrolidine or piperidine derivatives 1 in good to moderate yields. The lithium alkyl sulfones 4 are first reacted with the desired protected lactams and then

Full text of DOI:10.1002/jhet.5570380104

Jan-Feb 2001
Synthesis of Functionalized Cyclic Enamines from Lithium
Alkylphenyl Sulfones and N-Carbo-tert-butoxy Lactams
Luis A. Arias*, David Arbelo, Arnaldo Alzérreca and José A. Prieto
29
Department of Chemistry, Inter American University of Puerto Rico, Metropolitan Campus, P. O. Box 191293,
San Juan, Puerto Rico 00919-1293
Received March 27, 1999
Alkylphenyl sulfones 3 are appropriate synthons for the synthesis of 2-phenylsulfonyl alkylidene pyrro-
lidine or piperidine derivatives 1 in good to moderate yields. The lithium alkyl sulfones 4 are first reacted
with the desired protected lactams and then subjected to acidic methanolysis to afford the unusual enam-
1
1
1
13
ines 1a-e. NMR studies (COSY H- H, COSY H- C, NOE) showed the Z enamines to exist in a dynamic
equilibrium with the corresponding imines 2. The stereochemistry of the described compounds was
confirmed by molecular calculations.
J. Heterocyclic Chem., 38, 29 (2001).
Introduction.
These functionalized enamines show characteristic IR
absorptions near 3400 and 1610 cm and only one spot
by silica gel thin layer chromatography. However,
H-NMR studies indicated that the enamines are in a
dynamic equilibrium with the imine tautomers 2. Enamine
1a (R = H) was formed in a 5:1 ratio together with imine
2a which was identified by its absorption at 4.20 ppm
corresponding to the exocyclic methylene protons. On the
-1
Functionalized enamines can be useful precursors for
the synthesis of many biologically active compounds
such as the guanidine alkaloids, including ptilomycalin
1
2
A 6, and the crambescidins which display antitumor,
antifungal, and antiviral activities [1]. In order to
further develop a synthetic methodology toward these
targets we have envisaged a reaction sequence in which
the lithium anions 4a-e derived from alkylphenyl
sulfones 3 are transformed into β-enaminosulfones
1a-e (Scheme 1). The synthetic utility of alkyl phenyl-
sulfones has been well explored. For example, their
magnesium derivatives, formed by reaction with an
alkyl Grignard reagent have been added to aldehydes
or ketones for the preparation of vinyl sulfones [2].
Some years ago, we used these precursors for the
preparation of trisubstituted and tetrasubstituted vinyl
ethers [3]. The reports of Giovannini and coworkers
that organometallic reagents react with N-carbo-tert-
butoxy lactams, leading to regiospecific ring opening,
has made a large variety of cyclic imines readily
available [4].
other hand, enamine 1b (R = n-C H ) was formed in a 2:1
3
7
ratio with imine 2b, which showed a doublet of doublets
at 4.15 ppm arising from the hydrogen atom adjacent to
the phenylsulfonyl group. Enamine 1c (R = n-C H ) was
6
13
formed in a 6:15 ratio together with imine 2c probably
due to the length of the side chain. Enamine 1d (R = CH )
3
was formed in a 5:6 ratio together with imine 2d and
1
13
identified by infrared and NMR ( H, and C); 2D NMR
1
1
1
13
correlation spectra ( H- H, H- C) further supported the
structure assignments for enamines 1a, b. The piperidine
derivative 1e (R = H, N = 2) showed a 3:2 ratio with
respect to imine 2e. Contrary to the pyrrolidine deriva-
tives, the ratio for enamine 1e and imine 2e was lower
presumably because of the ring size difference since an
exocyclic double bond in a six-member ring is more
stable than that of a five-member ring.
Results and Discussion.
The Z geometry for the major enamine isomer 1a was
unambiguously established by 1D NOE studies. Thus,
irradiation of the vinylic proton at 4.65 ppm produced a
4% enhancement of the allylic pyrrolidine methylene
protons at 2.57 ppm. Correspondingly, irradiation at the
2.57 ppm signal produced a 3% enhancement at the 4.65
ppm resonance. A similar result was obtained for the
piperidine analogue 1e where the signals for the vinylic
and allylic protons at 4.45 and 2.30 ppm respectively,
showed a 5% enhancement when their partners, via
dipolar coupling, were irradiated. Interestingly, the NOE
studies showed the existence of a dynamic equilibrium
between the enamine and imine isomers. Irradiation of the
vinylic proton (4.65 ppm) in the pyrrolidine analogue 1a,
simultaneously saturated the 4.25 ppm resonance for the
phenyl sulfone methylene in 2a producing a negative
The lithium anions 4a-e, prepared from sulfones 3, by
direct lithiation with n-butyllithium in tetrahydrofuran
(THF) at -25 °C, were trapped with N-carbo-tert-butoxy-
2-pyrrolidinone or piperidinone [4] at -78 °C, to give the
corresponding N-carbo-tert-butoxy ω-amino α-phenyl-
sulfonyl ketones 5. The latter were purified by crystalliza-
tion from isopropanol and/or recrystallization from
hexane/ethyl acetate and identified by their characteristic
-1
infrared absorptions near 3460 and 1720 cm and also by
1D and 2D NMR techniques. The protected ω-amino keto
sulfones 5 were converted into the enamines 1 either by
refluxing with methanolic p-toluenesulfonic acid or with
excess trifluoracetic acid at 0-25 °C. In both cases the
resulting products 1 were isolated in 50-75% overall yield
after basic workup and crystallization with hexane/ethyl
acetate at 0 °C.

Vol. 38
L. A. Arias, D. Arbelo, A. Alzérreca, and J. A. Prieto
30
NOE (-10%) after spectral substraction. Accordingly,
irradiation of the 4.25 ppm resonance in 2a created nega-
tives NOE's on the signals at 7.30 (-22%) and 4.65
(-103%) for the N-H and vinylic protons in 1a, respec-
tively. Again, very similar results were obtained for the
piperidine system 1e/2e.
hydrogen alpha to the phenylsulfonyl group. They also
show that the α-carbon is more nucleophilic than nitrogen
because when 1a was reacted with n-butyllithium
followed by addition of acetic anhydride, the enol imine 7
was the predominant product. Meanwhile, for tetra-
substituted cyclic β-enaminosulfones their ratio with
imines are side chain dependant.
To further study the equilibration process, enamine 1a
was reacted with acetic anhydride under basic conditions
to afford the enol imine 7 after column chromatography
and crystallization. Its structure determination was based
EXPERIMENTAL
1
1
1
13
on IR, NMR ( H- H, H- C) and mass spectroscopy
(MS).
All melting points were determined on an Electrothermal
apparatus and are given uncorrected. Chemicals and solvents
were used as received; tetrahydrofuran was distilled from
sodium metal in the presence of benzophenone under dry
nitrogen. Infrared spectra were determined on a Perking-Elmer
1620 FT-IR spectrophotometer in carbon tetrachloride solutions.
The one- and two-dimensional nuclear magnetic resonance
spectra were recorded on a Bruker DRX 500 (500.13, 125.77
MHz) spectrometer in deuteriochloroform solutions. The 1D
NOE studies were recorded on a G.E. QE-300 (300.15 MHz).
Electron impact MS spectra were obtained on a VG Fisons
Autospec spectrometer (70 eV) equipped with a direct insertion
probe (DIP) attachment. Thin-layer chromatography was carried
out utilizing silica gel precoated TLC plates on polyester with
254 nm fluorescent indicator, catalog Z12, 278-5, and E. Merck
silica gel 60 F (230-400 mesh) was used for flash chromato-
graphy. Combustion analysis were performed by Oneida
Research Services, Whitesboro, NY 13492 or Atlantic Microlab,
Norcross, GA 30091. Protected lactams and sulfones were
prepared following the procedures described by Savoia et al. or
Jacobs [7]. Computational calculations were done on an Indigo 2
Silicon Graphics workstation.
Molecular mechanics calculations [5] were performed
on the E and Z isomers of enamines 1a-e. Also ab initio
Hartree-Fock 6-31G* calculations were performed on
both E/Z isomers of enamines 1a (N = 1, R = H) and 1d
(N = 1, R = CH ) [6]. Consistently, both calculations
3
showed the Z enamines to be more stable than E enamine
by 3.0-4.0 kcal/mol. This is in agreement with the
observed predominance of the Z isomer established by
NMR studies. This significant difference may be attribut-
able to the intramolecular hydrogen bond stabilization
between the N-H hydrogen and the sulfonyl group which
is also in agreement with our experimental results.
Conclusions.
Alkyl sulfones are convenient precursors for the prepa-
ration of 2-phenylsulfonyl pyrrolidine and piperidine
derivatives via the corresponding ω-enamino α-phenyl-
sulfonyl ketones. In spite of their dynamic equilibrium
with the corresponding imines, the trisubstituted cyclic
β-enaminosulfones, with a secondary nitrogen, are the
major product. This is due to the higher acidity of the
General Procedure for the Preparation of N-Carbo-tert-butoxy
ω-Amino Keto Sulfones (5).
To a magnetically stirred solution of the required sulfone 3
(12 mmoles) in dry tetrahydrofuran (50 mL) was added n-butyl-
lithium (13.2 mmoles of a 2.5 M solution in hexanes) at -25 °C
and stirred for 30 minutes to generate a yellow to orange solu-
tion of the corresponding anion. The solution was cooled at -78
°C, at this temperature the protected lactam dissolved in tetra-
hydrofuran (12 mmoles, 15 mL) was added dropwise and after 3
hours the mixture was quenched by the addition of ammonium
chloride (20 mL, saturated aqueous solution). After extraction
with diethyl ether, the organic layer was dried with anhydrous
magnesium sulfate and concentrated under reduced pressure
(25-35 /20-40 torr) to afford the protected ω-N-amino keto
sulfones 5.
5-(N-Carbo-tert-butoxy)amino-1-phenylsulfonyl-2-pentanone
N
[5a (R = H, = 1)].
This compound was recrystallized from isopropanol (60%
yield; mp 73-73.5 °C); ir: υ 3463, 3076, 2980, 2932, 1720,
-1
1
1503, 1460, 1392, 1366, 1330, 1160 cm ; H nmr: δ 7.85 (m,
2H, ArH), 7.7 (m, 1H, ArH), 7.6 (m, 2H, ArH), 4.65 (br s, 1H,
NH), 4.20 (s, 2H, CH SO ), 3.10 (q, 2H, CH N), 2.74 (t, 2H,
2
2
2
CH CH CO), 1.74 (qt, 2H, CH CH CH ), 1.40 (s, 9H,
2
2
2
2
2
13
(CH ) C); C nmr: δ 197.7 (C=O), 156.0 (NHC=O), 138.7
3 3
(=C-SO ), 134.3, 129.3, 128.2 (ArC), 79.2 (C-O), 66.9
2

Jan-Feb 2001
Synthesis of Functionalized Cyclic Enamines from Lithium Alkylphenyl Sulfones
31
-1
1
(OCCSO ), 41.3 (C-NH), 39.3 (C-C-O), 28.3 [(CH ) C], 23.7
1503, 1448, 1326, 1157 cm ; H nmr: δ 7.84 (d, 2H, ArH),
7.65-7.50 (m, 3H, ArH), 4.71 (br s, 1H, NH), 4.14 (s, 2H,
PhSO CH ), 3.02 (q, 2H, CH CH NH), 2.67 (t, 2H,
2
3 3
(CH CH CH ).
2
2
2
Anal. Calcd. For C
H
NO S: C, 56.29; H, 6.79; N, 4.10; S,
16 23
5
2
2
2
2
9.39. Found: C, 56.17; H, 6.69; N, 4.20; S, 9.42.
CH CH CO), 1.46-1.28 (m, 4H, COCH CH CH CH NH), 1.38
2
2
2
2
2
2
13
[s, 9H, (CH ) C]; C nmr: δ 197.9 (C=O), 163.1 (NCO ), 138.6
3 3
2
1-(N-Carbo-tert-butoxy)amino-5-phenylsulfonyl-4-octanone [5b
(=CSO ), 134.2, 129.3, 128.5, 128.1 (ArC), 79.0 [OC(CH ) ],
2
3 3
(R = n-C H , N =1)].
3
7
66.6 (CH SO ), 43.8 (CH N), 39.9 (CH C=O), 29.0
2
2
2
2
Compound 5b was obtained in 50% yield (2.30 g) mp
84-85 °C crystallized from isopropanol at -5 °C and recrystal-
lized from hexane/benzene; ir: υ 3458, 3068, 2966, 2940, 2910,
1722, 1586, 1509, 1466, 1448, 1390, 1365, 1323, 1245, 1149
(CH CH NH), 28.3[(CH ) C], 20.0 (COCH CH CH CH N).
2
2
3 3
2
2
2
2
Anal. Calcd. for C
H NO S: C, 57.44; H, 7.09; N, 3.94; S,
17 25 5
9.02. Found: C, 57.05; H, 6.96; N, 3.94; S, 9.02.
-1
1
cm ; H nmr: δ 7.66 (d, 2H, ArH), 7.59 (t, 1H, ArH), 7.56 (t,
2H, ArH), 4.68 (br s, 1H, NH), 4.12 (dd, 1H, CHSO ), 3.11 (m,
General Procedure for the Preparation of Enamines (1).
2
A mixture of the appropriate N-carbo-tert-butoxy amino
keto sulfone 5 (10 mmol), p-toluenesulfonic acid (10 mmol)
and methanol (40-50 mL) was refluxed while the reaction
progress was monitored by thin layer chromatography
(hexane/ethyl acetate 1:1). Methanol was removed under
vacuum, the residue dissolved with water (20 mL), washed
with diethyl ether and basified with solid sodium carbonate.
After extraction with methylene chloride, the organic layer
was dried with anhydrous magnesium sulfate and concen-
trated under reduced pressure (25-35 °C/20-40 torr) to give
the enamines 1.
2H, CH NH), 2.93 (dt, 1H, COCHaHbCH ), 2.54 (dt, 1H,
2
2
COCHaHbCH ), 1.79 (m, 4H, CH CH CHSO ), 1.45 [s, 9H,
2
2
2
2
(CH ) C], 1.22 (sext, 2H, CH CH CH ), 0.91 (t, 3H, CH CH );
3 3
2
2
3
3
2
13
C nmr: δ 201.9 (C=O), 156.0 (NCO ), 136.5 (=CSO ), 134.3,
2
2
129.4, 129.0 (ArC), 77.4 [O-C(CH ) ], 75.0 (C-SO ), 42.2
3 3
2
(CH N), 39.5 (CH CH CO), 29.1 (CH CH CHSO Ph), 28.4
2
2
2
2
2
2
[(CH ) C], 23.5 (CH CH CH NH), 20.3 (CH CH CH ), 13.7
3 3
2
2
2
3
2
2
(CH CH ).
3
2
Anal. Calcd. for C
H NO S: C, 59.50; H, 7.62; N, 3.65; S,
19 29 5
8.36. Found: C, 59.62; H, 7.45; N, 3.70; S, 8.40.
1-(N-Carbo-tert-butoxy)amino-5-phenylsulfonyl-4-undecanone
Z-2-(Phenylsulfonylmethylene)pyrrolidine [1a (R = H, N = 1)].
[5c (R = n-C H , N = 1)].
6
13
Compound 1a was obtained in 71% yield, mp 80-82 °C,
recrystallized from hexane/ethyl acetate; ir: υ 3400, 3068, 2982,
2872, 1613, 1487, 1446, 1328, 1286, 1134 cm ; H nmr: δ 7.80
Compound 5c was obtained in 40% yield, mp 70-70.5 °C.
Purified by silica gel chromatography with chloroform and recrys-
tallized from isopropanol; ir: υ 3462, 2960, 2930, 1720, 1505,
-1
1
-1 1
1448, 1390, 1368, 1324, 1248, 1172, 1084 cm ; H nmr: δ 7.80 (d,
(m, 2H, ArH), 7.50 (m, 3H, ArH), 7.19 (br s, 1H, NH), 4.65 (s,
2H, ArH), 7.60 (t, 1H, ArH), 7.50 (m, 2H, ArH), 4.75 (br s, 1H,
NH), 4.10 (dd, 1H, CHSO ), 3.10 (m, 2H, CH N), 2.90 (dt, 1H,
1H, =CHSO ), 3.47 (t, 2H, CH CH N), 2.57 (t, 2H,
2
2
2
13
CH CH C=), 1.92 (qt, 2H, CH CH CH ); C nmr: δ 161.7
2
2
2
2
2
2
2
COCHaHbCH ), 2.54 (dt, 1H, COCHaHbCH ), 1.80 (m, 4H,
(=C-N), 145.4 (=CSO ), 131.6, 128.7, 125.4 (ArC), 82.6
2
2
2
CH CH CHSO , CH CH CH NH), 1.48 [s, 9H, (CH ) C], 1.20
(=CHSO ), 47.4 (CH N), 33.0 (CH C=), 21.5 (CH CH CH );
2
2
2
2
2
2
3 3
2
2
2
2
2
2
13
[br s, 8H, CH (CH ) ], 0.80 (t, 3H, CH CH ); C nmr: δ 202.0
+
3
2 4
3
2
Ms; m/z 158 (100%), 223 (M ).
Anal. Calcd. for C H NO S: C, 59.17; H, 5.87; N, 6.27; S,
(C=O), 156.0 (N-CO ), 136.0 (=CSO ), 134.0, 129.0, 128.5 (ArC),
2
2
11 13
2
79.1 [O-C(CH ) ], 75.0 (C-SO Ph), 42.1 (CH N), 39.4
3 3
2
2
14.36. Found: C, 58.85; H, 5.84; N, 6.21; S, 14.58.
(CH CH CO), 31.5 (CH CH CHSO Ph), 29.0 (CH CH CH NH),
2
2
2
2
2
2
2
2
2-(Phenylsulfonylmethyl)-1,2-dehydropyrrolidine [2a (R = H,
N = 1)].
28.5 [(CH ) C], 26.8 (CH CH CH CHSO Ph), 26.5
3 3
2
2
2
2
(CH CH CH ), 23.5 (CH CH CH ), 13.9 (CH CH ).
3
2
2
3
2
2
3
2
Anal. Calcd. for C
7.53. Found: C, 61.88; H, 8.14; N, 3.46; S, 7.36.
H NO S: C, 62.09; H, 8.29; N, 3.29; S,
22 35 5
Aliphatic hydrogen and carbon chemical shift assignments.
1
H nmr: δ 4.20 (s, 2H, CH SO ), 3.73 (t, 2H, CH CH N), 2.68
2
2
2
2
13
(t, 2H, CH CH C=), 1.90 (qt, 2H, CH CH CH ); C nmr: δ
6-(N-Carbo-tert-butoxy)amino-2-phenylsulfonyl-2-hexanone
2
2
2
2
2
166.7 (=CN), 133.9 (=CSO ), 129.1, 127.9 (ArC), 61.3
[5d (R = CH , N = 1)].
2
3
(C-CH SO ), 60.4 (CH N), 37.7 (CH C=), 22.7 (CH CH CH ).
2
2
2
2
2
2
2
Compound 5d was obtained in 40% yield as a colorless oil.
Purified by silica gel chromatography with hexane followed by
dichloromethane; ir: ν 3458, 3072, 2979, 2925, 1720, 1585, 1504,
1480, 1388, 1366, 1324, 1248, 1152, 1085, 1015 cm ; H nmr:
δ 7.66 (d, 2H, ArH), 7.59 (t, 1H, ArH), 7.56 (t, 2H, ArH), 4.68
2-(1-Phenylsulfonylbutylidene)pyrrolidine [1b (R = n-C H ,
3
7
N = 1)].
-1
1
Compound 1b was obtained in 58% yield, mp 83-85 °C,
recrystallized from hexane/ether/ethyl acetate; ir: υ 3396, 3068,
(br s, 1H, NH), 4.12 (q, 1H, CHSO ), 3.11 (m, 2H, CH NH),
2
2
-1
1
2962, 2870, 1614, 1446, 1321, 1288, 1151, 1132, 1050 cm ; H
nmr: δ 7.80 (m, 2H, ArH), 7.65 (m, 1H, ArH), 7.50 (m, 2H,
ArH), 7.30 (br s, 1H, NH), 3.50 (t, 2H, CH CH NH), 2.60 (t,
2.93 (dt, 1H, COCHaHbCH ), 2.54 (dt, 1H, COCHaHbCH ),
2
2
1.79 (qt, 2H, CH CH CH NH), 1.45 [s, 9H, (CH ) C], (d, 3H,
2
2
2
3 3
13
2
2
CH CHSO ); C nmr: δ 201.9 (C=O), 156.0 (NCO ), 136.5
3
2
2
2H, CH CH CH C=), 1.95 (t, 2H, CH CH C=), 1.85 (sext, 2H,
3
2
2
2
2
(=CSO ), 134.3, 129.4, 129.0 (ArC), 77.4 [O-C(CH ) ], 75.0
2
3 3
CH CH CH ), 1.40 (qt, 2H, CH CH CH ), 0.80 (t, 3H,
2
2
3
2
2
2
(C-SO ), 42.2 (CH N), 39.5 (CH CH CO), 28.4 [(CH ) C],
2
2
2
2
3 3
13
CH CH ); C nmr: δ 171.0 (=C-N), 144.2, 133.6, 128.9, 128.6,
13.7 (CH CH).
3
2
3
126.0 (ArC), 94.0 (=C(SO )CH CH ), 48.0 (CH N), 37.0
2
2
2
2
6-(N-Carbo-tert-butoxy)amino-1-phenylsulfonyl-2-hexanone
[5e (R = H, N = 2)].
(=CCH CH C), 29.0 [=C(N)CH CH ], 27.5 (CH CH CH ),
2
2
2
2
2
2
3
23.0 (CH CH CH ), 14.5 (CH CH ).
2
2
2
3
2
Compound 5e was obtained in 70% yield, mp 92-93 °C,
recrystallized from isopropanol; ir: υ 3460, 3069, 2978, 1720,
Anal. Calcd. for C
12.08. Found: C, 63.54; H, 7.10; N, 5.45; S, 11.87.
H NO S: C, 63.36; H, 7.22; N, 5.28; S,
14 19 2

Vol. 38
L. A. Arias, D. Arbelo, A. Alzérreca, and J. A. Prieto
32
2-(1-Phenylsulfonylbutyl)-1,2-dehydropyrrolidine [2b
(CHSO Ph), 60.9 (CH N=C), 36.1 (CH C=C), 21.7
2 2 2
(R = n-C H , N = 1)].
(CH CH CH ), 12.3 (CHCH ).
3
7
2 2 2 3
Aliphatic hydrogen and carbon (aliphatic & olefinic) NMR
chemical shift assignments. H nmr: δ 4.15 (dd, 1H,
Z-2-(Phenylsulfonylmethylene)-piperidine [1e, R = H, N = 2)].
1
Compound 1e was obtained in 70% yield, mp 73.5-74 °C,
recrystallized from hexane/ethyl acetate); ir: υ 3353, 3056,
PhSO CHCH ), 3.65 (m, 2H, CH CH NH), 2.70 (t, 2H,
2
2
2
2
CH CH C=), 2.00 (m, CH CH CH), 1.85 (CH CH CH ), 1.30
2
2
2
2
2
2
2
-1 1
2953, 2867, 1604, 1331, 1282, 1156, 1080 cm ; H nmr: δ 7.85
13
(CH CH CH ), 0.90 (t, 3H, CH CH ); C nmr: δ 160.0 (C=N),
2
2
3
3
2
(m, 2H, ArH), 7.63 (m, 1H, ArH), 7.55 (m, 2H, ArH), 7.49 (m,
70.0 (CHSO ), 61.0 (CH N), 33.0 (CH CH C=), 32.0
2
2
2
2
3H, NH & ArH), 4.45 (s, 1H, =CHSO ), 3.25 (br s, 2H,
2
(CHCH CH ), 24.0 (CH CH CH ), 21.0 (CH CH CH ), 14.0
2
2
2
2
3
2
2
3
CH CH N), 2.30 (br s, 2H, CH CH C=), 1.80 (br s, 2H,
2
2
2
2
(CH CH ).
13
3
2
CH CH CH C=), 1.65 (br s, 2H, CH CH CH ); C nmr: δ
2
2
2
2
2
2
158.1 (=C-N), 145.4 (=CH-SO Ph), 131.7, 128.7, 128.5, 125.4
2-(1-Phenylsulfonylheptylidene)-pyrrolidine [1c (R = n-C H ,
N = 1)].
2
6
13
(ArC), 85.6 (=CH-SO ), 41.4 (NCH ), 29.6 (CH -C=), 22.4
2
2
2
(NCH CH CH ), 19.6 (CH CH CH C=). Ms: m/z 172 (100%),
237(M ).
2
2
2
2
2
2
Compound 1c was obtained in 70% yield, as a yellow oil.
Purified by silica gel chromatography with 1:1 cyclohexane/ethyl
acetate; ir: ν 3398, 3063, 2953, 2929, 2859, 1614, 1479, 1466,
+
Anal. Calcd. for C
H
NO S: C, 60.73; H, 6.37; N, 5.90; S,
2
12 15
13.51. Found: C, 60.37; H, 6.29; N, 5.87; S, 13.91.
-1
1
1447, 1374, 1321, 1282, 1151, 1135, 1085, 1024 cm ; H nmr: δ
2-(Phenylsulfonylmethyl)-1,2-dehydropiperidine [2e (R = H,
N = 2)].
7.82 (m, 2H, ArH), 7.62 (m, 1H, ArH), 7.40 (m, 2H, ArH), 7.25
(br s, 1H, NH), 3.45 (t, 2H, CH NH), 2.55 [t, 2H, CH (CH ) ],
2
2
2 4
1.92 (t, 2H, NC=CCH CH ), 1.85 [m, 4H, CH CH CH NH,
1
2
2
2
2
2
Hydrogen and carbon NMR for compound 2e. H nmr: δ 7.85
CH CH (CH ) CH ], 1.18 [m, 6H, CH (CH ) CH ], 0.80 [t, 3H,
2
2
2 3
3
2
2 3
3
(m, 2H, ArH), 7.55 (m, 3H, ArH), 3.90 (s, 2H, CH SO ), 3.50
(br s, 2H, CH N), 2.40 (br s, 2H, CH C=), 1.75 (br s, 2H,
CH CH CH N), 1.50 (br s, 2H, (CH CH CH C=); C nmr: δ
160.7 (-C=N), 138.5 (=C-SO ), 133.8, 129.0, 128.2, 125.2
2
2
13
CH (CH ) CH ]; C nmr: δ 159.5 (=C-NHCH ), 144.2, 1131.7,
2
2 3
3
2
2
2
128.6, 126.2 (ArC), 93.4 (=C-SO -Ph), 47.3 (CH CH NH), 31.4
13
2
2
2
2
2
2
2
2
2
(CH CH C=C), 31.3 [=CCH (CH ) ], 30.3 (CH CH CH NH),
2
2
2
2 4
2
2
2
2
29.0 [CH CH (CH ) CH ], 28.7 [CH CH (CH ) CH ], 26.8
2
2
2 3
3
2
2
2 3
3
(ArC), 66.6 (CH SO ), 50.0 (CH N), 30.3 (CH -C=), 21.1
2
2
2
2
[CH (CH ) CH CH ], 22.5 [(CH ) CH CH ], 13.9
2
2 3
2
3
2 4
2
3
(CH CH CH N), 19.9 (CH CH CH C=).
2
2
2
2
2
2
[CH (CH ) CH ].
2
2 4
3
Acylation of 2-(Phenylsulfonylmethylene)-pyrrolidine (1a).
2-(1-Phenylsulfonylheptyl)-1,2-dehydropyrrolidine [2c
(R = n-C H , N = 1)].
To a magnetically stirred solution of enamine 1a (0.65 g, 2.91
mmol) in 15 mL dry tetrahydrofuran was added n-butyllithium
(1.3 mL of a 2.5 M solution in hexanes) at -50 °C, stirred for 35
minutes. The orange solution was cooled at -78 °C, and reacted
with acetic anhydride (0.30 g, 2.91 mmol) in 3 mL dry tetra-
hydrofuran while stirring and then allowing the temperature bath
to raise to -28 °C. The reaction mixture was quenched with
ammonium chloride (5 mL, saturated aqueous solution) and
extracted with methylene chloride. The organic layer was dried
with anhydrous magnesium sulfate, concentrated under reduced
pressure (25-35/20-40 torr) and the residue crystallized
(hexane/ethyl acetate, -10 °C) to afford the iminodienol 7 (0.25
g, 36%), mp 139.5-141.5 °C ir: υ 3068, 3000, 2982, 1600, 1552,
1479, 1460, 1310, 1236, 1150, 1095 cm ; H nmr: δ 11.95 (br s,
1H, OH), 7.80 (m, 2H, ArH), 7.50 (m, 2H, ArH), 3.61 (t, 2H,
CH CH N), 3.25 (t, 2H, CH CH C=), 2.28 (s, 3H, CH ), 1.98
(qt, 2H, CH CH CH ); C nmr: δ 194.0 (=C-O), 173.0
(=N-C-SO ), 145.0 (=C-SO ), 132.0, 128.0, 126.0 (ArC), 106.0
(-C=N), 48.0 (CH N), 35.0 (CH CH C=), 30.0 (CH ), 21.0
(CH CH CH ); Ms: m/z 200 (100%), 266 (M + 1).
6
13
Aliphatic hydrogen and carbon (aliphatic & olefinic) NMR
1
chemical shift assignments. H nmr: δ 4.15 (dd, 1H,
PhSO CHCH ), 3.65 (m, 2H, CH CH NH), 2.70 (t, 2H,
2
2
2
2
CH CH C=), 2.00 (m, CH CH CH), 1.85 (CH CH CH ), 1.30
2
2
2
2
2
2
2
13
(CH CH CH ), 0.90 (t, 3H, CH CH ); C nmr: δ 160.0 (C=N),
2
2
3
3
2
70.0 (CHSO ), 61.0 (CH N), 33.0 (CH CH C=), 32.0
2
2
2
2
(CHCH CH ), 24.0 (CH CH CH ), 21.0 (CH CH CH ), 14.0
2
2
2
2
3
2
2
3
(CH CH ).
3
2
2-(1-Phenylsulfonylethylidene)-pyrrolidine [1d (R = CH ,
3
N = 1)].
-1
1
Compound 1d was obtained in 60% yield, mp 74-75 °C,
crystallized from hexane/ethyl acetate; ir: υ 3403, 3072, 2980,
2943, 1624, 1587, 1479, 1442, 1322, 1292, 1152, 1133, 1089,
2
2
2
2
3
-1
1
13
1066 cm ; H nmr: δ 7.80 (m, 2H, ArH), 7.64 (t, 1H, ArH),
7.55 (m, 2H, ArH), 7.27 (br s, 1H, NH), 3.45 (t, 2H,
CH CH NH), 2.52 (t, 2H, CH CH C=N), 1.93 (qt, 2H,
2
2
2
2
2
2
2
2
2
2
2
2
3
13
+
CH CH CH ), 1.70 (s, 3H, CH C=); C nmr: δ 158.9 (C=C-N),
2
2
2
3
2
2
2
136.9, 131.9, 129.0, 126.3 (ArC), 89.6 (CH CSO ), 47.6
Anal. Calcd. for C
H
NO S: C, 58.85; H, 5.70; N, 5.28; S,
3
2
13 15
3
(CH NH), 35.3 (C=C-CH ), 22.5 (CH CH CH ), 13.4
12.08. Found: C, 58.42; H, 5.59; N, 5.19; S, 12.31.
2
2
2
2
2
(CH C=).
Anal. Calcd. for C
3
Acknowledgements.
H NO S: C, 60.73; H, 6.37; N, 5.90; S,
12 15 2
13.51. Found: C, 60.88; H, 6.28; N, 6.02; S, 13.27.
Financial support for this work from National Institute of
Health (NIGMS-MBRS Grant S06 GM08159) is gratefully
acknowledged.
2-(Phenylsulfonylethyl)-1,2-dehydropyrrolidine [2d (R = CH ,
N = 1)].
3
1
Hydrogen and carbon NMR chemical shift assignments. H
nmr: δ 7.80 (m, 2H, ArH), 7.50-7.42 (m, 3H, ArH), 4.20 (q, 1H,
REFERENCES AND NOTES
CHCH ), 3.52 (t, 2H, CH CH N=), 2.72 (t, 2H, CH CH C=N),
3
2
2
2
2
13
1.88 (qt, 2H, CH CH CH ), 1.55 (d, 3H, CHCH ); C nmr: δ
*
Corresponding author, E-mail: larias@ariasoctane.metro.inter.edu
2
2
2
3
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Jan-Feb 2001
Synthesis of Functionalized Cyclic Enamines from Lithium Alkylphenyl Sulfones
33
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[6a] Ab initio calculations were performed using Gaussian 94