A sequence of electrophile induced cyclisation and concomitant N-deprotection of alkenylsulfinimines and alkenylsulfinamides as a direct route to cyclic or spirocyclic imines, pyrrolidines and piperidines

Article abstract of DOI:10.1016/j.tetlet.2005.04.060

Alkenylsulfinimines and alkenylsulfinamides underwent electrophile induced cyclisation reactions with phenylselenyl bromide, iodine and bromine to cyclic and spirocyclic imines, pyrrolidines and piperidines with spontaneous cleavage of the protective grou

Full text of DOI:10.1016/j.tetlet.2005.04.060

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4179–4182
A sequence of electrophile induced cyclisation and concomitant
N-deprotection of alkenylsulfinimines and alkenylsulfinamides
as a direct route to cyclic or spirocyclic imines, pyrrolidines
and piperidines
H. Ali Dondas and Norbert De Kimpe*
Ghent University, Department of Organic Chemistry, Faculty of Bioscience Engineering, Coupure Links 653, B-9000 Ghent, Belgium
Received 11 April 2005; accepted 13 April 2005
Available online 3 May 2005
Abstract—Alkenylsulfinimines and alkenylsulfinamides underwent electrophile induced cyclisation reactions with phenylselenyl bro-
mide, iodine and bromine to cyclic and spirocyclic imines, pyrrolidines and piperidines with spontaneous cleavage of the protective
group at nitrogen in good to excellent yield.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Electrophile induced cyclisations of nitrogen derivatives
carrying an alkenyl group such as amines,1 imines,2
hydrazines,3 hydrazones,4 hydroxamic acids,5 oximes6
and oxime ethers7 have been extensively studied.1–7 Var-
ious electrophiles such as halogenating agents (I2, Br2,
NBS, NIS), chalcogen (PhSeBr), metal ions (Pd, Hg,
Ag) have been reported to promote cyclisation.8–13
anesulfinyl moiety along the reaction is a great advan-
tage of this cascade reaction.
The tert-butanesulfinimines (3a,b) were prepared from
the corresponding aldehydes (1)14 and tert-butanesulfin-
amide (2)15 in the presence of Ti(OEt)4 (THF, N2, rt) in
excellent yield by modification of a literature procedure
(96–98%).15 Reduction of these imines with NaBH4
(THF, ꢀ40 ꢁC, 8 h) gave the corresponding sulfinamides
(10) in excellent yield (94–98%). The tert-butanesulfin-
imines (3a,b) react readily with electrophiles such as
phenylselenyl bromide, iodine or bromine in dichloro-
methane or acetonitrile at 0 ꢁC to room temperature
via attack of the N-atom on the intermediate onium
ion to give the intermediate iminium salts (4). Stirring
the reaction mixture at room temperature for 22 h
resulted in fragmentation in the N-deprotected iminium
salts (5) in quantitative yield (Scheme 1). Treatment with
2 N aqueous NaOH (E = PhSe) or aqueous Na2S2O3
(E = I) afforded cyclic and spirocyclic imines (6) in 74–
89% overall yield from the corresponding N-sulfinyl-
imines (3). Reduction of the cyclic imines (6) or iminium
compounds (5) with NaBH4 (MeOH/CH2Cl2, rt, 8 h) or
LiAlH4 (ether, reflux, 12 h) afforded pyrrolidines (7) in
84–89% overall yield from (3). Addition of dry HCl to
pyrrolidines (7) in 4:1 ether/CH2Cl2 gave pyrrolidinium
salt (8) in quantitative yield.17
To date, tert-butanesulfinimines and tert-butanesulfin-
amides have not been used as nitrogen nucleophiles in
electrophile induced cyclisation processes. As part of
our ongoing research program developing novel electro-
phile induced cyclisation reactions, we now report the
use of sulfinimines and sulfinamides, which can undergo
electrophile induced cyclisation and, most importantly,
spontaneous N-fragmentation in the presence of phenyl-
selenyl bromide, iodine or bromine under mild condi-
tions to generate cyclic and spirocyclic imines,
pyrrolidines and piperidines in good to excellent yield.
These substances can also undergo further modification
particularly depending on the introduced heteroatom by
the electrophile. Spontaneous removal of the tert-but-
Keywords: Electrophile induced cyclisation; Alkenylsulfinimines;
Alkenylsulfinamides.
*
Corresponding author. Tel.: +32 9 264 59 51; fax: +32 9 264 62 43;
e-mail: norbert.dekimpe@ugent.be
Treatment of iminium salts (5) with KCN in THF/H2O
(1:1, v/v) at room temperature for 16 h gave rise to
On leave from Mersin University, Faculty of Pharmacy, Yenisehir
Campus, 33342 Mersin, Turkey.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.060

4180
H. A. Dondas, N. De Kimpe / Tetrahedron Letters 46 (2005) 4179–4182
H
H
R1
R2
R1
R2
X-
O
R1
R2
O
S
PhSeBr, I2 or Br2
O
S
Ti(OEt)4
O
S
N
+
N
+
H2N
CH2Cl2 or MeCN
0 oC --> rt, 1 - 22h
THF,N2, rt, 16h
(2)
(1)
E
(3)
a. R1, R2 = Me (98%)
(4)
b. R1, R2 = (CH2)5 (96%)
R1
R2
R1
R2
X-
2N NaOH, E = PhSe
or
N
NH
+
2N Na2S2O3, E = I
E
E
(6)
a. R1, R2 = Me, E = PhSe (89%)
(5)
b. R1, R2 = (CH2)5, E = PhSe (87%)
c. R1, R2 = Me, E = I (74%)
a. R1, R2 = Me, E = PhSe, X- = Br- (100%)
b. R1, R2 = (CH2)5, E = PhSe, X- = Br- (100%)
c. R1, R2 = Me, E = I, X- = I- (100%)
d. R1, R2 = (CH2)5, E = I (78%)
d. R1, R2 = (CH2)5, E = I, X- = I- (100%)
e R1, R2 = Me, E = Br, X- = Br- (100%)
f. R1, R2 = (CH2)5, E = Br , X- = Br- (100%)
NaBH4
CH2Cl2 : MeOH, rt, 8h
or
LiAlH4
KCN
Ether, reflux, 12h
THF: H2O (1:1)
rt, 16h
NaBH4
CH2Cl2 : MeOH
rt, 8h
R1
R2
R1
R2
Cl-
dry HCl
CN
R1
NH
NH2
+
R2
NH
Ether : CH2Cl2 (4:1)
E
E
c / t 4:1
a. R1, R2 = Me, E = PhSe (NaBH4) (89%)
(LiAlH4) (62%)
(7)
E
(8)
(9)
a. R1, R2 = Me, E = PhSe (84%)
b. R1, R2 = (CH2)5, E = PhSe (NaBH4) (84%)
(LiAlH4) (65%)
a. R1, R2 = Me, E = PhSe (100%)
b. R1, R2 = (CH2)5, E = PhSe (89%)
b. R1, R2 = (CH2)5, E = PhSe (100%)
Scheme 1.
2-cyanopyrrolidines (9) in 82–84% yield as a 4:1 mixture
of cis- and trans-isomers.
by-products15,16 of the fragmentation step provided the
iminium salts and ammonium salts in high yield and
purity.
An alternative route to cyclic and spirocyclic pyrrol-
idines and piperidines was investigated as outlined in
Scheme 2. The reaction of tert-butanesulfinamides (10)
with PhSeBr or I2 in dichloromethane resulted in the
cyclisation to pyrrolidinium salts, which suffered N-
deprotection into pyrrolidinium salts (12). Treatment
of these salts with 2 N NaOH (E = PhSe) or Na2S2O3
(E = I) afforded pyrrolidines (7) in 77–94% overall yield
from the corresponding sulfinamide (10).18
Attempts to try out the chiral version of cyclisation did
not meet with great success as very low eeÕs were
obtained. For example, reaction of imine (R)-(3b) pre-
pared from enantiomerically pure (R)-tert-butanesulfin-
amide (2), in the presence of phenylselenyl bromide in
dichloromethane at 0 ꢁC for 6 h and reduction with
NaBH4 (MeOH/CH2Cl2, rt, 8 h), afforded spiropyrrol-
idine (7b) in 20% ee, measured by chiral HPLC. Because
of this result, no further experiments were directed
towards the use of chiral substrates in this cyclisation
protocol.
In the case of the reaction of tert-butanesulfinamides
(10a,b) with bromine as electrophile (CH2Cl2, rt, 16 h),
the piperidinium salts 15a,b and pyrrolidinium salts
14a,b were obtained in a 1:1 ratio quantitative yield
(Scheme 3).
A highly practical and efficient synthesis of cyclic and
spirocyclic imines, pyrrolidines and piperidines in good
yield is described by two routes.
The tert-butanesulfinamide moiety is fragmented in the
conversion 4!5 or 13!14 presumably owing to its
instability to acid.15,16 The acid is formed during the
course of the reaction. Thus, the expulsion of volatile
The efficiency of this strategy for the synthesis of azahet-
erocycles stems from the electrophile induced cyclisation
and fragmentation in a one pot cascade procedure.

H. A. Dondas, N. De Kimpe / Tetrahedron Letters 46 (2005) 4179–4182
4181
X-
R1
R2
R1
R2
X-
O
R1
R2
PhSeBr or I2
O
S
NaBH4
NH S
+
NH2
+
N
H
(3a,b)
CH2Cl2
THF, -40 oC, N2
0 oC --> rt, 1 - 6h
E
E
(12)
(11)
(10)
a. R1, R2 = Me, (98%)
a. R1, R2 = Me, E = PhSe, X- = Br-
(100%)
b. R1, R2 = (CH2)5, (94%)
b. R1, R2 = (CH2)5, E = PhSe, X- = Br-
(100%)
c. R1, R2 = (CH2)5, E = I, X- = I- (100%)
2N NaOH, E = PhSe
or
2N Na2S2O3, E = I
R1
R2
NH
(7)
E
a. R1, R2 = Me, E = PhSe (94%)
b. R1, R2 = (CH2)5, E = PhSe (88%)
c. R1, R2 = (CH2)5, E = I (77%)
Scheme 2.
Br-
O
Br-
R1
R2
Br-
R1
R2
R1
R2
Br2
NH2
+
NH S
+
NH2
+
(10a,b)
+
CH2Cl2
0 oC --> rt, 16h
Br
Br
Br
(15a,b)
(14a,b)
100%, 1:1 ratio
a. R1, R2 = Me
(13)
b. R1, R2 = (CH2)5
Scheme 3.
Baele, J. J. Org. Chem. 1994, 5485–5487; (c) De Kimpe,
N.; Boelens, M.; Piqueur, J. Tetrahedron Lett. 1994, 35,
1925–1928.
Varieties of functionalised cyclic and spirocyclic pyrrol-
idines and piperidines can be prepared from these simple
and high yielding processes.
3. Tiecco, M.; Testaferri, L.; Marini, F.; Santi, C.; Bagnoli,
L.; Temperini, A. Tetrahedron 1997, 53, 10591–10602.
4. Tiecco, M.; Testaferri, L.; Marini, F.; Santi, C.; Bagnoli,
L.; Temperini, A. Tetrahedron 1997, 53, 7311–7318.
5. Tiecco, M.; Testaferri, L.; Tingoli, M.; Marini, F. J.
Chem. Soc., Chem. Commun. 1995, 237–238.
6. (a) Dondas, H. A.; Grigg, R.; Frampton, C. S. Tetrahe-
dron Lett. 1997, 38, 5719–5722; (b) Dondas, H. A.; Grigg,
R.; Hadjisoteriou, M.; Markandu, J.; Thomas, W. A.;
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Acknowledgements
We are indebted to the Belgian National Fund for Scien-
tific Research (FWO-Flanders) for a postdoctoral
fellowship to Assoc. Professor Dr. H. Ali Dondas.
References and notes
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(d) Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. In
Organoselenium Chemistry; Wiley-Interscience: New
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Commun. 1993, 916–918; (b) De Kimpe, N.; Boelens, M.;

4182
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8. Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997,
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9. Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 863–
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10. Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 3099–
3114.
11. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.; Santi,
C.; Temperini, A. Heterocycles 1996, 43, 2679–2686;
Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L.;
Marini, F. J. Chem. Soc., Perkin Trans. 1 1993, 1989–
1993.
12. Shaw, R. W.; Lathbury, D. C.; Bates, P. A.; Hurthouse,
M. B.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1989,
2415–2424.
129.7, 128.2, 66.9, 53.67, 37.9, 34.1, 32.5, 30.3, 24.6, 21.96,
21.7. MS m/z (%) (ES): 308 (MH-Br, 100). IR (NaCl,
cmꢀ1): 2960, 2930, 1650. Compound (6b): the product
(87%) was obtained as a pale yellow thick oil. 1H NMR dH
(300 MHz, CDCl3): 7.65–7.61 (m, 2H, ArH), 7.30–7.29
(m, 3H, ArH), 7.27 (s, 1H, CH@N), 4.27 (m, 1H, NCH),
3.33 (dd, 1H, J 12.4 and 3.5 Hz, HCHSe), 3.01 (dd, 1H, J
12.4 and 6.0 Hz, HCHSe), 2.04 (dd, 1H, J 13.0 and 8.0 Hz,
HCHCHN), 1.78–1.32 (m, 11H, HCHCHN and (CH2)5).
13C NMR dC (75 MHz, CDCl3): 174.7, 132.6, 131.60
(2CH–Ar), 129.2, 129.1, 71.8, 55.3, 40.1, 35.4, 34.7, 33.2,
25.6, 23.1, 23.0. MS m/z (%) (ES): 308(M+1, 100). IR
(NaCl, cmꢀ1): 2965, 2929, 1625. Compound (7b): the
1
product (84%) was obtained as a colourless thick oil. H
13. Lathbury, D. C.; Shaw, R. W.; Anderson, M.; Gallagher,
T. J. Chem. Soc., Perkin Trans. 1 1991, 659–660.
14. (a) Salomons, G.; Ghost, S. Org. Synth. 1990, Coll. Vol. 7,
177–181; (b) Brannock, K. C. J. Am. Chem. Soc. 1959, 81,
3379–3383.
15. (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc.
1997, 119, 9913–9914; (b) Cogan, D. A.; Liu, G.; Kim, K.;
Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120,
8011–8019; (c) Cogan, D. A.; Ellman, J. A. J. Am. Chem.
Soc. 1999, 121, 268–269.
NMR dH (300 MHz, CDCl3): 7.49–7.48 (m, 2H, ArH),
7.23–7.21 (m, 3H, ArH), 3.36 (m, 1H, NCH), 3.04–3.03
(m, 2H, HCH2Se), 2.81 and 2.82 (2 · d, 2H, J 10.4 Hz,
CH2N), 2.33 (br, NH), 1.82 (dd, 1H, J 12.0 and 5.9 Hz,
HCHCH), 1.41–1.31 (m, 10H, (CH2)5), 1.21 (dd, 1H, J
12.0 and 3.1 Hz, HCHCH). 13C NMR dC (75 MHz,
CDCl3): 132.5, 130.6, 129.1, 128.8, 58.5, 57.9, 45.1, 43.9,
38.3, 37.0, 35.0, 31.5, 26.8, 23.9. MS m/z (%) (ES): 310
(M+1, 100). IR (NaCl, cmꢀ1): 3333, 2950, 1470. Com-
pound (10b): the product was obtained as a white
amorphous solid in quantitative yield. 1H NMR dH
(300 MHz, CDCl3): 8.04 (br, 2H, +NH2), 7.92–7.90 (m,
2H, ArH), 7.28–7.26 (m, 3H, ArH), 3.83 (m, 1H, NCH),
3.51 (dd, 1H, J 13.7 and 3.7 Hz, HCHSe), 3.38–3.17 (m,
3H, HCHSe and CH2NH), 2.09 (dd, 1H, J 12.7 and
6.1 Hz, HCHCH), 1.63–1.03 (m, 11H, HCHCH and
(CH2)5). 13C NMR dC (75 MHz, CDCl3): 134.0 129.5,
128.3, 128.0, 59.24, 54.9, 43.0, 42.8, 36.9, 35.5, 31.0, 25.5,
23.6, 22.9. MS m/z (%) (ES): 310 (MHꢀCl, 100). IR
(NaCl, cmꢀ1): 3432, 2925, 1454.
16. Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnich, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051–2054.
17. General procedure for the cascade PhSeBr-induced cycli-
sation of sulfinylimines: Phenylselenyl bromide (1.0 mmol)
in 5 ml of dry solvent (CH2Cl2 or MeCN) was added
dropwise to a stirred solution of tert-butanesulfinylimine
(3) (1 mmol) in the same solvent (10 ml) at 0 ꢁC under
nitrogen atmosphere, and stirring was continued at room
temperature for 18–22 h. The solvent was then evaporated
under vacuum to give the iminium salt (5). The iminium
salt (5) was treated with 2 N aq NaOH and extracted with
CH2Cl2 (two times), dried (MgSO4) and the solvent was
evaporated (at room temperature) under reduced pressure
to give the cyclic imines (6), which were further purified by
short flash chromatography eluting with ether to give a
pale yellow thick oil. These imines (6) can be reduced by
LiAlH4 (ether, reflux, 12 h) or NaBH4 (CH2Cl2/MeOH,
1:1 rt, 8 h) to afford the desired pyrrolidines (7). The
iminium salts (5) can also be reduced with sodium
borohydride (2 equiv) in 1:1 (v/v) methanol/CH2Cl2 at
room temperature for 8 h. Removal of the solvent under
reduced pressure afforded the crude pyrrolidines (7), which
were purified by flash chromatography on silica gel.
Diphenyldiselenide was first eluted by ether. The pyrrol-
idines (7) were next eluted with EtOAc/CH2Cl2 (4:1) to
give the desired cyclic and spirocyclic pyrrolidines (7) as a
colourless thick oil. These pyrrolidines when treated with
dry HCl in 4:1 ether/CH2Cl2 afforded the pyrrolidinium
salts (8) in quantitative yield. Compound (5b): The
product (100%) was obtained as a pale brown thick oil.
1H NMR dH (300 MHz, CDCl3): 9.92 (br s, 1H, CH@N+),
7.59–7.58 (m, 2H, ArH), 7.30–7.29 (m, 3H, ArH), 6.91 (br,
1H, NH), 4.71 (m, 1H, NCH), 3.68 (dd, 1H, J 13.5 and
3.65 Hz, HCHSe), 3.10 (dd, 1H, J 13.4 and 6.6 Hz,
HCHSe), 2.37 (dd, 1H, J 13.3 and 8.6 Hz, HCHCHN),
1.84 (dd, 1H, J 13.3 and 5.1 Hz, HCHCHN), 1.80–1.30
(m, 10H, (CH2)5). 13C NMR dC: 185.01, 133.63, 131.5,
18. General procedure for the cascade PhSeBr-induced cycli-
sation of sulfinylamides: Phenylselenyl bromide
(1.05 mmol) in 5 ml of dry (CH2Cl2) was added dropwise
to a stirred solution of tert-butanesulfinamide (1 mmol) in
CH2Cl2 (10 ml) at 0 ꢁC under nitrogen atmosphere and
stirring was continued at room temperature for 16–20 h.
The solvent was then evaporated under vacuo to give
ammonium salts (12). The salts were then treated with 2 N
aq NaOH and extracted with CH2Cl2 (two times), the
combined extracts were dried (MgSO4) and the solvent
was evaporated under reduced pressure to give the
pyrrolidines (7), which were further purified by flash
chromatography on silica gel. Diphenyldiselenide was first
eluted by diethyl ether. The pyrrolidines (7) were next
eluted with EtOAc/CH2Cl2 (4:1) to give the desired cyclic
and spirocyclic pyrrolidines (7) as colourless thick oil.
Compound (12b): the product was obtained as a yellow
thick oil in quantitative yield. 1H NMR dH (300 MHz,
CDCl3): 9.17 and 9.61 (2 · br, 2H, +NH2), 7.70–7.54 (m,
2H, ArH), 7.29–7.27 (m, 3H, ArH), 3.80 (m, 1H, NCH),
3.54 (dd, 1H, J 13.7 and 3.7 Hz, HCHSe), 3.21–3.12 (m,
3H, HCHSe and CH2NH), 2.11 (dd, 1H, J 12.7 and
6.1 Hz, HCHCH), 1.59–1.13 (m, 11H, HCHCH and
(CH2)5). 13C NMR dC (75 MHz, CDCl3): 134.0, 131.60,
129.5, 128.04, 59.34, 54.8, 43.0, 42.7, 36.9, 35.5, 30.6, 25.4,
23.6, 22.9. MS m/z (%) (ES): 310 (MHꢀBr, 100); IR
(NaCl, cmꢀ1): 3430, 2925, 1476.