Asymmetric α-alkynylation of piperidine via N-sulfinyliminium salts

Article abstract of DOI:10.1021/jo070631c

(Chemical Equation Presented) Piperidine was stereoselectively α-alkynylated in a four-step sequence made up of transformation to a chiral nonracemic N-sulfinylpiperidine, anodic oxidation to N-sulfinyliminium ion equivalent, alkynylation through addition

Full text of DOI:10.1021/jo070631c

Asymmetric r-Alkynylation of Piperidine Wia N-Sulfinyliminium
Salts
Serge Turcaud, Emma Sierecki, Thierry Martens, and Jacques Royer*
Synthe`se et structure de mole´cules d’inte´reˆt pharmacologique, UMR 8638 CNRS-UniVersite´ Paris 5,
Faculty of Pharmacy, 4 aVenue de l’ObserVatoire, 75270 Paris cedex 6, France
jacques.royer@uniV-paris5.fr
ReceiVed March 27, 2007
Piperidine was stereoselectively R-alkynylated in a four-step sequence made up of transformation to a
chiral nonracemic N-sulfinylpiperidine, anodic oxidation to N-sulfinyliminium ion equivalent, alkynylation
through addition of a mixed organoaluminum derivative, and final acidic deprotection of the sulfoxide.
Overall yields are around 50%, and the diastereoselectivity of the nucleophilc addition was between 92
and 99% de, allowing isolation of the final product with 99% enantiomeric purity.
SCHEME 1. Complete Sequence of Alkynylation of
Piperidinea
Introduction
Asymmetric substitution R to the nitrogen of amines is still
a challenging synthetic problem particularly in cyclic series.
Though several successes were reported,1 there is no general
method available allowing functionalization of pyrrolidine,
piperidine, morpholine, etc. For example, while the carbanion
of N-Boc-pyrrolidine is stereoselectively alkylated in the pres-
ence of sparteine, the reaction is much more problematic with
piperidine.2 It thus seems important to further develop methods
for the asymmetric R-substitution of amines in general and
piperidine in particular. In this context, we recently reported
on the preparation of R-methoxy-N-sulfinylpiperidines 2 (Scheme
1) which are synthetic equivalent of N-sulfinyliminium ions3
and therefore could add nucleophiles.
a Conditions and reagents: (a) MeMgBr, THF, 0 °C, then ArSOMenthyl;
(b) MeOH, anodic oxidation; (c) CH2Cl2, TMSOTf, R-CC-AlMe2, -78 °C;
(d) 3 M HCl/MeOH.
They were synthesized from piperidine in two steps and 50-
70% overall yield Via the anodic oxidation4 of N-sulfinylpip-
eridine as the key step. We also already reported the addition
of silyl enol ether onto methoxy derivatives 2 which furnished
interesting R-functionalized piperidines with a good diastereo-
selectivity.3 While interesting, the method was somewhat
hampered by the formation of byproducts corresponding to the
addition at the sulfur atom5 and to the deprotonation of the
iminium to enamine. In the course of this study we further
investigated various nucleophiles and want to present herein
* Author to whom correspondence should be addressed. Phone: 33-1-53-
73-9749. Fax: 33-1-43-29-1403.
(1) See for example, (a) Wilkinson, T.; Stehle, N. W.; Beak, P. Org.
Lett. 2000, 2, 155-158. (b) Ashweek, N. J.; Brandt, P.; Coldman, I.; Gawley,
R. E.; Haeffner, F.; Klein, R.; Sanchez-Jimenez, G. J. Am. Chem. Soc. 2005,
127, 449-457. (c) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4497-4499 and in
nonasymmetric series. (d) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew.
Chem., Int. Ed. 2005, 44, 6931-6933. (e) Pastine, S. J.; Gribkov, D. V.;
Sames, D. J. Am. Chem. Soc. 2006, 128, 14220-14221. (f) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2004, 126, 11810-11811.
(2) (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231-3239. (b) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-
1117. (c) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B. J.
Am. Chem. Soc. 2002, 124, 1889-1896.
(3) Turcaud, S.; Martens, T.; Sierecki, E.; Pe´rard-Viret, J.; Royer, J.
Tetrahedron Lett. 2005, 46, 5131-5134.
(4) The anodic oxidation of carbamates is a classical reaction following
the seminal work of T. Shono; see (a) Shono, T.; Tsubata, K. J. Am. Chem.
Soc. 1981, 103, 1172-1176. (b) Shono, T. Tetrahedron 1984, 40, 811-
850. (c) Malmberg, M.; Nyberg, K. Acta Chem. Scand. Ser. B 1979, 33,
69-72. (d) Danielmeier, K.; Schierle, K.; Steckhan, E. Tetrahedron 1996,
52, 9743-9754. (e) Suga, S.; Nishida, T.; Yamada, D.; Nagaki, A.; Yoshida,
J. J. Am. Chem. Soc. 2004, 126, 14338-14339.
10.1021/jo070631c CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/25/2007
4882
J. Org. Chem. 2007, 72, 4882-4885

R-Alkynylation of Piperidine
TABLE 1. Addition of Dimethylalkynylaluminium to
r-Methoxy-N-sulfinyl Piperidines
the addition of acetylenic alanes which occurred cleanly without
byproducts and with an excellent diastereoselectivity.
The addition of acetylides to imines is a classical method
described for the preparation of enantioenriched propargyl
amines and has received a great deal of attention during recent
years.5,6 The chirality can be brought through different methods
including the use of chiral auxiliaries or asymmetric catalyst.
The use of more electrophilic species such as iminium or
N-acyliminium salts (or nitrones) is more scarcely represented.7
The addition of acetylides to chiral N-sulfinyl imines has also
been reported.8 It is noteworthy that only N-tert-butylsulfinyl
imines were studied and that the diastereoselectivity of the
reaction was dependent upon the choice of the metal of the
organometallic species as well as the nature of the Lewis acid.
We then envisaged the alkynylation of the R-methoxy-N-
sulfinyl 2 as iminium equivalent species. Thanks to the easy
acidic cleavage of the N-S bond, the overall sequence would
provide an efficient asymmetric synthesis of R-alkynylpip-
eridines from piperidine (Scheme 1).
The choice of the metal of the acetylide was first addressed.
Zinc acetylides have been largely used in several studies of
imine alkynylation and could be prepared in situ according to
the procedure described by Carreira.8a,10 In our hands, the
reaction of N-p-tolylsulfinylpiperidine 2a with phenylacetylene
and Zn(OTf)2 showed an important formation of enamine (about
30%), together with about 30% of attempted alkynylpiperidine11
in a modest diastereoselectivity. It was thus preferred to further
investigate other organometallic species.
alkynylated
compound
yield,a
%
de,b
%
X
R
p-CH3
Ph
Ph
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
30c
96
50
76
74
93
71
92
86
82
90
91
30
30c
34
30
82
88
94
99
92
97
96
96
93
Cl(CH2)3
Cl(CH2)3
Ph
CH3(CH2)2
Ph
Cl(CH2)3
CH3(CH2)2
(CH3)2CH(CH2)2
H
CH2dC(CH3)
1-cyclohexenyl
p-CF3
o-CH3
o-CF3
3j
3k
3l
a Isolated yields. b Determined by NMR and HPLC on crude reaction
mixtures. c Using the Zn acetylide according to ref 10.
reported that they are prone to give 1,4-addition product13 and
hopefully without any deprotonation. With the aim to avoid the
formation of enamine from R-methoxy-N-sulfinylpiperidines,
we choose to prepare the alkynylalanes under the conditions
developed by L. Micouin14 using only catalytic amount of base
(Et3N). First experiments were done from N-p-tolylsulfinyl
derivatives with phenylacetylene dimethylalane.
We turned our attention to aluminum derivatives. Alkyny-
lalanes received much less attention12 than the corresponding
magnesium, lithium, zinc, etc., derivatives. Nevertheless, it can
be anticipated that aluminum derivatives would react onto the
potential iminium with high regioselectivity since it has been
The iminium salt was generated by addition of 1.2 equiv of
TMSOTf to the methoxy derivative 2a in CH2Cl2 at -78 °C,
prior to the addition of the dimethylalkynylaluminum compound
(about 1.5 M in heptane; 2 equiv). After 30 min at low
temperature, a clean and complete reaction has occurred and
alkynylated piperidine was isolated in very high yield. There is
no addition onto the sulfur atom, and only trace amounts of
enamine was detected in a few cases. With this method in hands,
we then investigated the diastereoselectivity of the reaction
which, we thought, may be dependent upon the structure of the
aryl group borne at the sulfur atom.
The results are reported in the Table. It can be seen that the
diastereoselectivity was quite low with a p-tolylsulfinyl group
(compounds 3a,b) as well as with an electron-withdrawing group
at the para position of the aromatic group (X ) p-CF3,
compound 3c).
(5) This side reaction was known in the N-sulfinylimine series and was
generally circumvented by the use of t-Bu- instead of p-tolylsulfinylimine.
See (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396-3397.
(b) Davis, F. A.; Qu, J.; Srirajan, V.; Joseph, R.; Titus, D. D. Heterocycles
2002, 58, 251-258.
(6) For reviews, see (a) Blanchet, J.; Bonin, M.; Micouin, L. Org. Prep.
Proced. Int. 2002, 34, 467-492. (b) Cozzi, P. G.; Hilgraf, R.; Zimmermann,
N. Eur. J. Org. Chem. 2004, 4095-4105.
(7) For recent examples, including the one-pot Mannich type reaction,
see (a) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395-4398. (b) Wei, C.; Li,
C.-J. J. Am. Chem. Soc. 2003, 125, 9584-9585. (c) Benaglia, M.; Negri,
D.; Dell’Anna, G. Tetrahedron Lett. 2004, 45, 8705-8708. (d) Koradin,
C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J. 2003, 9,
2797-2811. (e) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107-
1110. (f) Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006,
71, 1558-1562.
(8) (a) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497-1499. (b)
Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143-146. (c) Topic, D.;
Aschwanden, P.; Fassler, R.; Carreira, E. M. Org. Lett. 2005, 7, 5329-
5330. (d) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107-1110.
(9) (a) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Slnick, H. G.; Nanternet,
P. G. Tetrahedron Lett. 2001, 42, 2051-2054. (b) Crucianelli, M.; De
Angelis, F.; Lazzaro, F.; Malpezzi, L.; Volonterio, A.; Zanda, M. J. Fluorine
Chem. 2004, 125, 573-577. (c) Kuduk, S. D.; DiPardo, R. M.; Chang, R.
K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45, 6641-6643. (d) Lettan,
R. B.; Scheidt, K. A. Org. Lett. 2005, 7, 3227-3230. (e) Tang, T. P.;
Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772-8778. (f)
Patterson, A. W.; Ellman, J. A. J. Org. Chem. 2006, 71, 7110-7112. (g)
Patterson, A. W.; Wood, W. J. L.; Hornsby, M.; Lesley, S.; Spraggon, G.;
Ellman, J. A. J. Med. Chem. 2006, 49, 6298-6307.
It thus clearly appears from the table that the methyl or
trifluoromethyl groups should be at the ortho position to have
a significant effect on the diastereoselectivity. Then, in all cases,
(compounds 3d-l) a very high diastereoselectivity was ob-
served, particularly if X ) o-CF3 since de values higher than
(12) (a) Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;
Husson, H.-P. Tetrahedron Lett. 1999, 40, 2935. (b) Ahn, J. H.; Joung, M.
J.; Yoon, N. M.; Oniciu, D.C.; Katritsky, A. R. J. Org. Chem. 1999, 64,
488. (c) Kessabi, J.;Beaudegnies, R.; Jung, P. M. J.; Martin, B.; Montel,
F.; Wendeborn, S. Org. Lett. 2006, 8, 5629-5632.
(13) Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320-7322.
(14) (a) Feuvrie, C.; Blanchet, J.; Bonin, M.; Micouin, L. Org. Lett. 2004,
6, 2333-2336. (b) Wang, B.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6,
3481-3484. (c) Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H. P.
Tetrahedron Lett. 2001, 42, 3171-3173.
(10) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
1999, 121, 11245-11246. (b) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.;
Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-371.
(11) The reaction of phenylacetylene in the presence of a zinc salt with
5-methoxypyrrolidin-2-one or 6-methoxypiperidin-2-one was reported to
occur with moderate yields: Pilli, R. A.; Robello, L. G. Synlett 2005, 2297-
2300.
J. Org. Chem, Vol. 72, No. 13, 2007 4883

Turcaud et al.
SCHEME 2. Absolute Configuration Determination
1.67 (m, 2H); 1.90 (m, 3H); 2.42 (s, 3H); 3.13 (m, 1H); 3.38 (ddd,
J ) 12.6, 3.0, 3.0 Hz, 1H); 4.62 (t, J ) 3.9 Hz, 1H); 7.22 (m, 1H);
7.31 (m, 3H); 7.42 (m, 4H); 7.97 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ (ppm): 18.7; 20.2; 25.9; 32.4; 41.8; 48.7; 85.7; 86.8;
122.9; 125.5; 126.2; 128.20; 128.21; 130.8; 131.1; 131.7; 136.3;
141.2. IR (neat) 3055, 2937, 2847, 2219, 1598, 1447, 1365, 1325,
1268, 1088, 1034, 916, 880. MS: m/z 346 (M + Na). Elemental
Analysis: calcd. C 74.30%, H 6.50%, N 4.33%; found: C 74.81%,
H 6.71%, N 4.43%.
(S)-2-Pent-1-ynyl-1-((S)-toluene-2-sulfinyl)piperidine (3e). Col-
orless oil (0.148 mmol, 0.043 g, 74%). [R]22D +57.3 (c 1.2, MeOH).
Rf ) 0.28 (diethyl ether/n-heptane 7/3). HPLC analysis was carried
out using Exsil CN (4.6 × 250 mm); 100 Å; 5 µm; n-heptane:
ethyl acetate ) 9:1; wavelength, 254 nm; flow rate 2.0 mL/min; tr
) 7.9 min 1H NMR (300 MHz, CDCl3) δ (ppm): 0.99 (t, J ) 7.2
Hz, 3H); 1.35 (m, 1H); 1.53 (m, J ) 7.2 Hz, 2H); 1.62 (m, 3H);
1.8 (m, 2H); 2.18 (ddd, J ) 7.2, 2.1, 2.1 Hz, 2H); 2.38 (s, 3H); 3.0
(m, 1H); 3.28 (ddd, J ) 12.6, 2.7, 2.7 Hz, 1H); 4.4 (m, 1H); 7.22
(m, 1H); 7.39 (m, 2H); 7.95 (m, 1H). 13C NMR (75 MHz, CDCl3)
δ (ppm): 13.5; 18.7; 20.1; 20.7; 22.2; 25.9; 32.7; 40.9; 48.9; 77.5;
86.2; 125.5; 126.0; 130.7; 131.0; 136.3; 141.3. IR (neat): 3048,
2930, 2237, 1716, 1451, 1332, 1275, 1095, 902. MS: m/z 312 (M
+ Na). Elemental Analysis: calcd. C 70.58%, H 7.96%, N 4.84%;
found: C 70.42%, H 7.64%, N 4.84%.
92% were observed. Several acetylenic groups could be
introduced on the piperidine skeleton, and the presence of double
bond or primary halide was also compatible with this simple
and efficient procedure. The major isomer could be easily
isolated after simple flash chromatography as a single isomer
furnishing enantiopure piperidine derivatives (as proved by
chiral HPLC on compounds 3d and 3f).
The configuration of the newly created center was determined
by chemical correlation. We choose to start from piperidine
derivative 3h obtained in 92% de, and the major diastereoisomer
was isolated as a pure isomer and submitted to a brief 3 M
HCl/MeOH treatment to give quantitatively the deprotected
piperidine 4h (Scheme 2). Hydrogenation of the triple bond led
to 2-pentylpiperidine (5) which optical rotation ([R]D -10.4
(CHCl3, c 0.7) indicated that the 2R configuration was attained
(lit.15 [R]D +10.0 (CHCl3, c 0.52) for the S isomer).
We eventually verified that the alkynyl group was intro-
duced on the same face of the iminium of both o-tolyl- and
o-trifluoromethylphenylsulfinyl derivatives since compound 4h
obtained from 3e or 3h exhibited the same sign of optical
rotation ([R]D -14 and -16 (MeOH, c 0.5), respectively). The
better diastereoselectivity is probably due to the larger steric
demand of the o-CF3 group.
(S)-2-Phenylethynyl-1-((S)-2-trifluoromethylbenzenesulfi-
nyl)piperidine (3f). Colorless oil (0.186 mmol, 0.07 g, 93%). [R]22
D
+29.1 (c 1.1, MeOH). Rf ) 0.33 (diethyl ether/n-heptane 6/4).
HPLC analysis was carried out using Exsil CN (4.6 × 250 mm);
100 Å; 5 µm; n-heptane:ethyl acetate ) 9:1; wavelength, 254 nm;
flow rate 2.0 mL/min; tr ) 8.4 min. Chiralpak AD (4.6 × 250 mm);
n-hexane/EtOH 95/5; 0.8 mL/min; tr ) 12.3 min; (rac, tr ) 11.7
1
min, tr ) 12.3 min). H NMR (300 MHz, CDCl3) δ (ppm): 1.38
(m, 1H); 1.63 (m, 2H); 1.90 (m, 3H); 2.90 (m, 1H); 3.26 (ddd, J )
12.6, 2.4, 2.4 Hz, 1H); 4.72 (t, J ) 3.6 Hz, 1H); 7.30 (m, 3H);
7.42 (m, 2H); 7.61 (m, 1H); 7.77 (m, 2H); 8.27 (d, J ) 7.5 Hz,
1H) ; 13C NMR (75 MHz, CDCl3) δ (ppm): 19.9, 25.3, 31.7, 40.3,
49.4, 85.9, 86.6, 121.9, 122.8, 126.6, 127.4, 127.5, 127.6, 128.1,
130.9, 131.7, 131.8. IR (neat): 2947, 2915, 2851, 2366, 1490, 1309,
1171, 1098, 1028. MS: m/z 400 (M + Na). Elemental Analysis:
calcd. C 63.66%, H 4.77%, N 3.71%; found: C 63.37%, H 4.78%,
N 3.63%.
(S)-2-(5-Chloropent-1-ynyl)-1-((S)-2-trifluoromethylbenzene-
sulfinyl)-pipe ridine (3g). Colorless oil (0.142 mmol, 0.054 g,
Experimental Section
General Experimental Procedure for the Synthesis of Com-
pounds 3d-l. To a solution of methoxy-N-sulfinylpiperidine 23
(0.2 mmol) in anhydrous dichloromethane (2 mL) was added at
-78 °C trimethylsilyl trifluoromethanesulfonate 99% (0.24 mmol).
After 45 min at the same temperature, the alkynylalane14b,c (0.4
mmol) was added and the reaction was monitored by HPLC (Exsil
CN; 100 Å; 5 µm; 250 × 4.6 mm; wavelength 254 nm; flow rate
2 mL/min; in n-heptane/ethyl acetate or TLC in diethyl ether/n-
heptane 7/3 and quenched by addition of 2 mL of a 2 M Rochelle’s
salt solution after 30 min at -78 °C. The product was extracted
with dichloromethane and the organic layer washed successively
with water and brine. After drying (Na2SO4), the organic layer was
evaporated under reduced pressure and the oily residue purified
by column chromatography on silica gel neutralized with triethy-
lamine. The major diastereomer was isolated and characterized.
(S)-2-Phenylethynyl-1-((S)-toluene-2-sulfinyl)piperidine (3d).
71%). [R]22 +10.9 (c 1.1, MeOH). Rf ) 0.54 (diethyl ether/n-
D
heptane 7/3). HPLC analysis was carried out using Exsil CN (4.6
× 250 mm); 100 Å; 5 µm; n-heptane:ethyl acetate ) 9:1;
wavelength, 254 nm; flow rate 2.0 mL/min; tr ) 6.2 min; 1H NMR
(300 MHz, CDCl3) δ (ppm): 1.25 (m, 1H); 1.63 (m, 5H); 1.94
(q, J ) 6.6 Hz, 2H); 2.39 (ddd, J ) 6.6, 2.4, 2.4 Hz, 2H); 2.74 (m,
1H); 3.11 (ddd, J ) 12.3, 2.4, 2.4 Hz, 1H); 3.67 (t, J ) 6.6 Hz,
2H); 4.49 (s, 1H); 7.61 (m, 1H); 7.74 (m, 2H); 8.20 (d, J ) 7.5
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 16.1; 19.7; 25.1;
31.3; 31.7; 39.4; 43.7; 49.6; 78.4; 84.3; 126.7; 127.4; 127.5; 130.9;
131.8. IR (neat): 3068, 2930, 2856, 2239, 1591, 1436, 1312, 1254,
1170, 1133, 1092, 1032. MS: m/z 400 (M + Na). Elemental
Analysis: calcd. C 54.04%, H 5.03%, N 3.70%; found: C 53.96%,
H 5.05%, N 3.66%.
(S)-2-Pent-1-ynyl-1-((S)-2-trifluoromethylbenzenesulfi-
nyl)piperidine (3h). Pale yellow oil (0.184 mmol, 0.063 g, 92%).
Colorless oil (0.152 mmol, 0.05 g, 76%). [R]22 +24.2 (c 1.45,
[R]22 +46.8 (c 1.54, MeOH). Rf ) 0.30 (diethyl ether/n-heptane
D
D
MeOH). Rf ) 0.43 (diethyl ether/n-heptane 7/3). HPLC analysis
was carried out using Exsil CN (4.6 × 250 mm); 100 Å; 5 µm;
n-heptane/ethyl acetate ) 9/1; wavelength, 254 nm; flow rate 2.0
mL/min; tr ) 10.6 min. Chiralpak AD (4.6 × 250 mm); n-hexane/
i-PrOH 9/ 1; 0.8 mL/min; tr ) 11.2 min; (rac, tr ) 11.2 min, , tr )
6/4). HPLC analysis was carried out using Exsil CN (4.6 × 250
mm); 100 Å; 5 µm; n-heptane:ethyl acetate ) 95:5; wavelength,
254 nm; flow rate 2.0 mL/min; tr ) 9.0 min; 1H NMR (300 MHz,
CDCl3) δ (ppm): 0.97 (t, J ) 6.6 Hz, 3H); 1.25 (m, 1H); 1.51
(m, 4H); 1.75 (m, 3H); 2.15 (ddd, J ) 7.2, 2.1, 2.1 Hz, 2H); 2.74
(m, 1H); 3.14 (ddd, J ) 12.6, 2.4, 2.4 Hz, 1H); 4.48 (s, 1H); 7.56
(m, 1H); 7.73(m, 2H); 8.20 (d, J ) 7.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ (ppm): 13.5, 19.7, 20.7, 22.2, 25.2, 31.9, 39.5,
49.6, 77.3, 86.3, 121.9, 125.6, 126.6, 127.3, 127.4, 127.5, 127.8,
1
12.2 min). H NMR (300 MHz, CDCl3) δ (ppm): 1.43 (m, 1H);
(15) Laurent; P.; Braekman, J.-C.; Daloze, D. Eur. J. Org. Chem. 2000,
2057-2062.
4884 J. Org. Chem., Vol. 72, No. 13, 2007

R-Alkynylation of Piperidine
130.8, 131.8, 143.1. IR (neat): 2937, 2863, 2244, 1593, 1439, 1377,
1174, 1133, 1101, 1029, 908. MS: m/z 366 (M + Na). Elemental
Analysis: calcd. C 59.47%, H 5.83%, N 4.08%; found: C 59.23%,
H 5.64%, N 4.11%.
91%). [R]22 +31.8 (c 1.2, MeOH). Rf ) 0.54 (diethyl ether/n-
D
heptane 7/3). HPLC analysis was carried out using Exsil CN (4.6
× 250 mm); 100 Å; 5 µm; n-heptane:ethyl acetate ) 9:1;
wavelength, 254 nm; flow rate 2.0 mL/min; tr ) 4.9 min; 1H NMR
(300 MHz, CDCl3) δ (ppm): 1.32 (m, 2H); 1.68 (m, 5H); 1.82 (m,
3H); 2.1 (m, 4H); 2.80 (m, 1H); 3.16 (ddd, J ) 12.9, 2.4, 2.4 Hz,
1H); 4.60 (t, 1H); 6.08 (m, 1H); 7.63 (m, 1H); 7.77(m, 2H); 8.25
(d, J ) 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 19.7,
21.5, 22.2, 25.2, 25.5, 29.1, 31.7, 39.8, 49.7, 83.7, 87.8, 120.25,
126.6, 127.5, 130.8, 131.8, 134.8, 143.1. IR (neat): 3066, 2930,
2854, 2219, 1594, 1436, 1314, 1257, 1167, 1124, 1092, 1031, 905.
MS: m/z 404 (M + Na). Elemental Analysis: calcd. C 62.99%, H
5.77%, N 3.67%; found: C 62.93%, H 5.87%, N 3.55%.
(S)-2-(5-Methylhex-1-ynyl)-1-((S)-2-trifluoromethylbenzene-
sulfinyl)piperidine (3i). Colorless oil (0.172 mmol, 0.064 g, 86%).
[R]22 +27.1 (c 1.9, MeOH). Rf ) 0.30 (diethyl ether/n-heptane
D
6/4). HPLC analysis was carried out using Exsil CN (4.6 × 250
mm); 100 Å; 5 µm; n-heptane:ethyl acetate ) 9:1; wavelength,
1
254 nm; flow rate 2.0 mL/min; tr ) 4.3 min H NMR (300 MHz,
CDCl3) δ (ppm): 0.89 (d, J ) 6.6 Hz, 3H); 1.26 (m, 1H); 1.38 (m,
2H); 1.55 (m, 2H); 1.65 (m, 1H); 1.75 (m, 3H); 2.18 (ddd, J )
7.5, 2.1, 2.1 Hz, 2H); 2.78 (m, 2H); 3.15 (ddd, J ) 12.6, 2.4, 2.4
Hz, 1H); 4.48 (s, 1H); 7.60 (m, 1H); 7.74(m, 2H); 8.20 (d, J ) 7.5
Hz, 1H) 13C NMR (75 MHz, CDCl3) δ (ppm): 16.8, 19.7, 22.2,
25.2, 27.3, 31.9, 37.7, 39.6, 49.5, 86.5, 126.6, 127.4, 127.5, 130.8,
131.8, 143.1. IR (neat): 2954, 2973, 2862, 2242, 1733, 1591, 1470,
1433, 1308, 1254, 1177, 1119, 1028, 907, 769. MS: m/z 394 (M
+ Na). Elemental Analysis: calcd. C 61.45%, H 6.47%, N 3.77%;
found: C 61.42%, H 6.49%, N 3.61%.
(S)-2-Pent-1-ynylpiperidine (4h). To a solution of 3h (0.051
g, 0.15 mmol) in methanol (1 mL) at 0 °C was added 0.15 mL of
aqueous HCl (3 N). The mixture was stirred 30 min at 0 °C and 1
h at room temperature. After removal of the solvent under reduced
pressure, the residue was solubilized in 3 M HCl (2 mL). The
aqueous layer was washed with Et2O and evaporated to dryness.
The product was obtained and used in the next step without
purification. White solid (0.132 mmol, 0.025 g, 88%). mp 126 °C.
(S)-2-Ethynyl-1-((S)-2-trifluoromethylbenzenesulfinyl)pip-
eridine (3j). White solid (0.164 mmol, 0.049 g, 82%). mp 102 °C.
[R]22 -16.7 (c 0.8, MeOH). 1H NMR (300 MHz, CDCl3) δ
D
[R]22 +67.5 (c 1.3, MeOH). Rf ) 0.40 (diethyl ether/n-heptane
(ppm): 0.96 (t, 3H); 1.54 (m, 3H); 1.84 (m, 4H); 2.19 (m, 3H);
3.18 (m, 1H); 3.31 (m, 1H); 4.28 (s, 1H); 9.52(m, 1H); 9.78 (m,
1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 13.5, 19.3, 20.7, 21.8,
22.0, 28.8, 41.0, 46.0, 73.2, 90.1. IR (neat): 3419, 2910, 2795,
2707, 2556, 2481, 2374, 2242. MS: m/z 152 [(MH)-HCl]+.
(R)-2-Pentylpiperidine (5). Compound 4h (0.025 g, 0.132
mmol) in methanol (1 mL) was hydrogenolyzed in the presence of
10% Pd/C at atmospheric pressure and room temperature for 12 h.
The mixture was filtered through Celite 545, and the filtrate was
concentrated in vacuo. The product was characterized without
purification. White solid (0.119 mmol, 0.023 g, 90%). mp 148 °C;
1H NMR (300 MHz, CDCl3) δ (ppm): 0.83 (t, 3H); 1.31 (m, 7H);
1.75 (m, 7H); 2.84 (m, 2H); 3.41 (m, 1H); 9.11(m, 1H); 9.39 (m,
1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 13.9, 22.2, 22.4, 25.0,
D
7/3). HPLC analysis was carried out using Exsil CN (4.6 × 250
mm); 100 Å; 5 µm; n-heptane:ethyl acetate ) 9:1; wavelength,
254 nm; flow rate 2.0 mL/min; tr ) 7.7 min; 1H NMR (300 MHz,
CDCl3) δ (ppm): 1.26 (m, 1H); 1.58 (m, 3H); 1.83 (m, 2H); 2.41
(d, J ) 2.4 Hz, 1H); 2.78 (m, 1H); 3.16 (ddd, J ) 12.9, 2.4, 2.4
Hz, 1H); 4.54 (s, 1H); 7.63 (m, 1H); 7.77(m, 2H); 8.25 (d, J ) 7.5
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 19.5, 24.9, 31.3,
39.3, 49.4, 74.1, 81.1, 126.7, 127.6, 127.7, 131.1, 131.9, 142.7. IR
(neat): 3217, 2947, 2854, 2366,, 2108, 1307, 1264, 1138, 1119,
1028. MS: m/z 324 (M + Na). Elemental Analysis: calcd. C
55.81%, H 4.65%, N 4.65%; found: C 55.91%, H 4.91%, N 4.39%.
(S)-2-(3-Methylbut-3-en-1-ynyl)-1-((S)-2-trifluoromethylben-
zenesulfinyl)piperidine (3k). Colorless oil (0.180 mmol, 0.061 g,
90%). [R]22 +26.9 (c 0.88, MeOH). Rf ) 0.48 (diethyl ether/n-
28.0, 31.4, 33.3, 44.9, 57.3. [R]22 -10.4 (c 0.7, CHCl3).(for the
D
D
free base obtained after using Amberlite resin IR 120). [R]22D +10
(c 0.52, CHCl3) (for the S configuration of the free base)15
heptane 7/3). HPLC analysis was carried out using Exsil CN (4.6
× 250 mm); 100 Å; 5 µm; n-heptane:ethyl acetate ) 9:1;
wavelength, 254 nm; flow rate 2.0 mL/min; tr ) 4.7 min; 1H NMR
(300 MHz, CDCl3) δ (ppm): 1.32 (m, 1H); 1.68 (m, 5H); 1.82 (m,
3H); 2.87 (m, 1H); 3.16 (ddd, J ) 12.9, 2.4, 2.4 Hz, 1H); 4.60 (t,
1H); 5.22 (d, 2H); 7.63 (m, 1H); 7.77(m, 2H); 8.25 (d, J ) 7.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 19.5, 24.9, 31.3, 39.3,
49.4, 74.1, 81.1, 126.7, 127.6, 127.7, 131.1, 131.9, 142.7. IR
(neat): 3098, 3062, 2942, 2860, 2212, 1612, 1594, 1440, 1334,
1259, 1213, 1174, 1100, 1030, 906. MS: m/z 364 (M + Na).
Elemental Analysis: calcd. C 59.82%, H 5.28%, N 4.10%; found:
C 59.88%, H 5.45%, N 4.04%.
Acknowledgment. The authors thank Dr. L. Micouin for
his precious help in this project as well as Dr. B. Wang and Dr.
T. Bunlaksananusorn for the gift of some alanes. The CNRS
and the French Ministry of Education and Research are
acknowledged for funding.
Supporting Information Available: 1H and 13C NMR spectra
of compounds 3a-h, 4h, and 5 are available free of charge via the
Internet at http://pubs.acs.org.
(S)-2-Cyclohex-1-enylethynyl-1-((S)-2-trifluoromethylbenze-
nesulfinyl)piperidine (3l). Pale yellow oil (0.182 mmol, 0.069 g,
JO070631C
J. Org. Chem, Vol. 72, No. 13, 2007 4885