Diastereoselective alkynylation of N-p-tolylsulfinylimines with aluminum acetylides

Article abstract of DOI:10.1021/jo071139w

(Chemical Equation Presented) The addition of alkynyl dimethyl aluminum compounds onto N-p-tolylsulfinylimines was investigated. The reaction was proved to be totally regioselective, leading to propargylamines with high diastereoselectivity (up to 99% de)

Full text of DOI:10.1021/jo071139w

Diastereoselective Alkynylation of N-p-Tolylsulfinylimines with
Aluminum Acetylides†
Serge Turcaud, Farouk Berhal, and Jacques Royer*
Synthe`se et Structure de Mole´cules d’Inte´reˆt Pharmacologique, UMR 8638 CNRS, UniVersite´
Paris-Descartes, Faculty of Pharmacy, 4 aVenue de l’ObserVatoire, 75270 Paris cedex 6, France
jacques.royer@uniV-paris5.fr
ReceiVed June 4, 2007
The addition of alkynyl dimethyl aluminum compounds onto N-p-tolylsulfinylimines was investigated.
The reaction was proved to be totally regioselective, leading to propargylamines with high diastereose-
lectivity (up to 99% de). Addition of aluminum derivatives gave a reversal of diastereoselectivity compared
to the addition reaction of lithium acetylide.
SCHEME 1
In recent years, the synthesis of propargyl amines via the
alkynylation of imines and related derivatives has received a
great deal of attention (Scheme 1).1-5 Several procedures were
described, including in situ preparation of the organometallic
species2 and one-pot Mannich-type reaction process.3 These
protocols have also been adapted for asymmetric synthesis by
the use of asymmetric catalysts4 or chiral auxiliaries5 with
† Dedicated to Prof. Henri-Philippe Husson on the occasion of his retirement.
(1) For reviews, see: (a) Blanchet, J.; Bonin, M.; Micouin, L. OPPI
2002, 34, 467-492. (b) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2004, 4095-4105.
(2) More recent examples of in situ preparation of acetylenide include:
(a) Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006, 71,
1558-1562. (b) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107-
1110. (c) Lee, K. Y.; Lee, C. G.; Na, J. E.; Kim, J. N. Tetrahedron Lett.
2005, 46, 69-74. (d) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2003, 44, 6767-
6768. (e) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497-1499. (f)
Topic, D.; Aschwanden, P.; Fassler, R.; Carreira, E. M. Org. Lett. 2005, 7,
5329-5330.
(3) For recent examples of 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) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003,
5, 4473-4475. (d) Lo, V. K.-Y.; Wong, Y.; Wong, M.-K.; Che, C.-M.
Org. Lett. 2006, 8, 1529-1532.
(4) For asymmetric catalysis, see: (a) Taylor, A. M.; Schreiber, S. L.
Org. Lett. 2006, 8, 143-146. (b) Benaglia, M.; Negri, D.; Dell’Anna, G.
Tetrahedron Lett. 2004, 45, 8705-8708. (c) Traverse, J. F.; Hoveyda, A.
H.; Snapper, M. L. Org. Lett. 2003, 5, 3273-3275. (d) Bisai, A.; Singh, V.
K. Org. Lett. 2006, 8, 2405-2408. (e) Gommermann, N.; Koradin, C.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (f)
Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638-5639. (g) Koradin,
C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem.sEur. J. 2003, 9,
2797-2811. (h) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int.
Ed. 2002, 41, 2535-2538.
various successes in terms of stereoselectivity. The use of more
reactive electrophilic species such as iminiums,4a acyliminiums,2b,e
tosylimines,2a,c and sulfinylimines5 was also reported.
In the chiral auxiliary strategy, the use of chiral sulfinylimine
appeared to be very attractive. This method6 possesses several
advantages such as the activation of imine function, the possible
separation of diastereomers to give optically pure compounds,
and the facile N-S bond cleavage. Furthermore, it was reported
that the choice of the metal would have a profound effect on
(5) For the use of a chiral auxiliary, see: (a) Barrow, J. C.; Ngo, P. L.;
Pellicore, J. M.; Slnick, H. G.; Nanternet, P. G. Tetrahedron Lett. 2001,
42, 2051-2054. (b) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.;
Bock, M. G. Tetrahedron Lett. 2004, 45, 6641-6643. (c) Tang, T. P.;
Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772-8778. (d)
Patterson, A. W.; Ellman, J. A. J. Org. Chem. 2006, 71, 7110-7112. (e)
Patterson, A. W.; Wood, W. J. L.; Hornsby, M.; Lesley, S.; Spraggon, G.;
Ellman, J. A. J. Med. Chem. 2006, 49, 6298-6307. (f) Wu, T. R.; Chong,
J. M. Org. Lett. 2006, 8, 15-18. (g) Lettan, R. B.; Scheidt, K. A. Org.
Lett. 2005, 7, 3227-3230. (h) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2003,
44, 6767-6768. (i) Ding, C.-H.; Chen, D.-D.; Luon, Z.-B.; Dai, L.-X.; Hou,
X.-L. Synlett 2006, 1272-1274.
(6) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869-8905.
10.1021/jo071139w CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/19/2007
J. Org. Chem. 2007, 72, 7893-7897
7893

Turcaud et al.
the diastereoselectivity, leading in some examples7 to the
reversal of the diastereofacial preference. Chiral sulfinylimines
were largely studied in particular by F.A. Davis, who proposed
the use of the N-p-tolylsulfinylimines,8 and by J. Ellman, who
developed the N-tert-butyl derivatives.9 The latter compounds
have the advantage to preclude the nucleophilic addition onto
the sulfur atom, which is a classical side reaction observed with
the tolylsulfinylimines.10 Ellman has reported that, while lithium
or magnesium derivatives gave poor results, these organome-
tallics coupled with AlMe3 used as Lewis acid gave better yield
and diastereoselectivity.11
TABLE 1. Addition of Phenylacetylides to
(S)-(+)-N-Benzylidene)-p-toluenesulfinamide (1)
yield
(%)
entry
metal
solvent
conditions
dra
We have recently studied12 the addition of acetylenic
aluminum derivatives onto potential chiral N-arylsulfinylimin-
ium ions. We observed that aluminum acetylenide derivatives
gave a very clean and totally regioselective addition: no side
products corresponding to the addition at the sulfur atom of
the arylsulfoxide function was observed. Furthermore, the
addition occurred with a very high diastereoselectivity. We thus
suggested that these organometallic compounds could react
regio- and diastereoselectively onto the N-tolylsulfinimines
(Davis imines). The use of alane derivatives was not very often
reported in the literature.13 They only appeared in a few cases
to be quite useful reagents for Michael-type addition.13a,c,d We
want to describe herein the addition of aluminum acetylenides
onto p-tolylsulfinylimines.
The first experiments were done with the very classical and
often used imine 1 derived from benzaldehyde and N-tolylsul-
finamide.14 Li or Mg acetylides were first checked as nucleo-
philes since their reaction was only reported with tert-
butylsulfinimine but not with p-tolylsulfinimine. The reaction
was conducted in two different solvents: CH2Cl2 and toluene.
With both metals and in both solvents, a nice reaction occurred,
leading to the sole C-alkynylated product 2 in good yield but
with a quite poor diastereoselectivity (Table 1, entries 1-3).
We checked the influence of AlMe3 (as reported by Ellman onto
tert-butylsulfinylketimines11) on the reaction of Li acetylide.
Indeed, only a slightly better diastereoselectivity was obtained
under these conditions (entries 4 and 5).
1
2
3
4
MgBr
MgBr
Li
CH2Cl2
toluene
toluene
CH2Cl2
2 equiv, -78 °C to rt
2 equiv, -78 °C to rt
2 equiv, 0 °C
2 equiv, -78 °C to rt +
AlMe3
2 equiv, -78 °C to rt +
AlMe3
2 equiv, rt
2 equiv, rt
4 equiv, 0 °C
65
51
92
86
65:35
51:49
74:26
76:24
Li
5
Li
toluene
86
82:18
6
7
8
9
Al(Me)2
Al(Me)2
Al(Me)2
Al(Me)2
CH2Cl2
toluene
CH2Cl2
toluene
7
43
86
85
-
5:95
0.5:99.5
2:98
4 equiv, 0 °C
a Determined by HPLC (250 × 4.6 mm CN Exsil column) and 1H NMR
on the crude reaction mixture.
The addition of the organoaluminum derivatives was then
tested. As already observed in our previous work,12 the reaction
needed 4 equiv of the organometallic species to occur cleanly
and rapidly. By the use of 2 equiv of alane (entries 6 and 7),
the reaction was very slow and gave poor yields (7% in CH2-
Cl2 and 43% in toluene), resulting in low conversion after 17 h
at room temperature. The best results were obtained when 4
equiv of alane was used in CH2Cl2 at 0 °C for 3 h (entry 8).
Under these conditions, the yield was excellent and the de was
99%. Furthermore, it is important to notice that, in this case,
the major isomer corresponds to the minor isomer of the addition
reaction of lithium acetylide. We can thus obtain, as will, the R
or the S configuration for the major isomer with a de of 64 or
99%, respectively.
The absolute configuration of the new created center has been
determined by transforming the amine 2a into known acetamide
4. The major isomer 2a from the alane reaction was treated
with an aqueous HCl solution in MeOH for 2 h followed by
N-acetylation (Ac2O, iPr2NEt, CH2Cl2, 2 h) to give acetamine
3 in 82% yield (Scheme 2). The hydrogenation of the triple
(7) (a) Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M. Tetra-
hedron 2002, 58, 9621-9628. (b) Plobeck, N.; Powell, D. Tetrahedron:
Asymmetry 2002, 13, 303-310.
(8) (a) Davis, F. A. J. Org. Chem. 2006, 71, 8993-9003 (b) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003-8030.
(9) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984-995.
SCHEME 2
(10) Chan, W.-H.; Lee, A. W. M.; Xia, P. F.; Wong, W. Y. Tetrahedron
Lett. 2000, 41, 5725-5728.
(11) (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268-
269. (b) Patterson, A. W.; Ellman, J. A. J. Org. Chem. 2006, 71, 7110-
7112. (c) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27,
13-18 and references cited therein.
(12) Turcaud, S.; Sierecki, E.; Martens, T.; Royer, J. J. Org. Chem. 2007,
72, 4882-4885.
(13) (a) Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320-
7322. (b) Carren˜o, M. C.; Garcia Ruano, J. L.; Maestro, M. C.; Pe´rez
Gonza´lez, M.; Bueno, A. B.; Fischer, J. Tetrahedron 1993, 49, 11009-
11018. (c) Carren˜o, M. C.; Pe´rez Gonza´lez, M.; Ribagorda, M. J. Org.
Chem. 1996, 61, 6758-6759. (d) Carren˜o, M. C.; Pe´rez Gonza´lez, M.;
Ribagorda, M.; Houk, K. N. J. Org. Chem. 1998, 63, 3687-3693. (e) Ahn,
J H.; Joung, M. J.; Yoon, N. M. J. Org. Chem. 1995, 60, 6173-6175. (f)
Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-
P. Tetrahedron Lett. 1999, 40, 2935. (g) Ahn, J H.; Joung, M. J.; Yoon, N.
M.; Oniciu, D.C.; Katritsky, A. R. J. Org. Chem. 1999, 64, 488. (h) Kessabi,
J.; Beaudegnies, R.; Jung, P. M. J.; Martin, B.; Montel, F.; Wendeborn, S.
Org. Lett. 2006, 8, 5629-5632. (i) Feuvrie, C.; Blanchet, J.; Bonin, M.;
Micouin, L. Org. Lett. 2004, 6, 2333-2336. (j) Wang, B.; Bonin, M.;
Micouin, L. Org. Lett. 2004, 6, 3481-3484.
(14) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Venkat Reddy, G.;
Burns, D. M.; Davis, F. A. Org. Synth. 2000, 77, 50.
7894 J. Org. Chem., Vol. 72, No. 21, 2007

Alkynylation of N-p-Tolylsulfinylimines
TABLE 2. Addition of Various Aluminum Acetylides to p-Tolylsulfylimines (1)
entry
R1
R2
conditions
0 °C, 3h
compound
yield (%)
dra
1
2
3
4
5
6
7
8
9
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
85
84
85
83
86
84
88
81
23
83
99.5:0.5
99.5:0.5
96:4
96:4
93:7
95:5
96:4
94:6
90:10
84:16
1-cyclohexenyl
(CH2)2CH2Cl
(CH2)4CH3
(CH2)2CH(CH3)2
0 °C, 3h
0 °C, 3 h, then rt 15 h
0 °C, 2 h, then rt 2 h
0 °C, 3 h, then rt 3 h
0 °C, 2 h, then rt 2 h
0 °C, 2 h
0 °C, 2 h
rt, 18 h
rt, 2 h
4-Br-C6H4
n-Pr
Ph
Ph
n-Pr
t-Bu
(CH2)2CH2Cl
Ph
Ph
10
2,4-diOMe-C6H3
2j
1
a Determined by HPLC (250 × 4.6 mm CN Exsil column or Kromasil modulo-Cart C18) and H NMR on the crude reaction mixture.
a sulfinyl-directed alkynyl transfer was occurring. In the case
of the alane addition, the observed configuration of the
propargylic amines as well as the necessity to use several
equivalents (4 equiv was optimum) of aluminum reagent was
consistent with the “alane model” shown in Figure 1. In this
model, we proposed that both the nitrogen and the oxygen of
sulfinimines were chelated by two different molecules of the
organoaluminum reagent. An antiperiplanar disposition of these
groups should result and explain the addition of a third reagent
molecule on the less hindered Si face. The use of 4 equiv of
alane in Michael addition of aluminum reagent to δ-sulfinyl-
R,â-unsaturated carbonyl systems was also reported by
Carren˜o,13b,c who proposed a mechanism involving complexation
with 3 equiv of aluminum reagent.
We thus investigated the addition of different alanes to a
variety of N-tolylsulfinylimines in order to check the generality,
the efficiency, and the diastereoselectivity of this process of
preparation of propargylamines.
With imine 1 derived from benzaldehyde, a variety of alanes
have been tested (Table 2, entries 1-5) and shown to give a
highly diastereoselective addition. Substituted aryl and some
aliphatic imines were tested (entries 6-10) and were shown to
give the reaction in excellent yield (excepted for compound 2i,
entry 9) and with very high diastereoselectivity (excepted for
compound 2j, entry 10).
In conclusion, the addition of aluminum acetylides onto
p-tolylsulfylimines was proved to occur cleanly with a total
regioselectivity and in very good yield, opening the way to
various chiral propargylamines. The diastereoselectivity of the
reaction was excellent (up to 99%) and opposite of the
diastereoselectivity obtained with lithium acetylides.
FIGURE 1. Proposed models for the diastereoselective addition of
aluminum and lithium acetylides.
bond furnished the acetamide 4 in 81% yield. The acetamide 4
exhibited a rotation of [R]D ) -48 (c 0.6, MeOH), which
allowed us to assign the configuration of the chiral center of
this compound as S. The R enantiomer has been described to
have a rotation of [R]D ) +53 (c 0.02, MeOH)15
The reversal of the diastereoselectivity could be tentatively
explained by the models shown in Figure 1. The configuration
of the new created center obtained with the lithium (or
magnesium) acetylide could be explained by the model proposed
by Ellman,11a in which the nitrogen was chelated by AlMe3 and
Experimental Section
General Experimental Procedure for the Preparation of
Alkynylalanes: The alkynylalanes were prepared as described,13j
and the obtained n-heptane solution was used as it stands. The
(15) La Manna, A.; Ghislandi, V.; Hulbert, P. B.; Scopes, P. M. Farmaco.
Ed. Sci. 1967, 22, 1037-1053.
J. Org. Chem, Vol. 72, No. 21, 2007 7895

Turcaud et al.
concentration of this solution can be established by NMR analysis
after reaction with benzaldehyde in toluene. In all cases, the
theoretical concentration was confirmed.
Na), 370 (M + 1 + Na). Anal. Calcd for C19H20ClNSO: C, 65.99;
H, 5.78; N, 4.05. Found: C, 66.01; H, 5.76; N, 4.28.
(SS,R)-N-(p-Toluenesulfinyl)-1-phenyloct-2-ynylamine (2d):
After 2 h at 0 °C and 2 h at room temperature, the product was
obtained as a white solid (0.341 mmol, 0.11 g, 83%); mp ) 60 °C;
General Experimental Procedure for the Preparation of
Imines 1a-e: The procedure described by Davis14,16 was used in
all cases. Imines 1a-d are known compounds.14,16
[R]22 -85.7 (c 0.93, CHCl3); Rf ) 0.27 (diethyl ether/n-heptane
D
(SS,R)-N-(p-Toluenesulfinyl)-2,4-dimethoxybenzylidene-
6/4); HPLC analysis, n-heptane/ethyl acetate ) 8:2; tr ) 5.8 min;
1H NMR (300 MHz, CDCl3) δ (ppm) 0.92 (t, 3H, J ) 6.99 Hz),
1.41 (m, 4H), 1.56 (m, 2H), 2.30 (td, 2H, J ) 2.11 Hz, J ) 7.03
Hz), 2.40 (s, 3H), 4.40 (d, 1H, J ) 5.19 Hz), 5.25 (m, 1H), 7.33
(m, 7H), 7.62 (d, 2H, J ) 8.20 Hz); 13C NMR (75 MHz, CDCl3)
δ (ppm) 14.0, 18.9, 21.3, 22.2, 28.3, 31.1, 48.7, 78.3, 87.9, 125.7,
127.5, 128.0, 128.6, 129.5, 139.7, 141.4, 141.5; MS m/z 362 (M +
Na). Anal. Calcd for C21H25NSO: C, 74.23; H, 7.36; N, 4.12.
Found: C, 74.41; H, 7.52; N, 4.06.
amine (1e): White solid (1.52 mmol, 0.460 g, 76%); mp ) 76 °C;
1
[R]22 +158.1 (c 1.02, CHCl3); H NMR (300 MHz, CDCl3) δ
D
(ppm) 2.40 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 6.44 (d, 1H, J )
2.31 Hz), 6.52 (m, 1H), 7.30 (d, 2H, J ) 8.47 Hz), 7.64 (d, 2H, J
) 8.20 Hz), 7.95 (d, 1H, J ) 8.71 Hz), 9.15 (s, 1H); 13C NMR (75
MHz, CDCl3) δ (ppm) 21.4, 55.6, 97.7, 105.9, 116.1, 124.9, 129.7,
130.1, 141.4, 142.9, 156.0, 161.4, 164.9; MS m/z 326 (M + Na),
342 (M + K). Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N,
4.62. Found: C, 63.15; H, 5.62; N, 4.51. IR (neat): 3451, 3030,
(SS,R)-N-(p-Toluenesulfinyl)-6-methyl-1-phenylhept-2-ynyl-
amine (2e): After 2 h at 0 °C and 3 h at room temperature, the
product was obtained as a white solid (0.353 mmol, 0.12 g, 86%);
2999, 2972, 2840, 1587 cm-1
.
General Experimental Procedure for the Synthesis of Com-
pounds 2a-j: To a solution of 1a-e (0.411 mmol) in anhydrous
dichloromethane (2 mL) was added at 0 °C alkynylalane13i,j (1.64
mmol). 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 6/4 and
quenched by addition of 3 mL of a 2 M La Rochelle’s salt solution.
After 15 min at room temperature, the product was extracted with
dichloromethane, and the organic layer was washed successively
with water and brine. After drying, the organic layer was evaporated
under reduced pressure, and the oily residue was purified by column
chromatography on silica gel neutralized with triethylamine. The
major diastereomer was isolated and characterized.
mp ) 58 °C; [R]22 -90.4 (c 1.15, CHCl3); Rf ) 0.36 (diethyl
D
ether/n-heptane 6/4); HPLC analysis, n-heptane/ethyl acetate ) 8:2;
tr ) 8.9 min; 1H NMR (300 MHz, CDCl3) δ (ppm) 0.92 (d, 6H, J
) 6.63 Hz), 1.46 (q, 2H, J ) 7.28 Hz), 1.73 (m, 1H, J ) 6.70 Hz),
2.30 (td, 2H, J ) 2.10 Hz, J ) 7.46 Hz), 2.39 (s, 3H), 4.44 (d, 1H,
J ) 5.17 Hz), 5.24 (m, 1H), 7.33 (m, 7H), 7.62 (d, 2H, J ) 8.22
Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 16.9, 21.4, 22.2, 27.3,
37.5, 48.7, 78.2, 87.9, 125.8, 127.5, 128.0, 128.6, 129.5, 139.7,
141.4, 141.5; MS m/z 362 (M + Na). Anal. Calcd for C21H25NSO:
C, 74.23; H, 7.36; N, 4.12. Found: C, 74.33; H, 7.45; N, 3.82.
(SS,R)-N-(p-Toluenesulfinyl)-1-(4-bromophenyl)-3-phenylprop-
2-ynylamine (2f): After 2 h at 0 °C and 2 h at room temperature,
the product was obtained as a white solid (0.345 mmol, 0.146 g,
(SS,R)-N-(p-Toluenesulfinyl)-1,3-diphenylprop-2-ynylamine (2a):
After 3 h at 0 °C, the product was obtained as a white solid (0.35
mmol, 0.12 g, 85%); mp ) 101 °C; [R]22D -95.0 (c 0.72, CHCl3);
Rf ) 0.18 (diethyl ether/n-heptane 6/4); HPLC analysis, n-heptane/
84%); mp ) 104-106 °C; [R]23 +42.6 (c 1.00, CHCl3); HPLC
D
1
analysis, n-heptane/ethyl acetate ) 8:2; tr ) 8.45 min; H NMR
(300 MHz, CDCl3) δ (ppm) 2.41 (s, 3H), 4.59 (d, 1H, J ) 5.60
Hz), 5.44 (d, 1H, J ) 5.48 Hz), 7.25-7.62 (m, 13H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 21.4, 47.9, 87.0, 87.1, 122.2, 125.8,
128.3, 128.7, 129.3, 129.6, 131.7, 131.8, 138.3, 140.9, 141.7; MS
m/z 448 (M + Na), 464 (M + K). Anal. Calcd for C22H18BrNSO:
C, 62.27; H, 4.28; N, 3.30. Found: C, 62.07; H, 4.52; N, 3.04. IR
1
ethyl acetate ) 8:2; tr ) 8.5 min; H NMR (300 MHz, CDCl3) δ
(ppm) 2.41 (s, 3H), 4.58 (d, 1H, J ) 5.43 Hz), 5.49 (d, 1H, J )
5.46 Hz), 7.34 (m, 8H), 7.45 (m, 4H), 7.65 (d, 2H, J ) 8.21 Hz);
13C NMR (75 MHz, CDCl3) δ (ppm) 21.4, 49.0, 86.8, 87.5, 122.5,
122.8, 127.6, 128.3, 128.6, 128.7, 129.6, 131.8, 139.1, 141.3, 141.6;
MS m/z 368 (M + Na). Anal. Calcd for C22H19NSO: C, 76.42; H,
5.50; N, 4.05. Found: C, 76.23; H, 5.83; N, 3.89.
(neat): 3448, 3221, 3050, 2923, 2346 cm-1
.
(SS,R)-N-(p-Toluenesulfinyl)-1-phenylethynylbutylamine (2g):
After 2 h at 0 °C, the product was obtained as a white solid (0.362
(SS,R)-N-(p-Toluenesulfinyl)-3-cyclohex-1-enyl-1-phenylprop-
2-ynylamine (2b): After 3 h at 0 °C, the product was obtained as
mmol, 0.112 g, 88%); mp ) 57-60 °C; [R]23 +144.7 (c 0.96,
a white solid (0.345 mmol, 0.12 g, 84%); mp ) 106 °C; [R]22
D
D
CHCl3); HPLC analysis, n-heptane/ethyl acetate ) 8:2; tr ) 8.56
-96.6 (c 0.93, CHCl3); Rf ) 0.24 (diethyl ether/n-heptane 6/4);
1
1
min; H NMR (300 MHz, CDCl3) δ (ppm) 0.91 (t, 3H, J ) 7.30
HPLC analysis, n-heptane/ethyl acetate ) 8:2; tr ) 6.6 min; H
Hz), 1.44-1.54 (m, 2H), 1.66-1.73 (m, 2H), 2.40 (s, 3H), 4.30-
4.42 (m, 2H), 7.29-7.36 (m, 5H), 7.43-7.50 (m, 2H), 7.66 (d,
2H, J ) 8.22 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 13.6, 18.9,
21.4, 39.4, 45.9, 85.0, 88.8, 122.8, 125.7, 128.2, 128.3, 129.6, 131.8,
141.4, 141.8; MS m/z 334 (M + Na), 350 (M + K); HRMS calcd
for C19H21NOS + Na, 334.1237; found, 334.1242. Anal. Calcd for
C19H21NOS + 0.5 H2O: C, 71.21; H, 6.61; N, 4.37. Found: C,
71.17; H, 6.82; N, 4.05. IR (neat): 3448, 3170, 3060,2955, 2936,
NMR (300 MHz, CDCl3) δ (ppm) 1.63 (m, 4H), 2.14 (m, 4H),
2.39 (s, 3H), 4.51 (d, 1H, J ) 5.34 Hz), 5.37 (d, 1H, J ) 5.34 Hz),
6.19 (m, 1H), 7.28 (m, 5H), 7.39 (m, 2H), 7.62 (d, 2H, J ) 8.23
Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 21.4, 21.5, 22.2, 25.6,
29.1, 49.1, 84.7, 88.7, 120.1, 125.8, 127.5, 128.1, 128.6, 129.5,
135.7, 139.5, 141.4; MS m/z 372 (M + Na). Anal. Calcd for C22H23-
NSO: C, 75.64; H, 6.59; N, 4.01. Found: C, 75.23; H, 6.58; N,
3.77.
2869, 2336 cm-1
.
(SS,R)-N-(p-Toluenesulfinyl)-6-chloro-1-phenylhex-2-ynyl-
amine (2c): After 3 h at 0 °C and overnight at room temperature,
the product was obtained as a white solid (0.35 mmol, 0.12 g, 85%);
(SS,R)-N-(p-Toluenesulfinyl)-6-chloro-1-propylhex-2-ynyl-
amine (2h): After 2 h at 0 °C, the product was obtained as a white
solid (0.333 mmol, 0.104 g, 81%); mp < 50 °C; [R]23D +113.8 (c
0.95, CHCl3); HPLC analysis, n-heptane/ethyl acetate ) 8:2; tr )
mp ) 64 °C; [R]22 -88.5 (c 0.87, CHCl3); Rf ) 0.19 (diethyl
D
ether/n-heptane 6/4); HPLC analysis, n-heptane/ethyl acetate ) 8:2;
tr ) 8.1 min; 1H NMR (300 MHz, CDCl3) δ (ppm) 2.04 (q, 2H, J
) 6.49 Hz), 2.40 (s, 3H), 2.5 (td, 2H, J ) 2.16 Hz, J ) 6.84 Hz),
3.70 (t, 2H, J ) 6.39 Hz), 4.49 (d, 1H, J ) 5.40 Hz), 5.21 (m,
1H), 7.33 (m, 7H), 7.62 (d, 2H, J ) 8.20 Hz); 13C NMR (75 MHz,
CDCl3) δ (ppm) 16.4, 21.4, 31.2, 43.7, 48.4, 79.6, 85.7, 125.8,
127.4, 128.2, 128.7, 129.5, 139.4, 141.3, 141.5; MS m/z 368 (M +
1
8.65 min; H NMR (300 MHz, CDCl3) δ (ppm) 0.87 (t, 3H, J )
7.29 Hz), 1.36-1.49 (m, 2H), 1.52-1.62 (m, 2H), 1.99 (qt, 2H, J
) 6.71 Hz), 2.41-2.49 (m, 5H), 3.62 (t, 2H, J ) 6.36 Hz), 4.03-
4.20 (m, 2H), 7.31 (d, 2H, J ) 7.99 Hz), 7.62 (d, 2H, J ) 8.23
Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 13.5, 16.2, 18.8, 21.4,
31.3, 39.5, 43.7, 45.2, 80.7, 83.5, 125.7, 129.5, 141.4, 141.8; MS
m/z 334 (M + Na), 350 (M + K). Anal. Calcd for C16H22ClNSO:
C, 61.62; H, 7.11; N, 4.49. Found: C, 61.75; H, 7.18; N, 4.29.
HRMS (M + Na) calcd, 334.1004 (M + Na); found, 334.1008. IR
(16) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403-1406. (b) Jiang, Z.-Y.; Chan,
W. H.; Lee, A. W. M. J. Org. Chem. 2005, 70, 1081-1083.
(neat): 3390, 3053, 2985, 2962, 2306 cm-1
.
7896 J. Org. Chem., Vol. 72, No. 21, 2007

Alkynylation of N-p-Tolylsulfinylimines
(SS,R)-N-(p-Toluenesulfinyl)-1-tert-butyl-3-phenylprop-2-ynyl-
amine (2i): After 18 h at room temperature, the product was
obtained as a clear oil (0.0945 mmol, 0.030 g, 23%); [R]23D +147.9
(c 0.76, CHCl3); HPLC analysis, n-heptane/ethyl acetate ) 8:2; tr
pylethylamine (70 µL, 0.4 mmol, 2 equiv) and acetic anhydride
(60 µL, 0.6 mmol, 3 equiv). After 30 min at 0 °C and 2 h at room
temperature, the resulting solution was extracted with water, and
the organic layer was dried over magnesium sulfate. The solvent
was removed under reduced pressure, and the product was used in
the next step without purification: white solid (0.164 mmol, 0.041
1
) 7.16 min; H NMR (300 MHz, CDCl3) δ (ppm) 0.99 (s, 9H),
2.42 (s, 3H), 3.97 (d, 1H, J ) 7.36 Hz), 4.26 (d, 1H, J ) 7.00 Hz),
7.29-7.36 (m, 5H), 7.45-7.51 (m, 2H), 7.67 (d, 2H, J ) 8.14
Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 21.4, 26.1, 35.7, 55.9,
86.1, 87.7, 122.9, 125.8, 128.2, 129.5, 131.7, 141.4, 142.1; MS
m/z 348 (M + Na), 364 (M + K); HRMS calcd for C20H23NSO +
Na, 348.1393; found, 348.1398. IR (neat): 3190, 3048, 2960, 2927,
g, 82%); mp ) 174 °C; [R]22 +36.1 (c 0.82, CHCl3); Rf ) 0.7
D
1
(dichloromethane/methanol 9/1); H NMR (300 MHz, CDCl3) δ
(ppm) 2.05 (s, 3H), 6.27 (s, 2H), 7.35 (m, 6H), 7.40 (m, 2H), 7.61
(d, 2H, J ) 8.14 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 23.3,
45.2, 84.8, 87.0, 122.5, 127.1, 128.2, 128.3, 128.6, 128.7, 128.8,
131.8, 139.1, 168.9.
2859, 2354 cm-1
.
(SS,R)-N-(p-Toluenesulfinyl)-1-(2,4-dimethoxyphenyl)-3-phe-
nylprop-2-ynylamine (2j): After 2 h at room temperature, the
product was obtained as a pale yellow oil (0.341 mmol, 0.137 g,
N-((S)-1.3-Diphenylpropyl)acetamide (4). Compound 3 (0.040
g, 0.16 mmol) in methanol (1 mL) was hydrogenolyzed in the
presence of 10% Pd/C at atmospheric pressure and room temper-
ature for 2 h. The mixture was filtered through Celite 545, and the
filtrate was concentrated in vacuo. The product was characterized
without purification: white solid (0.144 mmol, 0.036 g, 90%); mp
) 112 °C; [R]22 -48.0 (c 0.64, MeOH); [R]22 +53 (c 0.021,
83%); [R]22 +41.5 (c 0.95, CHCl3); HPLC analysis, Kromasil
D
Modulo-Cart C18; 5 µm; 250 × 4.6 mm; wavelength 254 nm; flow
rate 1 mL/min, MeOH/H2O ) 78:22; tr ) 11.4 min; 1H NMR (300
MHz, CDCl3) δ (ppm) 2.39 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H),
4.67 (d, 1H, J ) 5.15 Hz), 5.77 (d, 1H, J ) 5.16 Hz), 6.42 (d, 1H,
J ) 2.35 Hz), 6.50 (dd, 1H, J ) 2.3 Hz, J ) 8.35 Hz), 7.23-7.42
(m, 5H), 7.49-7.56 (m, 3H), 7.63 (d, 2H, J ) 8.22 Hz); 13C NMR
(75 MHz, CDCl3) δ (ppm) 21.4, 44.6, 55.5, 86.3, 87.5, 98.6, 104.5,
119.9, 122.9, 125.8, 128.2, 128.4, 129.4, 129.5, 131.8, 141.2, 142.1,
157.3, 161.1; MS m/z 428 (M + Na), 444 (M + K); HRMS calcd
for C24H23NO3S + Na, 428.1291; found, 428.1296. IR (neat): 3459,
D
D
MeOH);15 Rf ) 0.44 (diethyl ether); H NMR (300 MHz, CDCl3)
δ (ppm) 1.95 (s, 3H), 2.15 (m, 2H), 2.64 (m, 2H), 5.06 (q, 1H, J
) 7.47 Hz), 6.06 (d, 1H, J ) 8.32 Hz), 7.27 (m, 11H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 23.4, 32.6, 37.7, 53.4, 126.0, 126.7,
127.5, 128.3, 128.5, 128.8, 141.4, 142.1, 169.3; MS m/z 276 (M +
Na). Anal. Calcd for C17H19NO: C, 80.63; H, 7.51; N, 5.53.
Found: C, 80.38; H, 7.46; N, 5.28.
1
3206, 3050, 2957, 2932, 2836, 2360 cm-1
.
Acknowledgment. The CNRS and the French Ministry of
Education and Research are acknowledged for funding.
N-((R)-1.3-Diphenylprop-2-ynyl)acetamide (3). To a solution
of compound 2a (0.069 g, 0.2 mmol) in 1 mL of methanol at 0 °C
was added an aqueous solution of 3 M HCl solution (0.2 mL, 3
equiv). The reaction mixture was stirred for 30 min at 0 °C and
1.5 h at room temperature. The solvent was removed under reduced
pressure, and the residue was dissolved in 2 mL of dichloromethane.
To this solution stirred at 0 °C were added successively diisopro-
Supporting Information Available: 1H and 13C NMR spectra
of compounds 1e, 2a-i, 3, and 4. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO071139W
J. Org. Chem, Vol. 72, No. 21, 2007 7897