Synthesis of enantiomerically pure α-substituted propargylic amines by reaction of organoaluminum reagents with oxazolidines

Article abstract of DOI:10.1021/jo0003706

Various oxazolidines prepared in two steps from (R)-phenylglycinol react at 0 °C with dialkylalkynylalane-triethylamine complexes in the presence of trimethylaluminum in high yield and diastereoselectivity. Enantiomerically pure primary α-substituted propargylamines can be easily obtained in two steps after removal of ferrocenylmethyl protective group under smooth acidic conditions and oxidative cleavage of the chiral appendage.

Full text of DOI:10.1021/jo0003706

J . Org. Chem. 2000, 65, 6423-6426
6423
Syn th esis of En a n tiom er ica lly P u r e r-Su bstitu ted P r op a r gylic
Am in es by Rea ction of Or ga n oa lu m in u m Rea gen ts w ith
Oxa zolid in es
J . Blanchet, M. Bonin, L. Micouin, and H.-P. Husson*
Laboratoire de Chimie The´rapeutique UMR 8638 associe´e au CNRS et a` l’Universite´ Rene´ Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques 4, avenue de l’Observatoire,
75270 Paris Cedex 06, France
husson@pharmacie.univ-paris5.fr.
Received March 14, 2000
Various oxazolidines prepared in two steps from (R)-phenylglycinol react at 0 °C with dialkyl-
alkynylalane-triethylamine complexes in the presence of trimethylaluminum in high yield and
diastereoselectivity. Enantiomerically pure primary R-substituted propargylamines can be easily
obtained in two steps after removal of ferrocenylmethyl protective group under smooth acidic
conditions and oxidative cleavage of the chiral appendage.
In tr od u ction
unsaturated aldimines which had to be performed at
-100 °C.4d,e The nucleophilic addition of alkynyl Grignard
reagents on chiral oxazines has recently been reported
to proceed in the presence of BF3‚Et2O at a more elevated
temperature but with moderate de (ca. 65%) in most
cases.4h,j Nucleophilic ring opening of oxazolidines is
known to proceed in a diastereoselective fashion with
organometallic reagents, provided that the reaction
proceeds via a two-step mechanism and that the tran-
sient iminium ion adopts a well-defined geometry. Trouble-
some competitive concerted SN2-type reactions can how-
ever occur if organometallic reagents are too nucleophilic,
leading to a decrease in diastereoselectivity.
Enantiopure R-substituted propargylamines are useful
synthetic intermediates and can also be encountered as
part of bioactive compounds1 or natural products.2 Nu-
merous synthetic pathways have been devised for the
preparation of such compounds in racemic form, but
methods for the obtention of enantiomerically pure
material are still scarce.3,4 Among all of the asymmetric
preparative methods of optically pure R-substituted
amines, the diastereoselective addition of organometallic
reagents to the CdN bond of chiral imines or their
derivatives often proved to be very efficient.5 However,
this strategy gives unsatisfying results for the prepara-
tion of propargylamines. Enders and co-workers de-
scribed a general method in 1995 for the asymmetric
synthesis of propargylamines with a key step involving
a 1,2 addition of organocerium reagents to chiral R,â-
We recently reported preliminary results on the nu-
cleophilic opening of chiral oxazolidines with mixed
alkynylaluminum compounds.6 These species are indeed
known to be good Lewis acids and poor nucleophiles and
usually react by transferring preferentially their alkynyl
group.7 We report in this paper our full investigations in
this field, as well as the use of this reaction for the fast
and efficient preparation of enantiomerically pure R-sub-
stituted propargylamines.
(1) (a) Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E.
J . J . J . Org. Chem. 1995, 60, 1590. (b) Yu, P. H.; Davis, B. A.; Bouton,
A. A. J . Med. Chem. 1992, 35, 3705. (c) Zablocki, J . A.; Rico, G. J .;
Garland, R. B.; Rogers, T. E.; Williams, K.; Schretzman, L. A.; Rao, S.
A.; Bovy, P. R.; Tjoeng, F. S.; Lindmark, R. J .; Toth, M. V.; Zupec, M.
E.; McMackins, D. E.; Adams, S. P.; Miyano, M.; Markos, C. S.; Milton,
M. N.; Paulson, S.; Herin, M.; J aqmin, P.; Nicholson, N. S.; Panzer-
Knodle, S. G.; Hass, N. F.; Page, J . D.; Szalony, J . A.; Taite, B. B.;
Salyers, A. K.; King, L. W.; Campion, J . G.; Feigen, L. P. J . Med. Chem.
1995, 38, 2378.
(2) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.;
Clardy, J . J . Am. Chem. Soc. 1990, 112, 3715.
(3) For recent examples of preparation of R-substituted propargylic
amines in a racemic form, see: Mecozzi, T.; Petrini, M. J . Org. Chem.
1999, 64, 8970 and references herein cited. For preparation of
R-substituted propargylic hydroxylamines, see: Franz, D. E.; Fa¨ssler,
R.; Carreira, E. M. J . Am. Chem. Soc. 1999, 121, 11245.
(4) For asymmetric synthesis of propargylic amines, see: (a) Kolb,
M.; Barth, J . Angew. Chem. 1980, 753. (b) Chung, J . Y. L.; Wasicak,
J . T. Tetrahedron Lett. 1990, 31, 3957. (c) Manfre´, F.; Kern, J .-M.;
Biellmann, J .-F. J . Org. Chem. 1992, 57, 2060. (d) Enders, D.;
Schankat, J . Helv. Chim. Acta 1993, 76, 402. (e) Enders, D.; Schankat,
J . Helv. Chim. Acta. 1995, 78, 970. (f) Marshall, J . A.; Wolf, M. A.; J .
Org. Chem. 1996, 61, 3238. (g) Poerwono, H.; Higashiyama, K.;
Takahashi, H. J . Org. Chem. 1998, 63, 2711. (h) Rae, A.; Ker, J .; Tabor,
A. B.; Castro, J .; Parsons, S. Tetrahedron Lett. 1998, 39, 6561. (i)
Reginato, G.; Mordini, A.; Degl’Innocenti, A.; Manganiello, S.; Cappe-
rucci, A.; Poli, G. Tetrahedron 1998, 10227. (j) Rae, A.; Castro, J .;
Tabor, A. B. J . Chem. Soc., Perkin Trans. 1 1999, 1943.
Resu lts a n d Discu ssion
We first investigated the reactivity of dialkylalkynyl-
alanes with oxazolidines bearing a benzylic nitrogen
protective group and (R)-phenylglycinol (1) as chiral
amino alcohol. These oxazolidines were known to furnish,
under acidic conditions, only one iminium, whose geom-
etry is controlled by A(1,3) strain.8 They were prepared
according to reported procedures and used as such
(Scheme 1).9
(6) (a) Blanchet, J .; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;
Husson, H.-P. Tetrahedron Lett. 1999, 40, 2935. (b) For recent use of
diethylalkynylalanes and alkynylalanates in the preparation of pro-
pargylic amines and ethers, see: Ahn, J . H.; J oung, M. J .; Yoon, N.
M.; Oniciu, D. C.; Katritzky, A. R. J . Org. Chem. 1999, 64, 488.
(7) (a) Zweifel, G.; Miller, J . A. Org. React. 1984, 34, 375. (b) Negishi,
E.-I. Organometallics of Main Group Metals in Organic Synthesis; J ohn
Wiley: New York, 1980; p 286.
(8) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(5) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Enders, D.;
Reinhold: U.; Tetrahedron: Asymmetry 1997, 8, 1895.
(9) Maury, C.; Gharbaoui, T.; Royer, J .; Husson, H.-P. J . Org. Chem.
1996, 61, 3687.
10.1021/jo0003706 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/08/2000

6424 J . Org. Chem., Vol. 65, No. 20, 2000
Blanchet et al.
Ta ble 1
Sch em e 1
compound
Ar
R1
R2
yield (%)a d.e.(%)b
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
pent
Ph
69
79
69
77
69
72
71
75
94
91
(CH2)2Ph pent
(CH2)2Ph Ph
Me
(CH2)2Ph t-Bu
Ph
>97
>97
t-Bu
78c
91c
92
4g
4h
3,4-OMe-Ph Me
3,4-OMe-Ph (CH2)2Ph Ph
96
a
b
1
Isolated overall yield from 1. Determined by H NMR of the
crude reaction mixture. c Metalation was performed with AlMe3.
Sch em e 4
Sch em e 2
various N-protected propargylamines were obtained, with
an overall good yield and excellent diastereoselectivity,
under simple experimental conditions (0 °C, toluene, 1
h) (Table 1).
Removal of dimethoxybenzyl group was then per-
formed on compound 4g under acidic conditions12 without
any detectable epimerization to give 5b whose absolute
configuration was determined by X-ray analysis (Scheme
4).
Sch em e 3
However, when applying these harsh conditions on
substrate 4h , amino alcohol 2b was obtained as the major
reaction product. This result showed that, with compound
4h , the propargylic bound was more prone to be cleaved
than the benzylic one, probably because the benzylic
cationic leaving group was not stabilized enough.
We therefore decided to change the dimethoxyphenyl
for a ferrocenyl group. This group should induce analogue
allylic strain that with phenyl derivatives in the transi-
tion state and therefore lead to analogue diastereomeric
excesses. Moreover, thanks to the great stability of
methylene ferrocenyl cations, this protective group should
be easily cleaved under smooth acidic conditions already
described on amides and lactams, avoiding the competi-
tive propargylic bound cleavage.13
N-Protected oxazolidines 7 were prepared by classical
procedure and reacted with mixed organoaluminum
compounds in excellent overall yield and diastereoselec-
tivity (Scheme 5 and Table 2). Interestingly, the presence
of basic heteroaromatic groups (furyl, pyridine) did not
interfere with the alkynylation process.
As expected, deprotection could be performed using
smooth acidic conditions (5% TFA solution in dichloro-
methane, 0 °C) and led to secondary amines without any
cleavage of the propargylic bound. No epimerization could
be detected at this stage (Scheme 6 and Table 3).
The use of triethylsilyl hydride as cation scavenger
appeared to be unnecessary for completion of this depro-
tection and can be avoided, but work-up procedures are
simplified when this reagent is present in the reaction
mixture.
Dialkylalkynylalanes were prepared by stirring tri-
alkylalanes and alkynes in nonpolar solvents for several
hours. Their reactivity was first checked with compound
3a (Scheme 2). Two equivalents of alanes were necessary
for complete conversion of oxazolidine.10
Increasing the size of alkyl groups led to an improve-
ment of diastereoselectivity. However, with i-Bu3Al, a
large amount of competitive hydroalumination was ob-
served when preparing mixed alane, leading to a dra-
matic decrease of chemical yield. Since the i-Bu group
appeared to be crucial for a good diastereoselectivity, a
new procedure was developed (Scheme 3).
Alkynes metalation was performed with a DIBAH-
Et3N complex, which had been described to enable total
conversion of alkyne.11 However, the resulting tertiary
amine complexes did not react with oxazolidines, prob-
ably because the Lewis acidity of the alane was lost. The
reactivity of mixed alkynylalanes could be recovered by
adding 1 equiv of Me3Al to the reaction mixture, after
the addition of the oxazolidine. Following this procedure,
(10) The use of 1 equiv of alane lead to only 50% conversion. This
prompted us to propose a late dissociated transition state model, with
two molecules of alane involved in the alkynylation process (see ref
5a). A synchronous retentive alkylation has been proposed for the
opening of oxazines with trimethylaluminum: Andre´s, C.; Nieto, J .;
Pedrosa, R.; Villamanan, N. J . Org. Chem. 1996, 61, 4130. It is however
not clear why, starting from diastereomerically pure material, a
synchronous retentive SNi-like reaction requires 4 equiv of alanes and
lead to compounds with de between 33 and 99%.
(12) Phillips, G. B.; Morgan, T. K., J r.; Lumma, W. C., J r.; Gomez,
R. P.; Lind, J . M.; Lis, R.; Argentieri, T.; Sullivan, M. E. J . Med. Chem.
1992, 35, 5, 743.
(13) Garro-He´lion, F.; Guibe´, F. J . Chem. Soc., Chem. Commun.
1996, 641.
(11) Binger, P. Angew. Chem., Int. Ed. Engl. 1963, 2, 686.

Synthesis of R-Substituted Propargylic Amines
J . Org. Chem., Vol. 65, No. 20, 2000 6425
conditions were not racemizing.16 Optical purity of com-
pound 10i was determined by chiral HPLC to be 99.4%.
Since this reagent was probably the most likely to
epimerize if any loss of stereochemical purity was to
occur, the other derivatives prepared by the same method
are expected to be of comparable purity.
Sch em e 5
In conclusion, we performed a straightforward and
simple access to enantiopure R-substituted propargyl-
amines. The key step for the introduction of chirality does
not require low temperature and proceeds in very good
yield. Crucial points were the method for preparation of
fully metalated terminal alkynes, their in situ decom-
plexation, and the use of methylene ferrocenyl group as
cleavable nitrogen “benzylic” protective group. The use
of this new methodology for the elaboration of allylic
amines and their transformations is under investigation
in our laboratory.
Ta ble 2
compound
R1
R2
yield (%)a
d.e.(%)b
8a
8b
8c
8d
8i
Me
Me
pent
Ph
pent
Ph
pent
pent
81
78
86
87
75
78
94
92
>97
>97
92
(CH2)2Ph
(CH2)2Ph
2-furyl
Exp er im en ta l Section
8j
3-pyridyl
91
Gen er a l Com m en ts. NMR spectra were obtained at 300
MHz (1H field value). IR spectra were recorded as thin film
unless otherwise stated. Optical rotation measurement were
performed using a 1-dm path length cell. Elemental analyses
were obtained from the Service de microanalyse of the Institut
de Chimie des Substances Naturelles, Gif-sur-Yvette, France.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am in o
Alcoh ols 2 a n d 6. The preparation of amino alcohol 6 is
representative. To a solution of (R)-phenylglycinol (4 g, 29.2
mmol) in MeOH (40 mL) was added ferrocenecarboxaldehyde
(6.38 g, 29.2 mmol) in one portion. The mixture was stirred
for 1 h and cooled at 0 °C. NaBH4 (1.6 g, 42 mmol) was then
slowly added. After overnight stirring, the reaction was
quenched with water (40 mL) and the aqueous phase extracted
twice with dichloromethane (40 mL). Organic layer was
washed with a saturated aqueous NaCl solution and dried over
anhydrous MgSO4. Recrystallization of the crude reaction
mixture from cyclohexane/ethyl acetate 1:1 gave 9.3 g of 6
(95%).
(2R)-F er r ocen ylm eth yla m in o-2-p h en yl-eth a n ol 6: or-
ange crystals, mp ) 76 °C (Et2O), [R]D ) - 54 (c 1.15, MeOH);
1H NMR (CDCl3) δ ppm: 2.76 (br. s, 1H), 3.32 (d, J ) 12.9 Hz,
1H), 3.46 (d, J ) 12.9 Hz, 1H), 3.53 (dd, J ) 10.6, 8.5 Hz, 1H),
3.69 (dd, J ) 10.6, 4.0 Hz, 1H), 3.81 (dd, J ) 8.5, 4.0 Hz, 1H),
4.03 (s, 5H), 4.04-4.18 (m, 4H), 5.22 (br. s, 1H), 7.25-7.42
(m, 5H); 13C NMR (CDCl3) δ ppm 46.3, 64.0, 66.7, 67.7, 67.8,
68.2, 68.4, 86.6, 127.4, 127.5, 128.7, 140.5. IR (cm-1, neat):
3378, 3092, 2926, 2868, 1492, 1453. MS: 336 (MH+), 199. Anal.
Calcd for C19H21FeNO: C, 68.08; H, 6.31; N, 4.18. Found: C
67.78, H 6.33, N 4.17.
a
b
1
Isolated overall yield from 1. Determined by H NMR of the
crude reaction mixture.
Sch em e 6
Ta ble 3
compound
R1
R2
yield (%)a
5a
5b
5c
5d
5i
Me
Me
(CH2)2Ph
(CH2)2Ph
2-furyl
pent
Ph
pent
Ph
pent
pent
80
72
87
87
73
73
5j
3-pyridyl
a
Isolated yield of diastereomerically pure material from 8.
Sch em e 7
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zo-
lid in es 3 a n d 7a . The preparation of oxazolidine 7a is
representative. To a solution of of N-ferrocenylmethyl-(R)-
phenylglycinol (6, 1 g, 2.98 mmol) in dichloromethane (10 mL)
in the presence 3 Å molecular sieves was added acetaldehyde
(504 µL, 8.94 mmol). The mixture was stirred at room
temperature for 2 h and filtered over Celite, and the solvent
and excess aldehyde were evaporated to furnish oxazolidine 7
as an orange oil (quantitative). For other nonvolatile alde-
hydes, a slight excess is used (maximum 2 equiv), and the
reaction is rapidly washed with aqueous saturated met-
abisulfite solution, dried over anhydrous MgSO4, and solvent
is evaporated. Oxazolidine was used as such in the next step.
(2R,4R)-3-F er r ocen ylm eth yl-2-m eth yl-4-p h en yl-oxa zo-
lid in e (7a ): 1H NMR (CDCl3) δ ppm 1.30 (d, J ) 5.1 Hz, 1H),
3.43 (d, J ) 14.4 Hz, 1H), 3.57 (t, J ) 7.8 Hz, 1H), 3.64 (d, J
Final deprotection was performed using standard
oxidative cleavage of chiral amino alcohol.14 Primary
amines 9 could be isolated in good yield but most of them
proved to be quite unstable.15 They could however be
handled and stored without any problem as benzamides
10 (Scheme 7).
Because of the great unstability of primary substituted
propargylamines, we checked that the oxidative cleavage
(16) Partial racemization of R-substituted amines has been sus-
pected in the oxidative cleavage step with Pb(OAc)4: Gawley, R. E.;
Rein, K.; Chemburkar, S. J . Org. Chem. 1989, 54, 3002. It can be
avoided if the reaction is “carefully controlled”: Wu, M.-J .; Pridgen, L.
N. J . Org. Chem. 1991, 56, 1340. No racemization has been noticed
with H5IO6 as oxidizing reagent (see ref 14).
(14) Chang, Z.-Y.; Coates, R. M. J . Org. Chem. 1990, 55, 3475.
(15) The unstability of primary R-substituted propargylamines has
already been noticed, see: ref 4j.

6426 J . Org. Chem., Vol. 65, No. 20, 2000
Blanchet et al.
) 14.4 Hz, 1H), 3.81 (t, J ) 8.0 Hz, 1H), 4.03 (m, 10 H), 4.27
(q, J ) 5.1 Hz, 1H) 7.27-7.41 (m, 5H); 13C NMR (CDCl3) δ
ppm 20.4, 47.3, 65.1, 67.8, 68.2, 68.4, 70.0, 70.4, 73.0, 81.2,
90.5, 127.6-128.5, 139.8. IR (cm-1, neat) 2989, 1554; MS 362
(MH+), 199.
2.48 (br. s, 2H), 3.52 (qt, J ) 6.6, 2.0 Hz, 1H), 3.57 (dd, J )
10.9, 6.7 Hz, 1H), 3.71 (dd, J ) 10.9, 4.7 Hz, 1H), 3.98 (dd, J
) 6.7, 4.7 Hz, 1H), 7.24-7.35 (m, 5H); 13C NMR (CDCl3) δ ppm
13.9, 18.5, 22.0, 22.4, 28.4, 30.9, 43.0, 61.4, 65.4, 82.2, 83.1,
127.2-128.4, 141.1; IR (cm-1, neat) 3330, 2931, 2859, 1603;
MS: 260 (MH+). Anal. Calcd for C17H25NO‚0.5H2O: C, 76.08;
H, 9.71; N, 5.22. Found: C, 76.48; H, 9.35; N, 5.03.
Gen er a l P r oced u r e for th e Oxid a tive Clea va ge. The
preparation of compound 9a is representative. To a cold (0 °C)
solution of propargylamine 5a (370 mg, 1.43 mmol) in metha-
nol (8.5 mL) were added aqueous methylamine (40% solution,
1 mL) and slowly an aqueous solution of periodic acid (845
mg, 3.72 mmol in 7.5 mL H2O). The turbid solution was stirred
at room temperature for 3 h and became limpid. The reaction
mixture was extracted twice with ether. After evaporation of
ether, the methanolic solution was treated with 3 M aqueous
HCl, methanol was evaporated, and the aqueous phase was
washed twice with ether. Then, the aqueous phase was treated
with an aqueous saturated solution of K2CO3 to reach pH 9
and extracted twice with dichloromethane. The organic layer
was dried over anhydrous MgSO4, and the primary amine was
purified by column chromatography (silica gel, ethyl acetate)
to give 9a (139 mg, 70%).
(1R)-Meth yloct-2-yn yla m in e 9a : oil, [R]D ) +24.1 (c )
1.6, CHCl3) (unstable, fully characterized as benzamide 10a );
1H NMR (CDCl3) δ ppm 0.89 (t, J ) 7.1 Hz, 3H), 1.32 (d, J )
6.7 Hz, 3H), 1.29-1.36 (m, 4H), 1.49 (quint, J ) 7.1 Hz, 2H),
1.61 (br. s, 2H), 2.16 (dt, J ) 7.1, 2.0 Hz, 2H), 3.69 (qt, J )
6.7, 2.0 Hz, 1H); 13C NMR (CDCl3) δ ppm 13.9, 18.6, 22.1, 24.9,
28.5, 31.0, 38.9, 81.6, 84.7.
Gen er a l P r oced u r e for P r ep a r a tion of Ben za m id es 10.
The preparation of compound 10a is representative. Freshly
purified primary amine 9a (100 mg, 0.72 mmol) was dissolved
in dichloromethane (10 mL). Benzoyl chloride (337 µL, 2.9
mmol) and triethylamine (407 µL, 2.9 mmol) were added, and
the reaction mixture was stirred overnight and washed with
water. The organic layer was dried over anhydrous MgSO4 and
evaporated. Crude residue was purified by column chroma-
tography (silica gel, 7/3 cyclohexane/ethyl acetate) to give 10a
(166 mg, 66% from 8a ).
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gyl-
a m in es 4 a n d 8. The preparation of compound 8a is repre-
sentative. To a DIBAL solution (1 M in toluene, 6.3 mL, 6.3
mmol) under argon was slowly added freshly distilled triethy-
lamine (920 µL, 6.6 mmol). The solution was stirred for 15 min
and cooled to 0 °C, and heptyne (1.6 mL, 12.2 mmol) was added
dropwise. The reaction mixture was allowed to reach room
temperature, stirred until hydrogen evolution stopped, and
cooled to 0 °C, and a solution of oxazolidine 7 (1.08 g, 3.0 mmol)
in toluene (10 mL) was slowly added over 30 min, followed by
Me3Al solution (2 M in heptane, 3.3 mL, 6.6 mmol). The
solution was stirred for another 30 min at 0 °C and allowed to
reach room temperature. The mixture was slowly poured on
a
cold solution of saturated Rochelle’s salts,17 and after
vigorous stirring, the aqueous layer was twice extracted with
diethyl ether. Organic layer was dried over anhydrous MgSO4,
the solvent was evaporated, and the crude residue was purified
by column chromatography (silica gel, two successive elutions
9/1 cyclohexane/ethyl acetate then 7/3 cyclohexane/ethyl ac-
etate to give 8a (1.08 g, 2.37 mmol, 75% from 1).
(1R,2R)-2-[F e r r oce n ylm e t h yl-(1-m e t h yl-oct -2-yn yl)-
a m in o]-2-p h en yleth a n ol 8a : red-brown oil, yield ) 75%, [R]D
1
) +8.8 (c ) 1.0, MeOH); H NMR (CDCl3) δ ppm 0.89 (t, J )
7.1 Hz, 3H), 1.12 (d, J ) 6.9 Hz, 3H), 1.30-1.43 (m, 4H), 1.44-
1.56 (m, 2H), 2.19 (td, J ) 7.1, 1.9 Hz, 2H), 2.71 (br. s, 1H),
3.59 (d, J ) 14.1 Hz, 1H), 3.75 (d, J ) 14.1 Hz, 1H), 3.78-
3.89 (m, 3H), 3.96-4.14 (m, 5H), 4.09 (s, 5H), 4.19 (d, J ) 11.6
Hz, 2H), 7.35-7.24 (m, 5H); 13C NMR (CDCl3) δ ppm 14.0, 18.5,
20.9, 22.0, 28.4, 30.9, 45.3, 46.5, 61.4, 64.0, 67.6-69.6, 81.2,
84.6, 86.3, 127.1-128.4, 139.7; IR (cm-1, neat) 3452, 3090,
2928, 2859, 1601; MS 458 (MH+), 199. Anal. Calcd for C28H35
-
NOFe: C, 73.52; H, 7.71; N, 3.06. Found: C, 73.33; H, 7.84; N,
3.02.
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gyl-
a m in es 5. The preparation of compound 5a is representative.
To a cold (0 °C) solution of propargylamine (1.36 g, 3.0 mmol)
in dry dichloromethane (10 mL) were added successively
triethylsilane (1.2 mL, 7.5 mmol) and a solution of trifluoro-
acetic acid (1.2 mL, 15 mmol) in dichloromethane (15 mL). The
reaction was allowed to reach room temperature, stirred for 2
h, and quenched with water and saturated aqueous solution
of K2CO3. The aqueous layer was extracted twice with dichlo-
romethane, the organic layer was dried over anhydrous
MgSO4, and the solvent was evaporated. The crude residue
was purified by column chromatography (silica gel, two suc-
cessive elutions 9/1 cyclohexane/ethyl acetate then 1/1 cyclo-
hexane/ethyl acetate to give 5a (621 mg, 80%).
(1R)-N-(1-Meth yloct-2-yn yl)ben za m id e 10a : white solid,
1
mp 70 °C, [R]D ) + 41.6 (c ) 1.2, CHCl3); H NMR (CDCl3) δ
ppm 0.90 (t, J ) 7.0 Hz, 3H), 1.30-1.38 (m, 4H), 1.48 (d, J )
6.9 Hz, 3H), 1.47-1.53 (m, 2H), 2.17 (td, J ) 7.0, 5.1 Hz, 2H),
4.94-5.07 (m, 1H), 6.27-6.48 (br. s, 1H), 7.38-7.53 (m, 3H),
7.69 (d, J ) 6.8 Hz, 2H); 13C NMR (CDCl3) δ ppm 14.0, 18.6,
22.2, 22.9, 28.3, 31.0, 37.9, 80.2, 83.1, 126.9, 128.5, 131.5, 134.2,
166.1; IR (cm-1, neat) 3286, 2928, 1632; MS 244 (MH+). Anal.
Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C,
78.51; H, 8.46; N, 5.66.
Ack n ow led gm en t. One of us (J .B.) thanks MENRT
for a grant.
(1R,2R)-2-(1-Met h yloct -2-yn yla m in o)-2-p h en yl-et h a -
n ol 5a : oil, [R]D ) -13.6 (c ) 1.25, MeOH); 1H NMR (CDCl3)
δ ppm 0.88 (t, J ) 7.0 Hz, 3H), 1.28 (d, J ) 6.6 Hz, 3H), 1.28-
1.37 (m, 4H), 1.38-1.46 (m, 2H), 2.08 (td, J ) 6.9, 2.0 Hz, 2H),
Su p p or tin g In for m a tion Ava ila ble: Characterization of
compounds 3c, 4a -h , 5b-j, 8b-j, 9b, 9c, 9d , 9i, 10d , and
10i and NMR spectra of compounds 5a , 6, 7a , 8a , 9a , and 10a .
This material is available free of charge via the Internet at
http://pubs.acs.org..
(17) Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; Wiley: New York, 1995; Vol. 6, 4286.
J O0003706