New Synthesis of Propargylic Amines from 2-(Bromomethyl)aziridines. Intermediacy of 3-Bromoazetidinium Salts

Article abstract of DOI:10.1021/jo035759i

A new, efficient, and straightforward synthesis provides propargylamines in high overall yields (64-77%) by transformation of 1-(arylmethyl)-2-(bromomethyl)aziridines into N,N-di(arylmethyl)N-(2-propynyl)amines via N-(2,3-dibromopropyl)amines and N-(2-bromo-2-propenyl)amines. The conversion of N-(2,3-dibromopropyl)amines into N-(2-bromo-2-propenyl)amines is based on a novel analogue of the Hofmann elimination. A Yamaguchi-Hirao alkylation, a Sonogashira coupling, or a hydroarylation reaction further functionalized these propargylamines toward potentially interesting compounds for medicinal and agrochemical use.

Full text of DOI:10.1021/jo035759i

New Syn th esis of P r op a r gylic Am in es fr om
2-(Br om om eth yl)a zir id in es. In ter m ed ia cy of 3-Br om oa zetid in iu m
Sa lts
Matthias D’hooghe, Willem Van Brabandt, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@UGent.be
Received December 1, 2003
A new, efficient, and straightforward synthesis provides propargylamines in high overall yields
(64-77%) by transformation of 1-(arylmethyl)-2-(bromomethyl)aziridines into N,N-di(arylmethyl)-
N-(2-propynyl)amines via N-(2,3-dibromopropyl)amines and N-(2-bromo-2-propenyl)amines. The
conversion of N-(2,3-dibromopropyl)amines into N-(2-bromo-2-propenyl)amines is based on a novel
analogue of the Hofmann elimination. A Yamaguchi-Hirao alkylation, a Sonogashira coupling, or
a hydroarylation reaction further functionalized these propargylamines toward potentially interest-
ing compounds for medicinal and agrochemical use.
In tr od u ction
amines concerns the inhibition of the enzyme monoamine
oxidase (MAO, EC 1.4.3.4),1-3,27 which makes them po-
tential drugs for treatment of neurotic, psychiatric, and
other disorders, such as depression, panic disorder, social
phobia,5,6,27 Parkinson’s disease,7,27 and Alzheimer’s dis-
ease.8,9 The biochemical role of the enzyme MAO concerns
the oxidation of many monoamines, including important
neurotransmitter amines.27 Other biological activities of
propargylamines are for example related to treatment of
diabetics,4 blood lipid lowering activity,22 and use as
fibrin-stabilizing factor inhibitors.26 In the literature, a
variety of synthetic methods toward propargylamines is
found. A very common method consists of the alkylation
of primary or secundary amines with propargyl hal-
ides,28-35 although the latter compounds are rather
Propargylamines are very much in demand in medici-
nal chemistry, due to the pronounced physiological
activities of these compounds and their derivatives.1-27
A very generally occurring mode of action of propargyl-
* Address correspondence to this author. Phone: +0032 92645951.
Fax: +0032 92646243.
(1) Youdim, M. B.; Finberg, J . P. Biochem. Pharmacol. 1991, 41,
155.
(2) Yu, P. H. Monoamine Oxidase. In Neuromethods; Neurotrans-
mitter Enzymes; Baker, A. A., Yu, P. H., Eds.; Humana Press: Clifton,
NJ , 1986; Vol. 5, p 235.
(3) Yamada, H.; Yasunobu, K. T. J . Biol. Chem. 1962, 237, 3077.
(4) Yu, P. H.; Davis, B. A.; Boulton, A. A.; Zuo, D. M. J . Neural
Transm. 1994, 41, 397.
(5) Birkmayer, W.; Riederer, P.; Linaure, W.; Knoll, J . J . Neural
Transm. 1984, 59, 81.
(6) Quitkin, F. M.; Liebowitz, M. R.; Stewart, J . W.; McGrath, P. J .;
Harrison, H.; Rabkin, G.; Markowitz, J .; Davies, S. O. Arch. Gen.
Psychiatry 1984, 41, 777.
(7) Birkmayer, W.; Knoll, J .; Riederer, P.; Hars, V.; Marton, J . J .
Neural Transm. 1985, 64, 113.
(21) Lee, C.; Horrom, B. W.; Michaels, R. J .; Rasmussen, R. M.;
Plotnikoff, N. P. J . Med. Chem. 1975, 15, 1252.
(22) Kwatra, M. M.; Simon, D. Z.; Salvador, R. L.; Cooper, P. D. J .
Med. Chem. 1978, 21, 253.
(8) Tariot, P. N.; Cohen, R. M.; Sunderland, T.; Newhouse, P. A.;
Yount, D.; Mellow, A. M.; Weingarter, H.; Mueller, E. A.; Murphy, D.
L. Arch. Gen. Psychiatry 1987, 44, 427.
(9) Piccinin, G. L.; Finali, G.; Piccirilli, M. Clin. Neuropharmacol.
1990, 2, 147.
(23) Raveglia, L. F.; Vitali, M.; Artico, M.; Graziani, D.; Hay, D. W.;
Luttman, M. A.; Mena, R.; Pifferi, G.; Giardina, G. A. Eur. J . Med.
Chem. 1999, 34, 825.
(24) Trybulski, E. J .; Zhang, J .; Kramss, R. H.; Mangano, R. M. J .
Med. Chem. 1993, 36, 3533.
(10) Wood, D. R.; Reimherr, F. W.; Wender, P. H. Psychopharmacol.
Bull. 1983, 19, 627.
(11) Knoll, J .; Ecsery, Z.; Nievel, J . B.; Kelemen, K.; Knoll, B. Arch.
Int. Pharmacodyn. Ther. 1965, 155, 154.
(12) Reynolds, G. P.; Riederer, P.; Sandler, M.; J ellinger, K.; Seeman,
D. J . Neural Transm. 1978, 43, 271.
(25) Moon, W. M.; Chidester, C. G.; Heier, R. F.; Morris, J . K.;
Collins, R. J .; Russell, R. R.; Francis, J . W.; Sage, G. P.; Sethy, V. H.
J . Med. Chem. 1991, 34, 2314.
(26) Hoffmann, K. J .; Stenberg, P. L.; Christine, S. U.; Nilsson, J .
L.; Eriksson, O.; Hartkoorn, A.; Lunden, R. J . Med. Chem. 1975, 18,
278.
(13) Yoshida, T.; Yamada, Y.; Yamamoto, T.; Kuroiwa, Y. Xenobio-
tica 1986, 16, 129.
(14) Heinonen, E. H.; Myellyla, V.; Sotaniemi, K.; Lammintausta,
R.; Salonen, J . S.; Anttila, M.; Savijarvi, M.; Rinne, U.K. Acta Neurol.
Scand. 1990, 40, 61.
(27) Ling, L.; Urichuk, L. J .; Duff Sloley, B.; Coutts, R. T.; Baker,
G. B.; Shan, J . J .; Pang, P. K. T. Bioorg. Med. Chem. Lett. 2001, 11,
2715 and references cited therein.
(28) Hennion, G. F.; Hanzel, R. S. J . Am. Chem. Soc. 1960, 82, 4908.
(29) Barmettler, P.; Hansen, H. Helv. Chim. Acta 1990, 73, 1515.
(30) Laroch, R. C.; Burns, I. D.; Varaprath, S.; Russell, C. Z.;
Richardson, J . W.; J anakiraman, M. M.; J acobson, R. A. Organome-
tallics 1987, 6, 1790.
(31) Wolf, V. Liebigs Ann. Chem. 1952, 35, 576.
(32) Al-Iraqi, M. A.; Al-Rawi, J . M.; Khuthier, A. H. Org. Magn.
Reson. 1980, 14, 161.
(33) Al-Rawi, J . M.; Khuthier, A. H. Org. Magn. Reson. 1981, 15,
285.
(15) Golbe, L. I. Neurology 1989, 39, 1109.
(16) Ayd, F. J . Int. J . Neuropsychiatry 1965, 1, 233.
(17) Hallman, H.; J onsson, G. Eur. J . Pharmacol. 1984, 103, 269.
(18) Yu, P. H.; Davis, B. A.; Boulton, A. A. J . Med. Chem. 1992, 35,
3705.
(19) Yamada, H.; Yasunobu, K. T. J . Biol. Chem. 1963, 238, 2669.
(20) Hevey, R. C.; Babson, J .; Maycock, A. L.; Abeles, R. H. J . Am.
Chem. Soc. 1973, 95, 6125.
10.1021/jo035759i CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/12/2004
J . Org. Chem. 2004, 69, 2703-2710
2703

D’hooghe et al.
SCHEME 1
TABLE 1. Rea ction of
expensive. The Mannich reaction, in which an acetylene,
formaldehyde, and a primary or secundary amine are
reacted, is also a well-established and general procedure
for the preparation of propargylamines.36 Furthermore,
some methods in which 1-(dialkylaminomethyl)benzo-
triazoles,37,38 arylimines,39 propargyl phosphates40 or 1,1-
dibromo-1-alkenes41 are used for the synthesis of prop-
argylamines are known. Except for the last example, all
these procedures and methods are based on the use of a
commercially available alkyne moiety.
In the present report a new and efficient synthesis of
N,N-di(arylmethyl)propargylamines, based on three in-
novating steps and starting from 1-(arylmethyl)-2-(bro-
momethyl)aziridines, is presented. The chemistry of
2-(bromomethyl)aziridines is for the major part yet
unexplored. The possibility of ring-opening reactions at
the aziridine moiety and substitution and elimination
reactions due to the bromomethyl unit explains the great
synthetic potential of 2-(bromomethyl)aziridines as build-
ing blocks in organic synthesis.
1-(Ar ylm eth yl)-2-(br om om eth yl)a zir id in es 1 w ith
Differ en t Ben zyl Br om id es
crude
entry
product
R1
R2
yield (%)a
1
2
3
4
5
4a
4b
4c
4d
4e
4f
H
H
100
100
100
100
100
100
100
100
100
100
100
Me
MeO
Br
H
H
H
Me
MeO
Br
Me
MeO
Cl
Me
Me
Me
Br
Br
H
6
7
8
9
10
11
4g
4g
4h
4i
4j
Br
Br
a
Purity (NMR) >97%.
chromatography in 50-62% yield. These lower yields
illustrate the reactive nature of these â,γ-dibromoamines
4.
In addition, these results confirm the observation that
2-substituted aziridinium salts are preferably opened at
the more hindered position, when bromide acts as a
nucleophile. The reactivity of N-functionalized aziridines,
with respect to alkyl halides, has been investigated in
the past.43-50 In most cases, the formation of an inter-
mediate aziridinium salt is described. Generally, this
electrophilic species is then further attacked by a nu-
cleophilic counterion, resulting in an acyclic aminopro-
pane derivative. As recently demonstrated, the regiose-
lectivity of the ring opening of the aziridinium ion
depends on the nucleophile: the opening of a 1,1-di-
(arylmethyl)-2-benzylaziridinium ion occurs at the less
hindered position with cyanide, but at the more hindered
position with chloride or bromide.51-53 In a similar
example in the literature, a 2-cyano-1,1-dimethylaziri-
dinium salt was treated with LiCl. After reaction, 2-chloro-
3-(dimethylamino)propanenitrile was isolated, indicating
Resu lts a n d Discu ssion
1-(Arylmethyl)-2-(bromomethyl)aziridines 1 were treated
with 1 equiv of a benzyl bromide in acetonitrile under
reflux for 5 h to afford N-(2,3-dibromopropyl)amines 4
in a quantitative way. A nucleophilic attack of bromide
at the least hindered position of the intermediate aziri-
dinium salt 2, which could not be isolated, would have
given rise to 2-(di(arylmethyl)amino)-1,3-dibromopro-
panes, but instead only 1-(di(arylmethyl)amino)-2,3-
dibromopropanes 4 were formed. The synthesis of a large
number of analogues in excellent yields, starting from
different aryl-substituted aziridines 142 and/or different
benzyl bromides, illustrates the general character of this
reaction (Scheme 1, Table 1). The high purity of these
compounds allowed us to use them as such in the next
step. To provide analytically pure samples for elemental
analysis, compounds 4 were purified by means of column
(34) Khuthier, A. H.; Sheat, M. A.; Al-Rawi, J . M.; Salih, Z. S. J .
Chem. Res. 1987, 184.
(35) Gladych, J . M.; Hartley, D. In Barton and Ollis Comprehensive
Organic Chemistry; Sutherland, I. O., Ed.; Pergamon Press: Oxford,
UK, 1979; Vol. 2, p 79.
(36) Tramontini, M. Synthesis 1973, 703.
(37) Katrizky, A. R.; Gallos, J . K.; Yannakopoulou, K. Synthesis
1989, 31.
(38) Katritzky, A. R.; J iang, J .; Urogdi, L. Tetrahedron Lett. 1989,
30, 3303.
(43) Radell, J .; Connolly, J . W.; Reymond, A. J . J . Am. Chem. Soc.
1961, 83, 3958.
(44) Pierre, J .; Baret, P.; Rivoirard, E. J . Heterocycl. Chem. 1978,
15, 817.
(45) Bassindale, A. R.; Kyle, P. A.; Soobramanien, M.; Taylor, P. G.
J . Chem. Soc., Perkin Trans. 1 2000, 439.
(46) Lillocci, C. J . Org. Chem. 1988, 53, 1733.
(47) Di Vona, M. L.; Illuminati, G.; Lillocci, C. J . Chem. Soc., Perkin
Trans. 2 1985, 1943.
(48) Taguchi, T.; Eto, M. J . Am. Chem. Soc. 1958, 80, 4075.
(49) Park, C. S.; Choi, H. G.; Lee, H.; Lee, W. K.; Ha, H.-J .
Tetrahedron: Asymmetry 2000, 11, 3283.
(39) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. J . Org.
Chem. 1994, 59, 2282.
(40) Barluenga, J .; Canteli, R.; Flo´rez, J . J . Org. Chem. 1996, 61,
3646.
(41) Frey, H.; Kaupp, G. Synthesis 1990, 931.
(42) (a) De Kimpe, N.; J olie, R.; De Smaele, D. J . Chem. Soc., Chem.
Commun. 1994, 1221. (b) De Kimpe, N.; De Smaele, D.; Sakonyi, Z. J .
Org. Chem. 1997, 62, 2448.
(50) Katagiro, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama,
K. J . Org. Chem. 1999, 64, 7323.
(51) O’Brien, P.; Towers, T. D. J . Org. Chem. 2002, 67, 304.
(52) Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647.
(53) Nagle, A. S.; Salvatore, R. N.; Chong, B.-D.; J ung, K. W.
Tetrahedron Lett. 2000, 41, 3011.
2704 J . Org. Chem., Vol. 69, No. 8, 2004

New Synthesis of Propargylic Amines
SCHEME 2
SCHEME 3
that the aziridinium salt opened up spontaneously to
form a secondary carbenium ion, which was then trapped
by chloride.44
dure (Scheme 3). Treatment of epichlorohydrine 7 with
benzylamine in hexane resulted in amino alcohol 8,54
which was silylated by using trimethylsilyl chloride in
CH2Cl2 to afford the silyl ether 9 in good yield. Ring
closure of the protected alcohol 9 toward 3-(trimethylsi-
lyloxy)azetidine 10 was performed with triethylamine in
acetonitrile upon reflux for 48 h. The spectral data of
1-benzyl-3-(trimethylsilyloxy)azetidine 10 correspond well
with those mentioned in the literature.54 Subsequently,
3-hydroxyazetidine 11, prepared from the silyl ether 10
by treatment with TBAF in THF, was transformed into
the corresponding 3-chloroazetidine 12 upon reaction
with triphenylphosphine in tetrachloromethane and re-
flux for 3 days.55a As mentioned in the literature, 1-ben-
zyl-2-(chloromethyl)aziridine was formed as a side prod-
uct in a ratio of 3/2 (major/minor).55a Finally, the
3-chloroazetidine 12 was precipitated as an azetidinium
The N,N-di(arylmethyl)-N-(2,3-dibromopropyl)amines
4, prepared from 1-(arylmethyl)-2-(bromomethyl)aziri-
dines 1, were used for the synthesis of N,N-di(aryl-
methyl)-N-(2-bromo-2-propenyl)amines 6 in a straight-
forward reaction with KOtBu in diethyl ether under
reflux for 2 h. The underlying mechanism can be ex-
plained considering a neighboring group participation of
the N,N-dibenzylamino function. KOtBu is then respon-
sible for the deprotonation of the intermediate 3-bro-
moazetidinium salt 5, resulting in the desired vinyl
bromides 6 (Scheme 2). This reaction can be listed as a
variant of the well-known Hofmann elimination.
To support the suggested mechanism of this unusual
transformation, a halo-analogue of the presumptive
intermediate azetidinium salt 5, i.e. 1-benzyl-3-chloro-
azetidine 12, was synthesized via an alternative proce-
(54) Higgins, R. H. J . Heterocycl. Chem. 1987, 24, 1489.
J . Org. Chem, Vol. 69, No. 8, 2004 2705

D’hooghe et al.
SCHEME 4
SCHEME 5
salt upon quaternization with iodomethane in diethyl
ether (colorless precipitate) and this salt was immediately
treated with 1 equiv of a base (KOtBu) in ether furnish-
ing the desired vinyl chloride 13 in 79% yield. When the
trimethylsilyl ether 10 was alkylated with iodomethane,
the corresponding azetidinium salt 14 was isolated as a
colorless solid and subsequently treated with both KOtBu
in ether (reflux, 3 h) and sodium hydride in DMSO (80
°C, 2 h). However, in both cases only complex reaction
mixtures were formed without any trace of the allylamine
15. The structural identity of allylamine 13 was con-
firmed by comparison with spectral data found in the
literature.56 Consequently, the peculiar mechanism re-
sponsible for the dehydrohalogenation of N-(2,3-dibro-
mopropyl)amines 4 in the synthesis of the vinyl bromides
6 can be explained considering the intermediacy of
azetidinium salts 5. This novel transformation, in which
a 3-haloazetidine suffers ring opening to furnish a N-(2-
halo-2-propenyl)amine, clearly extends the present knowl-
edge of azetidine chemistry.
good yields. The presented method with NaH in DMSO
offers an easy and very efficient alternative for the
dehydrobromination of (2-bromo-2-propenyl)amines into
propargylamines in high yields.
Vinyl bromides are known to be good substrates for
Stille coupling reactions.66,67 The presence of an amino-
methyl functionality in the vinyl bromides 6 allows a new
approach toward R-(aminomethyl)-substituted R,â-un-
saturated ketones, which have an interest as antimicro-
bial agents and for the treatment of pain, fever, and
inflammation.68,69 To reach this objective, N,N-dibenzyl-
N-(2-bromo-2-propenyl)amine 6a was transformed in the
corresponding trimethylstannyl derivative 18 by reaction
with bis(trimethyltin) in the presence of a catalytic am-
ount of Hu¨nig’s base and tetrakis(triphenylphosphine)-
palladium in benzene at 80 °C for 15 h.66,67 This stannane
18 was then further reacted with 2-methylpropanoyl
(55) (a) Gaertner, V. R. J . Org. Chem. 1970, 35, 3952. (b) Isoda, T.;
Yamamura, K. J . J apanese Kokai Tokkyo Koho 2000355592 A2, Dec
26, 2000; Chem. Abstr. 2000, 134, 56662.
The synthesis of propargylamines 16 could be estab-
lished in excellent yields (90-94%) by treatment of N,N-
di(arylmethyl)-N-(2-bromo-2-propenyl)amines 6 with NaH
in DMSO. The dimsyl anion, resulting from the reaction
of NaH and dimethyl sulfoxide, appeared to be a suitable
base for the deprotonation of N,N-di(arylmethyl)-N-(2-
bromo-2-propenyl)amines 6 (Scheme 4). Also other bases
were evaluated, but in those cases no alkynes were
isolated. With NaNH2 in NH3/Et2O (-78 °C for 3 h, or
r.t. for 1 h, or ∆ for 15 h), no reaction occurred, and the
starting material was recovered. When n-BuLi (2.5 M in
hexane) in THF at room temperature was used, debro-
mination of 6e instead of dehydrobromination occurred
resulting in allylamine 17 in 90% yield (Scheme 4).57
Although the conversion of (2-bromo-2-propenyl)-
amines into propargylamines had been described in the
literature, only NaNH2 in NH3,58-62 KOtBu in THF,63
PhLi in THF,64 and NaOH65 were evaluated as bases
resulting in the desired propargylamines in moderate to
(56) Huerta, F. F.; Go´mez, C.; Guijarro, A.; Yus, M. Tetrahedron
1995, 51, 3375.
(57) Bruckner, R. In Advanced Organic Chemistry; Hayhurst, J ., Ed.;
Academic Press: San Diego, CA, 2002; p 528.
(58) Quast, H.; J akob, R.; Peters, K.; Peters, E. M.; Von Schnering,
H. G. Chem. Ber. 1984, 117, 840.
(59) Tkachenko, P. V.; Popov, I. I.; Simonov, A. M.; Medvedov, Y.
V. Khim. Geterotsikl. Soedin. 1975, 11, 1542; Chem. Abstr. 1976, 84,
90059.
(60) Caubere, P. Bull. Soc. Chim. Fr. 1966, 4, 1293.
(61) Butler, G. B.; J ohnson, R. A. J . Am. Chem. Soc. 1954, 76, 713.
(62) Parcell, R. F.; Pollard, C. B. J . Am. Chem. Soc. 1950, 72, 2385.
(63) Ohno, H.; Toda, A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry
1998, 9, 3929.
(64) Barluenga, J .; Foubelo, F.; Fananas, F.; Yus, M. J . Chem. Soc.,
Perkin Trans. 1 1989, 3, 553.
(65) Kurginyan, K. A.; Arakelova, S. V.; Kalaidzhyan, A. E. Arm.
Khim. Zh. 1986, 39, 516; Chem. Abstr. 1988, 108, 5302.
(66) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J . J . Am.
Chem. Soc. 1998, 120, 5921.
(67) Evans, D. A.; Kim, A. S. J . Am. Chem. Soc. 1996, 118, 11323.
(68) Grier, N.; Dybas, R. A.; Witzel, E. U.S. patent 4145426, March
20, 1979; Chem. Abstr. 1979, 91, 20335.
(69) Dybas, R. A.; Grier, N.; Witzel, E. U.S. patent 4250184, Feb
10, 1981; Chem. Abstr. 1981, 95, 24831.
2706 J . Org. Chem., Vol. 69, No. 8, 2004

New Synthesis of Propargylic Amines
SCHEME 6
SCHEME 7
chloride in a palladium-based Stille coupling reaction
with Hu¨nig’s base and tris(dibenzylideneacetone)dipal-
ladium in benzene at room temperature for 2 h,66,67
resulting in 2-[(dibenzylamino)methyl]-4-methyl-1-penten-
3-one 19 in 88% yield (Scheme 5). This reaction proves
that the conditions for a Stille coupling can be success-
fully applied for nitrogen-containing vinyl bromides,
pointing to the conclusion that vinyl bromides 6 can be
applied as useful synthetic intermediates in different
synthetic pathways.
Since many functionalized propargylamines are known
to possess various physiological activities,1-27 derivati-
zation of N,N-di(arylmethyl)-N-(2-propynyl)amines 16
was further investigated. To serve this purpose, the
Yamaguchi-Hirao alkylation of lithio-acetylides by ep-
oxides with 1.05 equiv of n-BuLi (2.5M in hexane) in the
presence of 1.3 equiv of a BF3‚THF complex was evalu-
ated.70 The applicability of this method on the acetylides
of propargylamines appeared to be very successful (Scheme
6) and offers a feasible alternative for the use of NaNH2
in NH3.71 However, when 2-methylthiirane was used
instead of an epoxide, no reaction occurred and the
starting material was recovered, even after reflux for 15
h. Other types of electrophiles, such as carbonyl com-
pounds, were also evaluated. The reaction of N,N-
dibenzyl-N-(2-propynyl)amine 16a with n-butylisocyan-
ate, using Yamaguchi-Hirao conditions, i.e. n-BuLi and
BF3‚THF, resulted in the corresponding amide 21 (Scheme
7). In the same way, γ-amino esters can be synthesized,
using methyl chloroformate as the electrophile (Scheme
7). The resulting methyl 4-(dibenzylamino)-2-butynoate
22 is the precursor of the corresponding γ-amino acid.
The use of â- and γ-amino acids in peptide chemistry has
become an important field of investigation during the last
decennium.72 When an acid chloride was used, e.g.
isobutyryl chloride, another type of compound could be
(71) Hartzoulakis, B.; Rutherford, T. J .; Ryan, M. D.; Gani, D.
Tetrahedron Lett. 1996, 37, 6911.
(70) Evans, A. B.; Knight, D. W. Tetrahedron Lett. 2001, 42, 6947.
(72) Abele, S.; Seebach, D. Eur. J . Org. Chem. 2000, 1.
J . Org. Chem, Vol. 69, No. 8, 2004 2707

D’hooghe et al.
SCHEME 8
SCHEME 10
hydrogenate the functionalized propargylamines 20.
Hydrogenation of the homopropargylic alcohol 20a in
pentane in the presence of a Lindlar catalyst (0.1 equiv
or an excess)82 under 5 bar of H2 pressure and 0 °C for
20 min to 15 h was not successful, even when the catalyst
was poisened with 0.05 equiv of quinoline, all resulting
in recovery of the starting material. On the basis of a
nickel-catalyzed hydroarylation of 4-octyne and diphen-
ylethyne, described in the literature,83 the reactivity of
propargylamine 20c and 2-phenyl-1,3,2-dioxaborinane
was evaluated. With 10 mol % of bis(1,5-cyclooctadiene)-
nickel, two isomeric allylamines 26 and 27 were isolated
and separated by flash chromatography (Scheme 10).
SCHEME 9
synthesized. The main compound in the reaction mixture
appeared to be the tertiary alcohol 23 (Scheme 7). This
can be rationalized considering a second nucleophilic
addition of the lithiated alkyne across the carbonyl group.
A second type of derivatization of N,N-di(arylmethyl)-
N-(2-propynyl)amines 16 concerned the Sonogashira
coupling.73,74 By means of a catalytic amount of Pd(PPh3)4
and CuI as cocatalyst, coupling of N,N-di((4-methylphen-
yl)methyl)-N-(2-propynyl)amine 16e and 4-iodoanisole
was realized in THF at room temperature for 15 h
(Scheme 8). N-(3-Phenyl-2-propynyl)-N,N-dialkylamines
are known to exhibit inhibition of MAO, which makes
propargylamine 24 an interesting target with potential
biological activity.22,23 When the iodoarene was replaced
by a vinyl chloride, based on a known coupling between
an alkyne and a vinyl chloride,74 the expected coupling
reaction did not occur although similar conditions, i.e. a
catalytic amount of Pd(PPh3)4 and CuI in THF, were
applied. Instead, the diyne 25 was isolated in a high yield
(Scheme 9). The formation of this diamine 25 under these
conditions is justified by some literature references, in
which for example the oxidative coupling of terminal
alkynes in the presence of Pd(PPh3)4, CuI, and BuNH2
in benzene is described.75 Similar diyne compounds are
used as pesticides to protect grain from various infections
caused by for instance the rice weevil (Sitophilus oryzae)
and the pulse beetle (Callosobruchus chinensis).76
Con clu sion s
A new and straightforward synthesis of N,N-di(aryl-
methyl)-N-(2-propynyl)amines, compounds with a broad
applicability, was developed in high overall yields (64-
77%), starting from 1-(arylmethyl)-2-(bromomethyl)aziri-
dines. This method for the synthesis of propargylamines
offers an excellent alternative for the double alkylation
of propargylamine since the latter is extremely expensive.
A novel and very interesting analogue of the Hofmann
elimination, in which N-(2,3-dibromopropyl)amines are
converted into N-(2-bromo-2-propenyl)amines via inter-
mediate azetidinium salts, was described and a general
method for the conversion of (2-bromo-2-propenyl)amines
into propargylamines is disclosed. Extension of the
Yamaguchi-Hirao alkylation and a known hydroaryla-
tion reaction to nitrogen-containing compounds was
discussed. Furthermore, a new approach for the synthesis
of R-((dibenzylamino)methyl)-R,â-unsaturated ketones,
based on a Stille coupling, was presented.
Exp er im en ta l Section
1. Gen er a l P r oced u r e for th e Syn th esis of N,N-Di-
(a r ylm eth yl)-N-(2,3-d ibr om op r op yl)a m in es 4. As an ex-
ample, the synthesis of N-benzyl-N-(2,3-dibromopropyl)-N-((4-
methylphenyl)methyl)amine 4b is described. To a solution of
2-(bromomethyl)-1-((4-methylphenyl)methyl)aziridine42 (3.60
g, 15 mmol) in acetonitrile (50 mL) was added benzyl bromide
(2.56 g, 15 mmol). After the solution was heated 5 h under
reflux, the solvent was removed in vacuo, resulting in N-ben-
zyl-N-(2,3-dibromopropyl)-N-((4-methylphenyl)methyl)amine
4b (6.15 g, 100%). N,N-Di(arylmethyl)-N-(2,3-dibromopropyl)-
amines 4 were purified by means of column chromatography
Driven by the numerous biological activities of N,N-
di(arylmethyl)allylamines, such as fungicidal,77-79 anti-
viral, and antitumor activity,80,81 attempts were made to
(73) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(74) Vourloumis, D.; Kim, K. D.; Petersen, J . L.; Margriotis, P. A.
J . Org. Chem. 1996, 61, 4848.
(75) Magriotis, P. A.; Vourloumis, D.; Scott, M. E.; Tarli, A.
Tetrahedron Lett. 1993, 34, 2071.
(76) Datta, M.; Datta, S.; Bhattacharya, A.; Majunder, K. P. Ento-
mon 1997, 22, 207.
(77) Zhang, H.; Bai, D. Zhongguo Yaowu Huaxue Zazhi 1997, 7, 303;
Chem. Abstr. 1998, 130, 75558.
(78) Balkis, M. M.; Leidich, S. D.; Mukherjee, P. K.; Ghannoum, M.
A. Drugs 2002, 62, 1025.
(79) Stuetz, A. Angew. Chem. 1987, 99, 323.
(80) J apanese Kokai Tokkyo Koho 58113105 A2, J uly 5, 1983; Chem.
Abstr., 1983, 99, 215838.
(81) Tahara, Y.; Komatsu, Y.; Koyama, H.; Kubota, R.; Yamaguchi,
T.; Takahashi, T. French Demande 2505826 A1, Nov 19, 1982; Chem.
Abstr., 1983, 98, 215838.
(82) Wovkulich, P. M.; Baggiolini, E. G.; Hennessy, B. M.; Uskokovic,
M. R.; Mayer, E.; Norman, A. W. J . Org. Chem. 1983, 48, 4436.
(83) Shirakawa, E.; Takahashi, G.; Tsuchimoto, T.; Kawakami, Y.
Chem. Commun. 2001, 2688.
2708 J . Org. Chem., Vol. 69, No. 8, 2004

New Synthesis of Propargylic Amines
on silica gel (SiO2) utilizing a mixture of hexane and ethyl
acetate as an eluent.
7.21-7.32 (5H, m). 13C NMR (67.8 MHz, CDCl3): δ 60.8, 63.8,
64.7, 127.4, 128.6, 137.6. IR (NaCl, cm-1): νmax 3086, 3063,
3029, 2958, 2837, 909, 733, 698. MS (70 eV): m/z (%) 181/3
(M+, 4), 180/2 (10), 146 (4), 145 (4), 119 (7), 104 (12), 91 (100),
65 (9).
3-(N-Ben zyl-N-m eth yl)am in o-2-ch lor o-1-pr open e 13: To
a solution of 1-benzyl-3-chloroazetidine 12 (0.36 g, 2 mmol) in
diethyl ether (10 mL) was added iodomethane (0.43 g, 1.5
equiv) and the solution was stirred for 3 h at room temperature
upon which a colorless solid separated. Subsequently, KOtBu
(0.22 g, 1.0 equiv) was added and the suspension was refluxed
for 2 h. Extraction with diethyl ether (3 × 10 mL), drying
(MgSO4), filtration of the drying agent, and removal of the
solvent in vacuo afforded 3-(N-benzyl-N-methyl)amino-2-chloro-
1-propene 13 (0.31 g, 79%). The spectral data obtained here
are in accordance with those mentioned in the literature.56
4. Stille Cou p lin g. N,N-Diben zyl-2-(tr im eth ylsta n n yl)-
2-p r op en -1-a m in e 18: This compound was prepared applying
Stille coupling conditions.58,59 To a solution of N,N-dibenzyl-
N-(2-bromo-2-propenyl)amine 6a (1.58 g, 5 mmol) in benzene
(40 mL) at room temperature and under nitrogen atmosphere
were added Hu¨nig’s base (0.17 g, 0.2 equiv) and hexameth-
ylditin (2.72 mL, 2.0 equiv) via a syringe, followed by tetrakis-
(triphenylphosphine)palladium (0.27 g, 0.05 equiv). The yellow
solution was heated for 1 h at 80 °C, gradually darkening from
yellow to black, and additionally stirred for 1 h at room
temperature. The reaction mixture was quenched by the
addition of a saturated aqueous solution of CuSO4 (40 mL).
Extraction with hexane (2 × 30 mL), washing with brine (1 ×
30 mL), drying over MgSO4, filtration through Celite, and
purification by column chromatography (SiO2, hexane/EtOAc
95/5) afforded N,N-dibenzyl-2-(trimethylstannyl)-2-propen-1-
amine 18 (1.34 g, 67%).
Light yellow oil, 67% yield; TLC Rf 0.64 (hexane/EtOAc 95/
5). 1H NMR (270 MHz, CDCl3): δ 0.08 (9H, t, J ) 26.7 Hz),
3.18 (2H, s), 3.50 (4H, s), 5.33 and 5.91 (2H, 2 × d, J ) 1.5
Hz), 7.27-7.36 (10H, m). 13C NMR (67.8 MHz, CDCl3): δ -9.2,
57.8, 63.7, 126.8, 127.1, 128.1, 129.2, 138.8, 154.7. IR (NaCl,
cm-1): νmax 3086, 3063, 3029, 2977, 2911, 2793, 1602, 1495,
1454, 748, 698, 521. MS (70 eV): m/z (%) 394/396/397/398/
399/400/401/402/404/405 (M+ + 1, 100), 300 (25) 270 (20), 268
(44), 250 (14), 239 (19), 238 (94), 236 (15), 198 (12). Anal. Calcd
for C20H27NSn: N 3.50. Found: N 3.41.
2-[(Dib en zyla m in o)m et h yl]-4-m et h yl-1-p en t en -3-on e
19: This compound was prepared applying Stille coupling
conditions.66,67 2-Methylpropanoyl chloride (0.21 g, 1.0 equiv)
was dissolved in benzene (10 mL) and treated with tris-
(dibenzylideneacetone)dipalladium (0.10 g, 0.05 equiv), fol-
lowed by Hu¨nig’s base (0.08 g, 0.3 equiv). To the resultant
purple solution was added vinylstannane 18 (0.80 g, 2 mmol)
and the mixture was stirred for 30 min at room temperature.
An additional amount of palladium (0.10 g, 0.05 equiv) was
added to the black solution, regenerating the purple color.
After an additional 2 h at room temperature, the reaction
mixture was filtered through a pad of SiO2 with EtOAc (40
mL) and concentrated in vacuo, affording 2-[(dibenzylamino)-
methyl]-4-methyl-1-penten-3-one 19 (0.54 g, 88%).
Yellow oil, 88% yield, filtration (SiO2) with EtOAc. 1H NMR
(270 MHz, CDCl3): δ 1.04 (6H, d, J ) 6.8 Hz), 3.14 (1H, sept,
J ) 6.8 Hz), 3.28 (2H, s), 3.54 (4H, s), 6.06-6.08 (2H, m), 7.20-
7.42 (10H, m). 13C NMR (67.8 MHz, CDCl3): δ 19.0, 35.0, 53.8,
58.1, 124.3, 126.9, 128.2, 128.6, 139.2, 145.2, 206.3. IR (NaCl,
cm-1): νmax 3085, 3062, 3028, 2972, 2931, 2873, 2798, 1738,
1673, 1623, 1495, 1451, 698. MS (30 V): m/z (%) 308 (M+ + 1,
100), (70 V), 308 (M+ + 1, 2), 181 (11), 166 (7), 91 (100). Anal.
Calcd for C21H25NO: C 82.04; H 8.20; N 4.56. Found: C 82.18;
H 8.35; N 4.46.
N,N-Diben zyl-N-(2,3-d ibr om op r op yl)a m in e 4a : Color-
less oil, 51% yield. 1H NMR (270 MHz, CDCl3): δ 2.88 and
3.08 (2H, 2 × d × d, J ) 13.9 Hz, J ) 7.3, 6.6 Hz, N(HCH)-
CHBr), 3.63 and 3.67 (4H, 2 × d, J ) 13.9 Hz, 2 × N(HCH)C),
3.60-3.77 (2H, m, CH2Br), 4.01 (1H, quint, J ) 6.3 Hz, CHBr),
7.22-7.44 (10H, m, 2 × C6H5). 13C NMR (67.8 MHz, CDCl3):
δ 35.7, 50.8, 59.1, 59.2, 127.2, 128.2, 128.9, 138.5. IR (NaCl,
cm-1): νmax 3085, 3062, 3028, 2929, 2804, 1494, 1453, 748, 699.
MS (70 eV): m/z (%) 395/7/9 (M+, 7), 316/8 (9), 302/4 (8), 212
(18), 211 (54), 210 (100), 181 (25), 146 (12), 127 (11), 125 (25),
120 (12), 92 (23), 91 (58), 89 (14), 84 (11), 65 (20), 51 (13), 49
(11). Anal. Calcd for C17H19Br2N: C 51.41; H 4.82; N 3.53.
Found: C 51.62; H 4.90; N 3.40.
2. Gen er a l P r oced u r e for th e Syn th esis of N,N-Di-
(a r ylm eth yl)-N-(2-br om o-2-p r op en yl)a m in es 6. As a rep-
resentative example, the synthesis of N-(2-bromo-2-propenyl)-
N,N-di((4-methylphenyl)methyl)amine 6e is described. To a
solution of N-(2,3-dibromopropyl)-N,N-di((4-methylphenyl)-
methyl)amine 4e (4.25 g, 10 mmol) in dry diethyl ether (50
mL) was added KOtBu (1.12 g, 10 mmol). After the mixture
was heated for 2 h under reflux, the reaction mixture was
poured into water (50 mL) and extracted with Et2O (3 × 20
mL). Drying (MgSO4), filtration of the drying agent, and
removal of the solvent yielded N-(2-bromo-2-propenyl)-N,N-
di((4-methylphenyl)methyl)amine 6e (2.67 g, 78%). N,N-Di-
(arylmethyl)-N-(2-bromo-2-propenyl)amines 6 were purified by
distillation under reduced pressure.
N,N-Diben zyl-N-(2-br om o-2-p r op en yl)a m in e 6a : Color-
less oil, 82% yield, bp 115 °C/0.02 mmHg. 1H NMR (270 MHz,
CDCl3): δ 3.26 (2H, s), 3.62 (4H, s), 5.60 (1H, s(broad)), 5.96
(1H, d, J ) 1.3 Hz), 7.21-7.43 (10H, m). 13C NMR (67.8 MHz,
CDCl3): δ 57.2, 61.3, 118.4, 126.9, 128.2, 128.6, 132.0, 138.7.
IR (NaCl, cm-1): νmax 3085, 3062, 3028, 2924, 2800, 1629, 1494,
1454, 746, 698. MS (70 eV): m/z (%) 315/7 (M+, 4), 210 (14),
91 (100), 65 (13). Anal. Calcd for C17H18BrN: C 64.57; H 5.74;
N 4.43. Found: C 64.44; H 5.80; N 4.48.
3. Syn th esis of 1-Ben zyl-3-ch lor oa zetid in e 12, Su bse-
qu en t Qu a t er n iza t ion , a n d R in g Op en in g. 1-Ben zyl-3-
h yd r oxya zetid in e 11: To an ice-cooled solution of 1-benzyl-
3-(trimethylsilyl)azetidine 1054 (1.17 g, 5 mmol) in THF (15
mL) was added TBAF‚3H2O (1.65 g, 1.05 equiv) and the
resulting mixture was stirred for 3 h at room temperature.
Afterward, the reaction mixture was poured in water (15 mL),
extracted with diethyl ether (3 × 10 mL), and dried (MgSO4).
Filtration of the drying agent and removal of the solvent in
vacuo afforded 1-benzyl-3-hydroxyazetidine 11 (0.68 g, 83%).
Purity (GC) >97%. The spectral data correspond well with
those published in the literature, where the deprotection was
realized in 73% yield with use of NaOMe in methanol.84
1-Ben zyl-3-ch lor oa zetid in e 12: To a solution of 1-benzyl-
3-hydroxyazetidine 11 (0.82 g, 5 mmol) in CCl4 (10 mL) at room
temperature was added triphenylphosphine (1.44 g, 1.1 equiv)
and the mixture was heated under reflux for 3 days upon
which a solid separated. The cooled reaction mixture was
filtered and the filtrate was extracted with dilute sulfuric acid
(2 × 10 mL, 1 N in H2O) and washed with water (2 × 20 mL).
The combined aqueous extracts were made strongly alkaline
with a 4 N NaOH solution (30 mL) and extracted with diethyl
ether (3 × 25 mL). Drying (MgSO4), filtration of the drying
agent, and removal of the solvent in vacuo afforded 1-benzyl-
3-chloroazetidine 12 and 1-benzyl-2-(chloromethyl)aziridine
(ratio 3/2 based on GC).55a The compound was purified by
distillation. Only 1H NMR data for 1-benzyl-3-chloroazetidine
12 were found in the literature.55b
Colorless liquid, 60% yield, bp 51 °C/0.02 mbar; TLC Rf 0.37
(hexane/EtOAc 6/4). 1H NMR (300 MHz, CDCl3): δ 3.20-3.25
(2H, m), 3.63 (2H, s), 3.72-3.82 (2H, m), 4.12-4.20 (1H, m),
5. Gen er a l P r oced u r e for th e Syn th esis of N,N-Di-
(a r ylm eth yl)-N-(2-p r op yn yl)a m in es 16. As a representative
example, the synthesis of N,N-dibenzyl-N-(2-propynyl)amine
16a is described. To DMSO (20 mL) was added sodium hydride
(0.25 g, 10.5 mmol) and the solution was stirred for 30 min at
(84) Higgins, R. H.; Eaton, Q. L.; Worth, L., J r.; Peterson, M. V. J .
Heterocycl. Chem. 1987, 24, 255.
J . Org. Chem, Vol. 69, No. 8, 2004 2709

D’hooghe et al.
80 °C. N,N-Dibenzyl-N-(2-bromo-2-propenyl)amine 6a (3.15 g,
10 mmol) was added and the mixture was further stirred for
3 h at 80 °C. After addition of water and extraction with diethyl
ether (3 × 20 mL), the organic phase was washed with water
(3 × 50 mL), dried (MgSO4), filtered, and evaporated in vacuo
to yield N,N-dibenzyl-N-(2-propynyl)amine 16a (2.18 g, 93%).
The N,N-di(arylmethyl)-N-(2-propynyl)amines 16 were puri-
fied by means of column chromatography on silica gel utilizing
a mixture of hexane and ethyl acetate as eluent.
solvent in vacuo, and purification by column chromatography
(SiO2) afforded the propargylamines 20, 21, 22, and 23 in high
yields.
7-(N,N-Diben zyla m in o)-5-h ep tyn -3-ol 20a : Colorless oil,
82% yield; TLC Rf 0.17 (CH2Cl2/methanol 100/1). 1H NMR (270
MHz, CDCl3): δ 1.01 (3H, t, J ) 7.4 Hz), 1.58-1.69 (2H, m),
1.96 (1H, s(broad)), 2.37-2.58 (2H, m), 3.26 (2H, t, J ) 2.2
Hz), 3.66 (4H, s), 3.66-3.71 (1H, m), 7.21-7.41 (10H, m). 13C
NMR (67.8 MHz, CDCl3): δ 10.0, 27.2, 29.1, 41.6, 57.6, 71.5,
77.1, 81.9, 127.1, 128.3, 129.0, 138.8. IR (NaCl, cm-1): νOH
3397, νmax 3029, 2963, 2927, 2877, 2824, 1495, 1454. MS (70
eV): m/z (%) 308 (M+ + 1, 100). Anal. Calcd for C21H25NO: C
82.04; H 8.20; N 4.56. Found: C 82.15; H 8.32; N 4.50.
7. R ed u ct ion of F u n ct ion a lized P r op a r gyla m in es.
Compounds 26 and 27 were prepared according to a method
known in the literature for alkynes without heteroatoms
present.83 To a solution of 6-(N,N-dibenzylamino)-4-hexyn-2-
ol 20c (1.18 g, 4 mmol) in dibutyl ether (40 mL) was added
under nitrogen atmosphere 2-phenyl-1,3,2-dioxaborinane (0.69
g, 1.05 equiv), bis(1,5-cyclooctadiene)nickel (0.11 g, 0.1 equiv),
and water (1.03 g, 14 equiv), and the resulting solution was
stirred for 5 h at room temperature. The reaction mixture was
poured into water (100 mL), extracted with diethyl ether (3 ×
20 mL), and dried over MgSO4. Filtration of the drying agent,
removal of the solvent in vacuo, and separation by means of
column chromatography (SiO2) afforded (4E)-6-[di(phenylm-
ethyl)amino]-5-phenyl-4-hexen-2-ol 26 (0.33 g, 21%) and (4Z)-
6-[di(phenylmethyl)amino]-5-phenyl-4-hexen-2-ol 27 (0.38 g,
24%).
N,N-Diben zyl-N-(2-p r op yn yl)a m in e 16a : Yellow crys-
tals, 93% yield; TLC Rf 0.38 (hexane/EtOAc 16/1); mp 42 °C.
1H NMR (270 MHz, CDCl3): δ 2.28 (1H, t, J ) 2.3 Hz), 3.26
(2H, d, J ) 2.3 Hz), 3.69 (4H, s), 7.22-7.42 (10H, m). 13C NMR
(67.8 MHz, CDCl3): δ 41.1, 57.4, 73.4, 78.5, 127.1, 128.3, 129.0,
138.7. IR (NaCl, cm-1): ν
3297, νmax 3062, 3028, 2923,
≡C-H
2805, 1495, 1454. MS (70 eV): m/z (%) 236 (M+ + 1, 100), 198
(27), 91 (12). Anal. Calcd for C17H17N: C 86.77; H 7.28; N 5.95.
Found: C 86.86; H 7.38; N 5.90.
N ,N -D i((4-m e t h y lp h e n y l)m e t h y l)-N -(2-p r o p e n y l)-
a m in e 17: To a solution of N-(2-bromo-2-propenyl)-N,N-di((4-
methylphenyl)methyl)amine 6e (0.35 g, 1 mmol) in THF (50
mL) at 0 °C and under nitrogen atmosphere was added n-BuLi
(0.43 mL, 2.5 M in hexane, 1.05 equiv) via a syringe and the
resulting solution was stirred for 15 h at room temperature.
The reaction mixture was poured out in water (50 mL),
extracted with diethyl ether (3 × 30 mL), and washed with
water (3 × 30 mL). Drying (MgSO4), filtration of the drying
agent, and removal of the solvent afforded N,N-di((4-meth-
ylphenyl)methyl)-N-(2-propenyl)amine 17 (0.24 g, 90%). Purity
(GC) >95%.
(4E)-6-[Di(p h en ylm et h yl)a m in o]-5-p h en yl-4-h exen -2-
ol 26: Colorless oil, 21% yield; TLC Rf 0.40 (hexane/EtOAc 4/1).
1H NMR (270 MHz, CDCl3): δ 1.11 (3H, d, J ) 6.3 Hz), 2.44
and 2.50 (2H, 2 × d × d, J ) 14.1 Hz, J ) 8.4, 4.9 Hz), 2.95
and 3.30 (2H, 2 × d × d, J ) 13.5, 7.1 Hz), 3.48 and 3.82 (4H,
2 × d, J ) 13.2 Hz), 3.65-3.72 (1H, m), 6.01 (1H, t, J ) 7.1
Hz), 7.15-7.45 (15H, m). 13C NMR (67.8 MHz, CDCl3): δ 23.8,
39.8, 50.8, 58.7, 65.8, 126.5, 127.4, 127.6, 128.3, 129.4, 129.5,
127.2, 133.6, 138.3, 142.4. IR (NaCl, cm-1): νOH 3388, νmax
3084, 3061, 3028, 2964, 2926, 2801, 1601, 1495, 1453, 1372,
1313. MS (70 eV): m/z (%) 372 (M+ + 1, 100). Anal. Calcd for
Colorless oil, 90% yield. 1H NMR (270 MHz, CDCl3): δ 2.34
(6H, s), 3.03 (2H, d, J ) 6.3 Hz), 3.52 (4H, s), 5.11-5.23 (2H,
m), 5.82-5.95 (1H, m), 6.96-7.41 (8H, m). 13C NMR (67.8
MHz, CDCl3): δ 21.1, 56.2, 57.3, 117.2, 128.7, 128.8, 136.1,
136.5. IR (NaCl, cm-1): νmax 3048, 3021, 2924, 2859, 2804,
1642, 1514, 1452, 806. MS (70 eV): m/z (%) 265 (M+, 2), 160
(11), 105 (100), 91 (18), 77 (26). Anal. Calcd for C19H23N: C
85.99; H 8.74; N 5.28. Found: C 86.13; H 8.83; N 5.17.
6. F u n ction a liza tion of P r op a r gyla m in es 16. The com-
pounds 20, 21, 22, and 23 were prepared in accordance with
a procedure adapted from the literature.70 General procedure
for the synthesis of propargylamines 20, 21, 22, and 23: To a
solution of a N,N-di(arylmethyl)-N-(2-propynyl)amine 16 (10
mmol) in THF (40 mL) at -78 °C and under nitrogen
atmosphere was added n-BuLi (2.5M in hexane, 1.05 equiv)
via a syringe, and the solution was stirred for 30 min at -78
°C. To this reaction mixture was added a solution of BF3-
THF (1.3 equiv) at -78 °C via a syringe in THF (10 mL) and,
after 15 min of stirring, a solution of the electrophile (1.05
equiv) in THF (10 mL). After an additional 2 h at -78 °C the
mixture was heated to ambient temperature, quenched with
a saturated NH4Cl solution (20 mL), extracted with diethyl
ether (3 × 20 mL), washed with water (3 × 20 mL), and dried
over MgSO4. Filtration of the drying agent, removal of the
C
26H29NO: C 84.06; H 7.87; N 3.77. Found: C 84.17; H 7.96;
N 3.69.
Ack n ow led gm en t. The authors are indebted to the
Fund for Scientific Research-Flanders (Belgium)
(F.W.O.-Vlaanderen) and Ghent University (GOA) for
financial support.
Su p p or tin g In for m a tion Ava ila ble: General information
and all spectroscopic data of compounds 4b-j, 6b-e, 16b-e,
20b, 21, 22, 23, 24, 25, and 27. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O035759I
2710 J . Org. Chem., Vol. 69, No. 8, 2004