Isomerization of chiral non-racemic α-substituted propargylic amines to terminal acetylenes

Article abstract of DOI:10.1002/1099-0690(200208)2002:15<2598::AID-EJOC2598>3.0.CO;2-V

Various α-substituted propargylamines, prepared in three steps from (R)-phenylglycinol, are readily isomerized at 0 °C with KAPA to form terminal acetylenic amines, without any detectable epimerization of the chiral center, as already observed for propargyl alcohols. Enantiomerically pure primary α-substituted alkynylamines can be easily obtained in two steps after removal of the ferrocenylmethyl protective group and oxidative cleavage of the chiral appendage, Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200208)2002:15<2598::AID-EJOC2598>3.0.CO;2-V

FULL PAPER
Isomerization of Chiral Non-Racemic α-Substituted Propargylic Amines to
Terminal Acetylenes
[a]
[a]
[a]
[a]
´
Jerome Blanchet, Martine Bonin,* Laurent Micouin,* and Henri-Philippe Husson
Keywords: Isomerization / Amines / Amino acids / Alkynes
Various α-substituted propargylamines, prepared in three
steps from (R)-phenylglycinol, are readily isomerized at 0 °C
with KAPA to form terminal acetylenic amines, without any
detectable epimerization of the chiral center, as already ob-
served for propargyl alcohols. Enantiomerically pure primary
α-substituted alkynylamines can be easily obtained in two
steps after removal of the ferrocenylmethyl protective group
and oxidative cleavage of the chiral appendage.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Results and Discussion
Introduction
The chiral, non-racemic α-substituted amino alcohols
4aϪc were prepared from (R)-phenylglycinol 1 using our
previously reported procedures (Scheme 1).
While ω-propargylic alcohols are common synthetic in-
termediates in natural product synthesis, their nitrogenated
counterparts have been less studied.[1] The lack of a simple
and straightforward preparation of ω-propargylic amines is
probably one of the reasons for this fact.
One of the simplest ways of synthesizing alcohols bearing
a terminal acetylenic function is the isomerization of in-
ternal triple bonds to terminal acetylenes with potassium 3-
aminopropylamide (KAPA).[2] Furthermore, the use of this
‘‘acetylene zipper’’ with an optically active secondary pro-
pargylic alcohol enables the rapid isomerization of the acet-
ylene unit away from the hydroxy center, without racemiz-
ation.[3] Although the usefulness of this reaction has been
proved both in several natural product total syntheses[4] and
for the efficient preparation of polydeuterated long chain
derivatives,[5] it has been mainly carried out only with dial-
kylacetylenes or alcohols.
We recently described a new access to enantiomerically
pure α-substituted propargylic amines via the nucleophilic
opening of chiral non-racemic oxazolidines with mixed or-
ganoaluminum reagents.[6] We report here that the isomeriz-
ation of chiral α-substituted propargylic amines to terminal
acetylenic compounds by KAPA also proceeds in an effici-
ent manner, without racemization.
Scheme 1. Reagents and conditions: (a) (i) FcCHO, NaBH4,
MeOH; (ii) RCHO, MgSO4, THF; (b) PentCCAl(iBu)2·Et3N,
AlMe3, toluene, 0 °C; (c) CH2Cl2, TFA 5%, Et3SiH, 0 °C to
room temp.
The clean preparation of KAPA was performed accord-
ing to the procedure described by Cossy and co-workers.[7]
The best results were obtained when this reagent was freshly
prepared and used immediately. The isomerization reaction
was carried out in 1,3-diaminopropane as solvent at 0 °C
(Scheme 2). The terminal acetylenic amino alcohols 5aϪc
were obtained in less than 30 min, in moderate to good
yields, without any detectable epimerization.[8]
[a]
´
´
`
Laboratoire de Chimie Therapeutique associe au CNRS et a
´
´
´
l’Universite Rene Descartes (UMR 8638), Faculte des Sciences
Pharmaceutiques et Biologiques,
4, av. de lЈObservatoire, 75270 Paris cedex 06, France
Fax: (internat.) ϩ33-1/4329-1403
E-mail: micouin@pharmacie.univ-paris5.fr
Bonin@pharmacie.univ-paris5.fr
2598
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0815Ϫ2598 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2598Ϫ2602

Isomerization of Chiral Non-Racemic α-Substituted Propargylic Amines
FULL PAPER
therefore to the protection of the base-sensitive stereogenic
center. In this study, the formation of the potassium alkox-
ide avoids epimerization and degradation by protecting the
base-sensitive protons α to the nitrogen atom, probably by
the formation of a five-membered chelate 10 with nitrogen
(Scheme 5).
Scheme 2
Final deprotection leading to the primary amines was
performed by oxidative cleavage of the amino alco-
hols.[6,9,10] Although these compounds proved to be more
stable than the previously described α-substituted propargy-
lamines, they are hygroscopic and were therefore protected
and stored as their benzamides 7aϪc (Scheme 3).
Scheme 5
Conclusion
We have described a new application of KAPA-induced
isomerization, leading in a simple and efficient way to op-
tically pure α-substituted amines bearing a terminal acetyl-
enic function. These compounds could be useful synthetic
intermediates for the elaboration of cyclic or acyclic enanti-
opure amino derivatives.
Scheme 3. Reagents and conditions: (a) (i) H5IO6, MeNH2; (ii)
HCl/MeOH, (iii) K2CO3; (b) PhCOCl, iPr2EtN, CH2Cl2
Experimental Section
All the attempts to isomerize N-protected compounds
3aϪc led to extensive degradation, probably because of the
base-sensitive ferrocenyl moiety.[11] The presence of the free
hydroxyl group proved to be essential for achieving comple-
tion of the reaction. Indeed, when submitted to KAPA iso-
merization, the O-protected compound 8 led to a complex
mixture of by-products, among which the rearranged deriv-
ative 9 could be separated and characterized in less than
20% yield (Scheme 4).[12]
General Procedures: NMR spectra were obtained at 300 MHz (1H
field value) on a Bruker AC 300. Routine infrared spectra (IR) were
recorded neat on a PerkinϪElmer 1600 spectrophotometer as thin
films, 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. Product puri-
fication was performed by flash chromatography on silica gel
(Merck, 230Ϫ400 mesh). Mass spectral data were recorded in the
chemical ionization mode (NH3) on a AEI MS-9 spectrometer.
High-resolution mass spectra were obtained on a Kratos MS
80RF spectrometer.
General Procedure for the Preparation of Propargylamines 3: The
preparation of compound 3b is representative. Freshly distilled trie-
thylamine (920 µL, 6.6 mmol) was slowly added to a DIBAL solu-
tion (1  in toluene, 6.3 mL, 6.3 mmol) under argon. The solution
was stirred for 15 min, cooled to 0 °C and heptyne (1.6 mL,
12.2 mmol) was added dropwise. The reaction mixture was allowed
to reach room temperature and stirred until hydrogen evolution
stopped. It was then cooled to 0 °C and a solution of oxazolidine
2b (1.17 g, 3.0 mmol) in toluene (10 mL) was slowly added over
30 min, followed by Me3Al solution (2  in heptane, 3.3 mL,
Scheme 4
In the case of the isomerization of propargyl alcohols, the
absence of racemization was explained by the quantitative
formation of the negatively charged alkoxide, leading to a
decrease of the acidity of the neighboring protons, and 6.6 mmol). The solution was stirred for another 30 min at 0 °C and
Eur. J. Org. Chem. 2002, 2598Ϫ2602 2599

J. Blanchet, M. Bonin, L. Micouin, H.-P. Husson
FULL PAPER
allowed to reach room temperature. The mixture was slowly poured
onto a cold solution of saturated Rochelle’s salts and, after vigor-
(m, 4 H), 1.38Ϫ1.46 (m, 2 H), 2.08 (td, J ϭ 6.9, 2.0 Hz, 2 H), 2.48
(br. s, 2 H), 3.52 (qt, J ϭ 6.6, 2.0 Hz, 1 H), 3.57 (dd, J ϭ 10.9,
ous stirring, the aqueous layer was extracted twice with diethyl 6.7 Hz, 1 H), 3.71 (dd, J ϭ 10.9, 4.7 Hz, 1 H), 3.98 (dd, J ϭ 6.7,
ether (25 mL each). The organic layer was dried over anhydrous
MgSO4, the solvent was evaporated and the crude residue was puri-
fied by column chromatography (silica gel: 9:1 cyclohexane/ethyl
acetate) to give 3b (1.21 g, 2.37 mmol, 83% from 1).
4.7 Hz, 1 H), 7.24Ϫ7.35 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 13.9, 18.5, 22.0, 22.4, 28.4, 30.9, 43.0, 61.4, 65.4, 82.2,
83.1, 127.2Ϫ128.4, 141.1 ppm. IR (neat): ν˜ ϭ 3330 cmϪ1, 2931,
2859, 1603. MS (CI, NH3): m/z ϭ 260 [MHϩ]. C17H25NO·1/2H2O
(258.4): calcd. C 76.08, H 9.71, N 5.22; found C 76.48, H 9.35,
N 5.03.
(1R,2R)-2-[Ferrocenylmethyl(1-methyloct-2-ynyl)amino]-2-phenyl-
ethanol (3a): Red-brown oil. [α]D ϭ ϩ8.8 (c ϭ 1.0, MeOH). 1H
NMR (300 MHz, CDCl3): δ ϭ 0.89 (t, J ϭ 7.1 Hz, 3 H), 1.12 (d,
J ϭ 6.9 Hz, 3 H), 1.30Ϫ1.43 (m, 4 H), 1.44Ϫ1.56 (m, 2 H), 2.19 [α]D ϭ Ϫ13 (c ϭ 1.15, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
(td, J ϭ 7.1, 1.9 Hz, 2 H), 2.71 (br. s, 1 H), 3.59 (d, J ϭ 14.1 Hz, 0.88 (t, J ϭ 7.0 Hz, 3 H), 0.97 (d, J ϭ 6.6 Hz, 3 H), 0.99 (d, J ϭ
1 H), 3.75 (d, J ϭ 14.1 Hz, 1 H), 3.78Ϫ3.89 (m, 3 H), 3.96Ϫ4.14 6.6 Hz, 3 H), 1.31 (m, 4 H), 1.42 (m, 2 H), 1.83 (m, 1 H), 2.11 (td,
(1R,2R)-2-(1-Isopropyloct-2-ynylamino)-2-phenylethanol (4b): Oil.
1
(m, 5 H), 4.09 (s, 5 H), 4.19 (d, J ϭ 11.6 Hz, 2 H), 7.35Ϫ7.24 (m,
J ϭ 6.6, 2.6 Hz, 2 H), 3.22 (m, 1 H), 3.53 (dd, J ϭ 10.7, 6.2 Hz, 1
5 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.0, 18.5, 20.9, 22.0, H), 3.72 (dd, J ϭ 10.7, 4.7 Hz, 1 H), 3.99 (dd, J ϭ 6.2, 4.7 Hz, 1
28.4, 30.9, 45.3, 46.5, 61.4, 64.0, 67.6Ϫ69.6, 81.2, 84.6, 86.3,
127.1Ϫ128.4, 139.7 ppm. IR (neat): ν˜ ϭ 3452 cmϪ1, 3090, 2928,
2859, 1601. MS (CI, NH3): m/z ϭ 458 [MHϩ]. C28H35FeNO
(457.4): C 73.52, H 7.71, N 3.06; found C 73.33, H 7.84, N 3.02.
H), 7.29 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 13.9,
17.4, 18.5, 19.6, 22.0, 28.4, 30.9, 32.2, 54.3, 61.8, 65.1, 79.7, 84.8,
127.3Ϫ128.5, 141.6 ppm. IR (neat): ν˜ ϭ 3349 cmϪ1, 2930, 2871,
2244. MS (CI, NH3): m/z ϭ 288 [MHϩ].
(1R,2R)-2-[Ferrocenylmethyl(1-isopropyloct-2-ynyl)amino]-2-phenyl-
ethanol (3b): Orange oil. [α]D ϭ ϩ 48 (c ϭ 1.2, CHCl3). H NMR
(1R,2R)-2-(1-Phenethyloct-2-ynylamino)-2-phenylethanol (4c): Oil.
[α]D ϭ Ϫ57.5 (c ϭ 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
1
(300 MHz, CDCl3): δ ϭ 0.64 (d, J ϭ 6.5 Hz, 3 H), 0.91 (m, 6 H), 0.89 (t, J ϭ 7.0 Hz, 3 H), 1.27Ϫ1.39 (m, 4 H), 1.39Ϫ1.48 (m, 2 H),
1.36 (m, 4 H), 1.48 (m, 2 H), 1.67 (m, 1 H), 2.19 (td, J ϭ 7.0, 1.78Ϫ2.02 (m, 2 H), 2.11 (td, J ϭ 6.9, 2.0 Hz, 2 H), 2.12 (m, 2 H),
1.7 Hz, 2 H), 2.50 (br. s., 1 H), 3.02 (dd, J ϭ 10.0, 1.4 Hz, 1 H), 2.67Ϫ2.88 (m, 2 H), 3.40 (ddt, J ϭ 7.7, 5.7, 2.0 Hz, 1 H), 3.54 (dd,
3.65 (d, J ϭ 14.0 Hz, 1 H), 3.72 (d, J ϭ 14.0 Hz, 1 H), 3.98 (m, 2 J ϭ 10.8, 6.6 Hz, 1 H), 3.70 (dd, J ϭ 10.8, 4.7 Hz, 1 H), 3.97 (dd,
H), 4.13 (m, 9 H), 7.22 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): J ϭ 6.6, 4.7 Hz, 1 H), 7.15Ϫ7.34 (m, 10 H) ppm. 13C NMR
δ ϭ 14.0, 18.6, 19.9, 20.5, 22.1, 28.6, 31.0, 32.2, 46.4, 59.0, 61.7,
64.9, 67.4, 70.3, 86.3, 127.0, 127.8, 128.8, 139.7 ppm. IR (neat): ν˜ ϭ
(75 MHz, CDCl3): δ ϭ 14.0, 18.6, 22.2, 28.4, 31.0, 32.1, 37.7, 47.8,
61.6, 65.3, 81.0, 84.6, 125.8Ϫ128.4, 141.4, 141.7 ppm. IR (neat):
3427 cmϪ1, 3085, 1598, 1490. MS (CI, NH3): m/z ϭ 486 [MHϩ]. ν˜ ϭ 3321 cmϪ1, 3026, 2930, 2859, 1603, 1495, 1454, 1330, 1107,
C30H39FeNO (485.5): calcd. C 74.22, H 8.10, N 2.89; found C
73.97, H 8.35, N 2.79.
1030. MS (CI, NH3): m/z ϭ 350 [MHϩ]. C24H31NO·1/4H2O
(348.5): calcd. C 80.89, H 8.76, N 4.10; found C 80.69, H 8.58,
N 3.77.
(1R,2R)-2-[Ferrocenylmethyl(1-phenethyloct-2-ynyl)amino]-2-
phenylethanol (3c): red-brown oil. [α]D ϭ ϩ9.4 (c ϭ 1.1, CHCl3).
General Procedure for the Isomerization of Propargylamines 4: The
1H NMR (300 MHz, CDCl3): δ ϭ 0.91 (t, J ϭ 7.0 Hz, 3 H), preparation of compound 5b is representative. 1,3-Diaminopropane
1.32Ϫ1.40 (m, 4 H), 1.44Ϫ1.53 (m, 2 H), 1.64Ϫ1.76 (m, 2 H), 2.21 (8 mL) was added to potassium hydride (328 mg, 8.2 mmol) at 0
(dt, J ϭ 6.9, 2.0 Hz, 2 H), 2.43Ϫ2.50 (m, 2 H), 2.59 (br. s, 1 H), °C under argon. The suspension was stirred at room temperature
3.53Ϫ3.61 (m, 1 H), 3.63 (d, J ϭ 14.0 Hz, 1 H), 3.77 (d, J ϭ for 30 min and cooled to 0 °C. Propargylamine 4b (470 mg,
14.0 Hz, 1 H), 3.82Ϫ3.92 (m, 1 H), 3.98Ϫ4.09 (m, 4 H), 4.07 (s, 5
1.64 mmol) in 1,3-diaminopropane (2 mL) was then added slowly,
H), 4.11Ϫ4.13 (m, 1 H), 4.20Ϫ4.22 (m, 1 H), 6.96Ϫ7.29 (m, 10 H) the reaction mixture was stirred for 30 min and treated with a sat-
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.0, 18.6, 22.1, 28.5, 31.0, urated aqueous ammonium chloride solution (10 mL). The aque-
32.7, 36.6, 45.9, 51.2, 61.5, 64.5, 67.8, 68.4, 69.6, 69.9, 80.1, 85.8,
ous phase was extracted twice with diethyl ether, the organic layers
86.3, 125.6, 127.2, 128.3Ϫ129.1, 139.6 141.7 ppm. IR (neat): ν˜ ϭ were washed with a saturated aqueous sodium chloride solution,
3446 cmϪ1, 3086, 3027, 2926, 2858, 1602, 1495, 1454, 1266, 1231, dried over anhydrous MgSO4 and the solvent was evaporated. The
1106, 1024. m/z ϭ 548 [MHϩ]. C35H41FeNO (547.6): C 76.77, H
crude residue was purified by column chromatography (silica gel,
7.55, N 2.56; found C 76.47, H 7.36, N 2.57.
9:1 cyclohexane/ethyl acetate) to give 5b (291 mg, 62%).
General Procedure for the Preparation of Propargylamines 4: The
preparation of compound 4b is representative. Triethylsilane [α]D ϭ Ϫ59 (c ϭ 1.15, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
(1R,2R)-2-(1-Methyloct-7-ynylamino)-2-phenylethanol (5a): Oil.
1
(1.2 mL, 7.5 mmol) and a solution of trifluoroacetic acid (1.2 mL,
15 mmol) in dichloromethane (15 mL) were added successively to
a cold (0 °C) solution of propargylamine 3b (1.45 g, 3.0 mmol) in
1.01 (d, J ϭ 6.2 Hz, 3 H), 1.29 (m, 6 H), 1.47 (m, 2 H), 1.89 (t,
J ϭ 2.6 Hz, 1 H), 2.12 (td, J ϭ 6.9, 2.6 Hz, 2 H), 2.24 (m, 1 H)
2.51 (br. s, 2 H) 3.48 (dd, J ϭ 10.6, 8.6 Hz, 1 H), 3.67 (dd, J ϭ
dry dichloromethane (10 mL). The reaction mixture was allowed 10.6, 4.5 Hz, 1 H), 3.87 (dd, J ϭ 8.6, 4.5 Hz, 1 H), 7.29 (m, 5 H)
to reach room temperature, stirred for 2 h and quenched with water
and a saturated aqueous solution of K2CO3. The aqueous layer
was extracted twice with dichloromethane, the organic layer was
dried over anhydrous MgSO4 and the solvent was evaporated. The
crude residue was purified by column chromatography (silica gel,
two successive elutions: 9:1 cyclohexane/ethyl acetate then 1:1
cyclohexane/ethyl acetate) to give 4b (723 mg, 84%).
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 18.2, 19.8, 25.3, 28.2, 28.6,
37.8, 49.3, 61.2, 66.7, 68.1, 84.5, 127.1, 127.3, 128.4, 141.1 ppm. IR
(neat): ν˜ ϭ 3300 cmϪ1, 2934, 2858. MS (CI, NH3): m/z ϭ 260
[MHϩ]. C17H25NO (259.4): calcd. C 78.72, H 9.71, N 5.40; found
C 78.53, H 9.87, N 5.36.
(1S,2R)-2-(1-Isopropyloct-7-ynylamino)-2-phenylethanol (5b): Oil.
1
[α]D ϭ Ϫ74 (c ϭ 1.05, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
(1R,2R)-2-(1-Methyloct-2-ynylamino)-2-phenylethanol (4a): Oil.
0.81 (d, J ϭ 6.7 Hz, 3 H), 0.88 (d, J ϭ 6.7 Hz, 3 H), 1.15 (m, 6 H),
[α]D ϭ Ϫ13.6 (c ϭ 1.25, MeOH). 1H NMR (300 MHz, CDCl3): 1.38 (m, 2 H), 1.85 (m, 1 H), 1.90 (t, J ϭ 2.6 Hz, 1 H), 2.06 (td,
δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H), 1.28 (d, J ϭ 6.6 Hz, 3 H), 1.28Ϫ1.37 J ϭ 6.9, 2.6 Hz, 2 H), 2.18 (br. s., 2 H), 2.25 (m, 1 H) 3.47 (dd,
2600
Eur. J. Org. Chem. 2002, 2598Ϫ2602

Isomerization of Chiral Non-Racemic α-Substituted Propargylic Amines
FULL PAPER
J ϭ 10.4, 8.8 Hz, 1 H), 3.64 (dd, J ϭ 10.4, 4.5 Hz, 1 H), 3.78 (dd, amine (407 µL, 2.9 mmol) were added and the reaction mixture was
J ϭ 8.8, 4.5 Hz, 1 H), 7.28 (m, 5 H) ppm. 13C NMR (75 MHz,
stirred overnight, and then washed with water. The organic layer
CDCl3): δ ϭ 16.8, 18.2, 18.7, 25.7, 28.2, 28.6, 29.2, 29.9, 59.2, 62.1, was dried over anhydrous MgSO4 and the solvents evaporated. The
66.4, 68.1, 84.5, 127.2, 127.4, 128.4, 141.5 ppm. IR (neat): ν˜ ϭ 3307
crude residue was purified by column chromatography (silica gel,
cmϪ1, 2935, 2863. MS (CI, NH3): m/z ϭ 288 [MHϩ]. C19H29NO cyclohexane/ethyl acetate 7:3) to give 7b (141 mg, 67% from 5b).
(287.4): calcd. C 79.39, H 10.17, N 4.87; found C 79.37, H 10.29,
N 4.79.
(R)-N-(1-Methyloct-7-ynyl)benzamide (7a): White solid. M.p. 57 °C.
[α]D ϭ Ϫ13 (c ϭ 1.05, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
1
1.21 (d, J ϭ 6.6 Hz, 3 H), 1.44 (m, 8 H), 1.92 (t, J ϭ 2.6 Hz, 1 H),
(1S,2R)-2-(1-Phenethyloct-7-ynylamino)-2-phenylethanol (5c): Oil.
[α]D ϭ Ϫ89 (c ϭ 1.15, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
1.30 (m, 8 H), 1.71 (m, 2 H), 1.92 (t, J ϭ 2.6 Hz, 1 H), 2.18 (td,
J ϭ 7.0, 2.6 Hz, 2 H), 2.24 (br. s., 2 H), 2.60 (m, 3 H) 3.49 (dd,
J ϭ 10.6, 8.7 Hz, 1 H), 3.64 (dd, J ϭ 10.6, 4.5 Hz, 1 H), 3.79 (dd,
J ϭ 8.7, 4.5 Hz, 1 H), 7.24 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 18.3, 24.1, 28.3, 28.7, 31.3, 34.4, 35.4, 53.6, 61.7, 66.5,
68.1, 84.5, 125.6, 128.5, 141.3, 142.5 ppm. IR (neat): ν˜ ϭ 3300
cmϪ1, 2932, 2857, 1602. MS (CI, NH3): m/z ϭ 350 [MHϩ].
C24H31NO (349.5): calcd. C 82.47, H 8.94, N 4.01; found C 82.31,
H 9.13, N 4.06.
1
2.17 (td, J ϭ 6.9, 2.6 Hz, 2 H), 4.17 (m, 1 H) 6.28 (d, J ϭ 8.0 Hz,
1 H), 7.39 (m, 3 H), 7.68 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 18.2, 20.8, 25.5, 28.2, 28.4, 36.7, 45.5, 68.1, 84.4,
126.7, 128.3, 131.1, 134.8, 166.7 ppm. IR (neat): ν˜ ϭ 3303 cmϪ1
,
2935, 2859, 1634. MS (CI, NH3): m/z ϭ 244 [MHϩ]. C16H21NO
(243.3): calcd. C 78.97, H 8.70, N 5.76; found C 78.33, H 8.66,
N 5.62.
(S)-N-(1-Isopropyloct-7-ynyl)benzamide (7b): White solid. M.p. 64
1
°C. [α]D ϭ Ϫ14 (c ϭ 0.95, CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 0.96 (d, J ϭ 6.8 Hz, 3 H), 0.98 (d, J ϭ 6.8 Hz, 3 H), 1.53 (m,
8 H), 1.85 (m, 1 H), 1.92 (t, J ϭ 2.6 Hz, 1 H), 2.17 (td, J ϭ 6.8,
2.6 Hz, 2 H), 4.03 (m, 1 H), 5.86 (d, J ϭ 9.3 Hz, 1 H), 7.46 (m, 3
H), 7.76 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 17.8,
18.3, 19.2, 25.8, 28.3, 28.7, 32.1, 32.3, 54.5, 68.1, 84.5, 126.7, 128.6,
131.2, 135.1, 167.3 ppm. IR (neat): ν˜ ϭ 3298 cmϪ1, 2937, 2857,
1631. MS (CI, NH3): m/z ϭ 272 [MHϩ]. C18H25NO (271.4): calcd.
C 79.66, H 9.28, N 5.16; found C 79.38, H 9.30, N 4.98.
General Procedure for the Oxidative Cleavage: The preparation of
compound 6b is representative. Aqueous methylamine (40% solu-
tion, 1 mL) and, slowly, an aqueous solution of periodic acid
(845 mg, 3.72 mmol in 7.5 mL H2O) were added to a cold (0 °C)
solution of propargylamine 5b (410 mg, 1.43 mmol) in methanol
(8.5 mL). The turbid solution was stirred at room temperature for
3 h and became limpid. The reaction mixture was extracted twice
with diethyl ether. After evaporation of the diethyl ether, the meth-
anolic solution was treated with 3  aqueous HCl, the methanol
was evaporated and the aqueous phase was washed twice with di-
ethyl ether. The aqueous phase was then 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 chromato-
graphy (silica gel, ethyl acetate) to give 6b (222 mg, 93%).
(S)-N-(1-Phenethyloct-7-ynyl)benzamide (7c): White solid. M.p. 91
°C. [α]D ϭ Ϫ63.0 (c ϭ 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
δ ϭ 1.48 (m, 8 H), 1.85 (m, 2 H), 1.91 (t, J ϭ 2.6 Hz, 1 H), 2.16
(td, J ϭ 6.8, 2.6 Hz, 2 H), 2.71 (t, J ϭ 7.9 Hz, 2 H), 4.22 (m, 1 H)
6.02 (d, J ϭ 9.1 Hz, 1 H), 7.17 (m, 3 H), 7.22 (m, 2 H), 7.43 (m, 3
H), 7.69 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 18.2,
25.4, 28.2, 28.6, 32.3, 35.2, 36.9, 49.7, 68.2, 84.5, 125.8, 131.3,
134.8, 141.8, 167.1 ppm. IR (neat): ν˜ ϭ 3302 cmϪ1, 2938, 2856,
2116, 1632. MS (CI, NH3): m/z ϭ 334 [MHϩ]. C23H27NO (333.5):
calcd. C 82.84, H 8.16, N 4.20; found C 82.76, H 8.35, N 4.05.
(R)-1-Methyloct-7-ynylamine (6a): Oil. [α]D ϭ Ϫ8 (c ϭ 1.05,
1
CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.06 (d, J ϭ 6.6 Hz, 3
H), 1.36 (m, 6 H), 1.53 (m, 2 H), 1.66 (br. s, 2 H), 1.93 (t, J ϭ 2-Methyl-4-pentyl-6-phenylpyridine (9): Oil. 1H NMR (300 MHz,
2.6 Hz, 1 H), 2.18 (td, J ϭ 6.6, 2.6 Hz, 2 H), 2.87 (m, 1 H) ppm.
CDCl3): δ ϭ 0.88 (t, J ϭ 6.8 Hz, 3 H), 1.31 (m, 4 H), 1.62 (m, 2
13C NMR (75 MHz, CDCl3): δ ϭ 18.3, 23.9, 25.8, 28.3, 28.7, 39.9, H), 2.57 (s, 3 H), 2.61 (t, J ϭ 7.6 Hz, 2 H), 6.92 (s, 1 H), 7.39 (m,
46.8, 68.1, 84.6 ppm. IR (neat): ν˜ ϭ 3306 cmϪ1, 2931, 2857, 2116.
MS (CI, NH3): m/z ϭ 140 [MHϩ].
3 H), 7.97 (d, J ϭ 7.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 14.0, 22.5, 24.5, 30.2, 31.4, 35.4, 118.3, 122.0, 127.1, 128.6,
152.9, 156.9, 158.0 ppm. IR (neat): ν˜ ϭ 3038 cmϪ1, 2927, 2856,
2232, 1728, 1604. MS (CI, NH3): m/z ϭ 240 [MHϩ].
(S)-1-Isopropyloct-7-ynylamine (6b): Oil. [α]D ϭ Ϫ18 (c ϭ 1.20,
1
CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 0.87 (d, J ϭ 6.8 Hz, 3
H), 0.92 (d, J ϭ 6.8 Hz, 3 H), 1.44 (m, 11 H), 1.92 (t, J ϭ 2.6 Hz,
1 H), 2.19 (td, J ϭ 6.6, 2.6 Hz, 2 H), 2.52 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 17.0, 18.3, 19.1, 26.0, 28.4, 28.8, 33.1, 34.4,
56.4, 68.1, 84.5 ppm. IR (neat): ν˜ ϭ 3308 cmϪ1, 2933, 2860, 2116.
MS (CI, NH3): m/z ϭ 168 [MHϩ].
Acknowledgments
One of us (J. B.) thanks MENRT for a grant.
(S)-1-Phenethyl-7-ynylamine (6c): Amorphous Ϫ [α]D ϭ ϩ5 (c ϭ
1.05, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.41 (m, 11 H),
1
[1]
For examples of intramolecular hydroaminations of aminoal-
kynes, see: Y. Li, T. J. Marks, J. Am. Chem. Soc. 1998, 120,
1757Ϫ1771 and references therein. For the reactivity of ter-
minal alkynes, see: K. Sonogashira, in Comprehensive Organic
Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon: New
York, 1991; vol. 3, pp. 521Ϫ548.
1.72 (m, 1 H), 1.95 (t, J ϭ 2.6 Hz, 1 H), 2.19 (td, J ϭ 7.0, 2.6 Hz,
2 H), 2.69 (m, 3 H), 7.17 (m, 3 H), 7.28 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 18.3, 25.5, 28.3, 28.7, 32.5, 37.9, 39.8, 50.7,
68.1, 84.5, 125.6, 128.3, 142.3 ppm. IR (neat): ν˜ ϭ 3303 cmϪ1
3026, 2931, 2856, 2116. MS (CI, NH3): m/z ϭ 230 [MHϩ].
,
[2] [2a]
C. A. Brown, A. Yamashita, J. Am. Chem. Soc. 1975, 97,
891Ϫ892. [2b] C. A. Brown, A. Yamashita, J. Chem. Soc., Chem.
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General Procedure for the Preparation of Benzamides 7: The pre-
paration of compound 7b is representative. Freshly purified prim-
ary amine 6b (120 mg, 0.72 mmol) was dissolved in dichlorome-
thane (10 mL). Benzoyl chloride (337 µL, 2.9 mmol) and triethyl-
[3] [3a]
M. M. Midland, R. L. Halterman, C. A. Brown, A. Ya-
[3b]
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M. M.
Eur. J. Org. Chem. 2002, 2598Ϫ2602
2601

J. Blanchet, M. Bonin, L. Micouin, H.-P. Husson
FULL PAPER
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[10]
[11]
C. H. Heathcock, J. C. Kath, R. B. Ruggeri, J. Org. Chem.
1995, 60, 1120Ϫ1130.
hedron 1990, 46, 1859Ϫ1870.
H5IO6-mediated oxidative cleavage of similar substrates is
known to occur without any racemization: see refs.[6,9]
KAPA has been described to be basic enough to cause D/H
exchange of [D6]benzene: C. A. Brown, J. Chem. Soc., Chem.
Commun. 1975, 222Ϫ223.
The exact mechanism of this unusual cycloaromatization pro-
cess is unclear. As pointed out by one referee, compound 9
could result from a possible deprotonation α to the OMe
group, leading to a 6-endo-dig cyclization and aromatization.
This explanation implies that several metalated species involved
in this process, bearing a CϪN bond in the β-position, undergo
cyclization or protonation faster than β-elimination.
Received January 7, 2002
[4b]
J. Cossy, D. Belotti, J.-P. Pete, Tetra-
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[5b]
S. R. Abrams, J. Org. Chem. 1984, 49, 3587Ϫ3590.
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[7]
[8]
[9]
J. Blanchet, M. Bonin, L. Micouin, H.-P. Husson, J. Org.
Chem. 2000, 65, 6423Ϫ6426.
J. Cossy, B. Gille, V. Bellosta, J. Org. Chem. 1998, 63,
3141Ϫ3146.
The diastereomeric purity of isomerized compounds was
checked by H and 13C NMR spectroscopy.
1
Z.-Y. Chang, R. M. Coates, J. Org. Chem. 1990, 55,
3475Ϫ3483.
[O02006]
2602
Eur. J. Org. Chem. 2002, 2598Ϫ2602