Diastereoselective carbozincation of propargylic amines

Article abstract of DOI:10.1016/S0040-4020(01)00069-2

The carbometalation of propargylic amines derived from methylbenzylamine takes place with good 1,3-diastereoselection in the presence of Lewis acids.

Full text of DOI:10.1016/S0040-4020(01)00069-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2477±2483
Diastereoselective carbozincation of propargylic amines
Hadi Rezaei,a Ilan Marekb and Jean F. Normanta,p
a
  Â
Laboratoire de Chimie des Organoelements, Universite P. et M. Curie, 4 Place Jussieu, Tour 44-45, Boite 183, 75252,
Paris Cedex 05, France
bDepartment of Chemistry and Institute of Catalysis, Science and Technology. Technion-Israel Institute of Technology, Technion City,
32000 Haifa, Israel
Dedicated to Henri B. Kagan on the occasion of his Tetrahedron Prize award
Received 25 May 2000; revised 7 July 2000; accepted 10 July 2000
AbstractÐThe carbometalation of propargylic amines derived from methylbenzylamine takes place with good 1,3-diastereoselection in the
presence of Lewis acids. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
occurred. We could check that zinc had a predominant
role in so far as the lithio analog of 4 did not rearrange to
the corresponding alkyne 5 (Scheme 2).
We have recently shown that the carbometalation by crotyl-
zinc bromide of a metalated propargylic alcohol, blocked by
a methoxyethoxymethyl (MEM) group, occurred with a
good diastereoselectivity1 (Scheme 1), whereas a tert-BuO
protection of the alcohol led to a d.r. of only 70/30.
Even more, the migration step from 4 takes place with
retention of con®guration,1 leading to a formal 1,4-induc-
tion in 5.1,3
In this paper we disclose our results in the nitrogen series,
and our efforts to obtain an appreciable diastereoselectivity
in the carbozincation of a propargylic amino derivative.
Since an array of enantiopure amines are commercially
available, such an approach should lead to nitrogen analogs
We also observed that when bismetallic reagent 2b is mono-
chlorinated into 4,2 the formed zinc carbenoid undergoes a
clean Fritsch±Buttenberg±Wiechell (FBW) rearrangement.1
Such rearrangement was so far restricted mostly to cases
where the migration of hydrogen, or of an aryl group
Scheme 1.
Scheme 2.
Keywords: diastereoselection; zinc derivatives.
Corresponding author. Tel.: 133-1-44-27-55-72; fax: 133-1-44-27-75-67; e-mail: normant@ccr.jussieu.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00069-2

2478
H. Rezaei et al. / Tetrahedron 57 (2001) 2477±2483
Scheme 3.
Scheme 4.
zincation process being reversible,7 it is then possible that a
homochiral tri- or tetramer be better matched than one of its
diastereomers.8 This point awaits further study.
Table 1. In¯uence of the ratio of crotylGrignard and zinc salts on the
diastereoselection
Entry
CrotylMgBr (equiv.)
ZnBr2 (equiv.)
% d.e. of 8
1
2
3
4
1.5
3
3
1
2
3
3
20
40
30
40
Our choice for methyl benzylamine was dictated by a
previous study of the crotyl zincation of an analogous
vinyl metal substrate9 where we postulated a p-stacking
between the zinc center and the aromatic residue. In order
to check this coordination, we performed the reaction of
Scheme 4 using (S)-(1)-methylcyclohexylamine, under
the same reaction conditions. In this case the dienyl amine
is indeed obtained in 69% yield but with a d.r. of 1/1.
2
of 3a in non-racemic form. However, until now, reports on
such diastereoselective carbometalation reactions are
scarce,4 in spite of their increasing interest. This is due to
the dif®culties associated with the enantio facial differen-
tiation of unactivated alkynes.5
The (S)-(2)-methyl-1-naphthylamine was then tried, in
order to improve the p-stacking, but the reaction required
a higher temperature, and the diastereoselectivity was not
better (d.r.ˆ87/13).
We chose the methylbenzylamino moiety as a cheap source,
available in (R) or (S) form. The starting derivative 6 is
prepared according to Scheme 3.
The hypothesis was to consider the transition state as a `late'
one with a C-metal bond of high sp2 character. Indeed,
computational methods6,10 in the case of the carbometa-
lation of a vinylmetal show the formation of a precomplex
A (Scheme 5) with a square planar Li±C±Zn±X arrange-
ment which is extremely stable as compared to the starting
organometallics (DH,40 kcal).
The carbometalation by crotylzinc bromide of lithiated 6
affords the dienylamine 8.
The diastereoselectivity depends highly on the ratio of
MgBr2 and ZnBr2 present in the reaction mixture. At the
outset of this study, we carried out the reaction of Scheme 4
with racemic N-methylbenzylamine, and the corresponding
in¯uence of added salts is quoted in Table 1.
If such was the case with the acetylenic reagent, nitrogen
chelation and p stacking bring the benzylic methyl in close
vicinity with the aromatic and propargylic hydrogens in B,
whereas in the other possible TS (C) this methyl is equa-
torial and stays apart from these hydrogens (Fig. 1). In order
to accentuate this difference of staggering between B and C
the N-Me group in 6 was replaced by a more bulky N-Et
group prepared according to Scheme 6
Use of an excess of zinc bromide is bene®cial, although
diastereoselectivity remains low. We were then much
surprised to observe that, by using non-racemic 1-methyl-
benzylamine, under the conditions of entry 4, the d.e. raised
to 76%! This result can be tentatively explained by con-
sidering that the bis metallic reagent 7 is in fact a di-, tri-
or tetra-mer (whose stabilities are much higher than that of
the monomer, as established computationally for saturated
gem biszinca compounds by Nakamura et al.6). The carbo-
When 9 was submitted to the crotyl zincation in the optimal
conditions described above, the amine 10 was formed with a
Scheme 5.

H. Rezaei et al. / Tetrahedron 57 (2001) 2477±2483
2479
d.r. of 90/10 (Scheme 7) thus only slightly better than the
one obtained from 6.
The geometry of 10 could be ascertained by an X-ray
pattern of its crystalline hydrochloride (Fig. 2).
However, if the ethylamino group is replaced by an iso-
propylamino group, the diastereoselection drops to 75/25.
In this case, it is possible that, due to the bulkiness of the
nitrogen substituent, p-stacking is no more ef®cient.
Figure 1. Face selection in a late transition step.
Scheme 6.
Scheme 7.
When the electron donating ability of the amine is lowered,
as is the case with amides, the diastereoselectivity also drops
signi®cantly: when the N-Me group in 6 is replaced by a
N-Boc, or a N-Tos group, the carbometallation takes place,
although at a higher temperature, but the d.r. is almost 1/1.
The allylic zinc reagent derived from titanated allyl ethyl
ether11 reacts in the same way, and leads to 11 which was
thus obtained with an appreciable d.e. (Scheme 8). Its
stereochemistry is attributed by analogy to 10.
Having at hand a reasonable 1,3-diastereoselection, we then
tried the FBW rearrangement.1
First 7 was submitted to monochlorination at 2208C and
hydrolyzed. NOE experiments showed that the unique
monochloroderivative thus obtained was indeed the E one,
12 (Scheme 9). However, by warming up the intermediate
chloro-zincio carbenoid we could detect no alkyne derived
Figure 2. X-Ray crystallographic structure of the hydrochloride of 10.
Scheme 8.

2480
H. Rezaei et al. / Tetrahedron 57 (2001) 2477±2483
Scheme 9.
from FBW rearrangement. We attribute this failure to a
stabilization of the carbenoid by electron donation from
the amine to the metal. Already in the oxygen series, the
chloro carbenoid derived from 2a, where oxygen to zinc
coordination is important, rearranged much slower than its
analog derived from 2b. This coordination of nitrogen,
although helpful for the diastereoselection of the addition
step, now turns to hamper dramatically the rearrangement.
We tried several ways to circumvent this dif®culty, namely
the addition of an excess of Lewis acids to coordinate
nitrogen:ZnBr2, ZrCl2Cp2, BF3±Et2O, BH3±THF, as well
as transmetalation of zinc to Al (AlCl3, AlMe2Cl), to Ti
(TiCl2(OiPr)2, to Cu (CuCN), or to Co (CoBr2),¼ were of
no help. We also tried the formation of a zincate complex
from the intermediate chloro-zincio carbenoid by addition
of tert-BuOK, PrSLi, or BuLi¼ but in no case did the
rearrangement take place.When the bismetallic 7b is trans-
formed to an iodozinciocarbenoid, (via NIS), the FBW
derived alkyne 13 is formed, however, but in only 20%
yield (Scheme 9).
200 mmol) in dichloromethane (100 mL) under nitrogen
were added triethylamine (6.3 mL, 1.1 equiv.) and, at
2308C,
dropwise,
ethyl
chloroformate
(21 mL,
1.1 equiv.), then the mixture was allowed to warm to rt.
When no starting material was left (TLC), the reaction
mixture was poured into a solution of 0.1 M HCl. The
aqueous layer was extracted with dichloromethane (2£
50 mL) and washed with a saturated solution of NaHCO3.
The organic layers were dried over MgSO4 and concentrated
1
in vacuo. Yield: 39.8 g (,100%), colorless oil. H NMR
(400 MHz, CDCl3) dˆ1.18 (t, 3H, Jˆ6.8 Hz), 1.41 (d,
3H, Jˆ6.9 Hz), 4.07 (m, 2H), 4.86 (m, 2H), 7.21±7.31
(m, 5H). 13C NMR (100 MHz, CDCl3) dˆ15.0, 22.9, 50.9,
61.2, 126.3, 127.7, 129.0, 143.8, 156.2. IR (neat): nˆ3340,
3010, 2990, 1700 cm21. [a]D ˆ170 (0.86, CHCl3).
20
2.1.2. (1)-(R)-N-methyl-1-phenylethylamine.13 A round
bottom ¯ask (500 mL) under nitrogen was charged with
lithium aluminium hydride (22.8 g, 3 equiv.) in dry THF
(150 mL). A solution of carbamate 15 (200 mmol) in THF
(50 mL) was added slowly at 08C and the mixture was
re¯uxed for 4 h. After cooling down at 08C, the reaction
was diluted with Et2O (100 mL) and quenched sequentially,
dropwise, under vigorous stirring with: H2O (12 mL),
NaOH 15% (22 mL) and H2O (25 mL). The resulting pre-
cipate was stirred for 30 min at rt, ®ltrated, washed with hot
AcOEt, and the ®ltrate was concentrated in vacuo. Yield:
In summary, the carbometalation of propargylamines derived
from methylbenzylamine can be realized with a good 1±3
diastereoselection in the presence of excess Lewis acid. The
zinc carbenoid, derived from monochlorination of the bis-
metallic thus obtained is however extremely stabilized,
and is not prone to the FBW rearrangement.
1
25.11 g (93%); colorless oil. H NMR (200 MHz, CDCl3)
dˆ1.32 (d, 3H, Jˆ6.6 Hz), 1.45 (s, 1H), 2.28 (s, 3H), 3.60
(q, 1H, Jˆ6.6 Hz), 7.18±7.34 (m, 5H). 13C NMR (50 MHz,
CDCl3) dˆ24.2, 34.8, 60.5, 126.8, 127.0, 128.5, 145.5.
2. Experimental
2.1. General
20
[a]D ˆ174.9 (1.02, CHCl3).
2.1.3. (R)-(1)-N-methyl-N-propargyl-1-phenylethylamine
6. A round bottom ¯ask (250 mL) under nitrogen was
charged with (R)-N-methyl-1-phenylethylamine (25.11 g,
186 mmol) and potassium carbonate (28.2 g, 1.1 equiv.) in
DMF (100 mL). Propargyl bromide (15.4 mL, 1.1 equiv.)
was added slowly at 08C and after 2 h stirring at rt,
100 mL water was added and the aqueous layer was
extracted with (cyclohexane/dichloromethane: 90/10)
(3£70 mL). The joined organic layers were washed with
brine (3£20 mL), dried over MgSO4, and concentrated in
vacuo. The product can be puri®ed by ¯ash chromatography
using cyclohexane/ether: 70/30 or by distillation under low
Experiments involving organometallics were carried out
under a positive pressure of dry nitrogen. Liquid nitrogen
was used as a cryoscopic ¯uid. A four-necked round bottom
¯ask was equipped with an internal thermometer, a septum
cap, a nitrogen inlet and a mechanic stirring, was used. Ether
and THF were distilled from sodium-benzophenone ketyl.
IR spectra were recorded on a PERKIN-ELMER 1420.
NMR spectra have been recorded on either a BRUKER
ARX 400 or a BRUKER AC 200, in CDCl3 as solvent.
Chemical shifts are reported in ppm relative to TMS. The
NMR shift corresponding to the major diastereoisomer is
indicated with an asterisk (p).
pressure. Yield: 31.2 g (97%); colorless oil. bp20 mmHg
1808C. 1H NMR (400 MHz, CDCl3) dˆ1.38 (d, 3H,
Jˆ6.6 Hz), 2.26 (t, 1H, Jˆ2.2 Hz), 2.33 (s, 3H), 3.24 (dd,
ˆ
2.1.1. (1)-(R)-Ethyl-N-(1-phenylethyl)-carbamate12 (15).
To a solution of R-(1)-1-phenyl-ethylamine (24.2 g,

H. Rezaei et al. / Tetrahedron 57 (2001) 2477±2483
2481
1H, Jˆ14.9, 2.2 Hz), 3.47 (dd, 1H, Jˆ14.9, 2.2 Hz), 3.53 (q,
1H, Jˆ6.6 Hz), 7.27±7.37 (m, 5H). 13C NMR (100 MHz,
CDCl3) dˆ21.6, 39.9, 44.0, 62.3, 73.5, 78.9, 127.2, 127.5,
amine. The procedure described for 6 was followed from
(S)-(1)-N-methyl-1-cyclohexylethylamine (1 g, 7.1 mmol).
Yield: 1.0 g (78%); colorless oil. 1H NMR (400 MHz,
CDCl3) dˆ0.93 (d, 3H, Jˆ6.6 Hz), 0.95±1.89 (m, 11H),
2.2 (s, 1H), 2.30 (s, 3H), 2.41 (qt, 1H), 3.30 (dd, 2H, Jˆ
14.4 Hz). 13C NMR (100 MHz, CDCl3) dˆ10.6, 26.5, 26.8,
29.0, 29.8, 31.0, 37.7, 40.9, 43.2, 61.6, 71.6, 80.9.
128.6, 144.8. IR (neat): nˆ3250, 3020, 1600, 700 cm21
.
20
[a]D ˆ1135 (2.4, CHCl3).
2.1.4. N-methyl-N-(3-methyl-2-methylene-pent-4-enyl)-
(R)-1-phenylethylamine 8. To a cooled (2308C) solution
of (R)-(1)-N-methyl-N-propargyl-1-phenylethylamine (346
mg, 2 mmol) in dry ether (10 mL) was added dropwise
n-butyllithium (1.6 M solution in hexane, 1.3 mL, 2 mmol,
1.05 equiv.). The reaction mixture was allowed to warm to
rt. After 10 min of further stirring a pale yellow solution was
obtained. To this solution were added at rt a solution of
crotylmagnesium bromide (1.2 M solution in ether,
3.3 mL, 2 equiv.) (the reaction mixture turned gray) and at
2258C a 1 M ethereal solution of zinc bromide (6 mL,
3 equiv.). The resulting mixture was stirred at 2258C for
6 h and a yellow paste was obtained. The reaction was then
hydrolyzed with an aqueous solution of NH3/NH4Cl: 1/2.
The mixture was then allowed to warm to rt and 0.5 mL of
ethanolamine is added. After stirring at rt for 30 min the
aqueous layer was extracted with ether (2£20 mL). The
combined organic layer was washed with a saturated
solution of NaHCO3, dried over MgSO4 and the solvents
were evaporated in vacuo. Flash chromatography on SiO2
(cyclohexane/AcOEt: 90/10) of the crude product yielded:
394 mg (86%) of a clear liquid. d.r.ˆ88/12. 1H NMR
(400 MHz, CDCl3) dˆ1.11/1.14p (d, 3H, Jˆ6.9 Hz), 1.37
(d, 3H, Jˆ6.8 Hz), 2.10 (s, 3H), 2.76 (d, 1H, Jˆ13.4 Hz),
3.05 (m, 2H), 3.06 (q, 1H, Jˆ6.9 Hz), 4.97(m, 4H), 5.57 (m,
1H), 7.24±7.38 (m, 5H). 13C NMR (100 MHz, CDCl3)
dˆ18.1, 19.0, 38.2, 40.6, 59.6, 63.5, 111.3, 113.3, 126.9,
127.9, 128.3, 143.1, 144.3, 151.3. IR (neat): nˆ3090, 2980,
1640, 1645, 1010, 700 cm21. Anal. Calcd for C16H23N
(229.12):C, 83.78%; H, 10.11%. found: C, 83.71%; H,
10.15%.
20
[a]D ˆ111 (2.9, CHCl3).
2.1.8. N-methyl-N-(3-methyl-2-methylene-pent-4-enyl)-
(S)-1-cyclohexylethylamine. The typical procedure
described for 10 was followed using (S)-(1)-N-methyl-N-
propargyl-1-cyclohexylethylamine (180 mg, 1 mmol). The
reaction mixture was hydrolyzed after stirring for 5 h at
2258C. Flash chromatography on SiO2 (cyclohexane/
AcOEt: 90/10) of the crude product yielded: 141 mg
1
(60%) of a clear liquid. d.r.ˆ50/50. H NMR (200 MHz,
CDCl3) dˆ0.82 (d, 3H, Jˆ6.7 Hz), 1.08 (d, 3H, Jˆ
6.9 Hz), 1.12±2.30 (m, 12 H), 1.96 and 2.00 (s, 3H),
2.85±3.00 (m, 3H), 4.80±5.03 (m, 4H), 5.75 (m, 1H). 13C
NMR (100 MHz, CDCl3) dˆ9.4/9.6, 18.9/19.1, 26.9, 27.2,
31.1, 31.4, 35.3, 36.2, 40.5, 40.6, 41.8/42.0, 59.4/60.1, 62.9/
63.5, 110.8, 113.3, 143.5, 151.9/152.0.
2.1.9. (1)-(R)-N-ethyl-1-phenylethylamine. To the pure
(R)-(1)-1-phenyl-ethylamine at 08C, under nitogen was
added dropwise acetaldehyde (11.2 mL, 2 equiv.). After
stirring for 4 h potassium hydroxyde (2 g) was added and
the solution was stirred for 5 h at rt (the solution became
red). Et2O (50 mL) was added and the organic layer was
separated from potassium hydoxide. The etheral solution
was dried on potassium hydroxide and concentrated in
vacuo to give a crude imine. The crude imine was dissolved
in methanol (60 mL) and at 1108C sodium borohydride
(6 g, 1.6 equiv.) was added slowly. The reaction was over
after 2 h stirring at rt as shown by TLC. The mixture was
hydrolyzed with an aqueous solution of NH3/NH4Cl: 1/2
(20 mL). Water (20 mL) was added and the aqueous layer
was extracted with AcOEt (3£30 mL). The combined
organic layers were dried over MgSO4 and concentrated in
vacuo to give the crude product witch can be puri®ed by
chromatography on SiO2 using saturated ammoniacal Et2O,
or by distillation under low pressure. Yield: 11.51 g (77%);
colorless oil. Bp15 mmHgˆ1408C. 1H NMR (400 MHz,
CDCl3) dˆ1.10 (t, 3H, Jˆ7.1 Hz), 1.38 (m, 4H), 2.52 (m,
2.1.5. N-methyl-N-(3-methyl-2-chloromethylene-pent-4-
enyl)-(R)-1-phenylethylamine 12. The typical procedure
described for 8 was followed without hydrolysis. At
2208C was added PhSO2Cl (3 equiv. 0.77 mL), and the
mixture was stirred 1 h at 2208C then warmed to rt. The
mixture was then hydrolyzed with a solution of NH3/NH4Cl:
1/2. After the usual work-up, ¯ash chromatography on SiO2
(cyclohexane/AcOEt: 95/5) of the crude product yielded:
432 mg (82%) of a clear liquid. d.r.ˆ88/12. 1H NMR
(400 MHz, CDCl3) dˆ1.14/1.17p (d, 3H, Jˆ7.1 Hz), 1.37
(d, 3H, Jˆ6.7 Hz), 2.09 (s, 3H), 2.87±2.93 (m, 2H), 3.60
(m, 2H), 4.97±5.09 (m, 2H), 5.88±5.92 (m, 1H), 6.14p/6.15
(s, 1H), 7.24±7.38 (m, 5H). 13C NMR (100 MHz, CDCl3)
dˆ16.9/17.1p, 17.9/18.0p, 38.1, 38.4, 56.4/56.6, 63.6, 114.1/
114.2p, 114.8/114.9p, 127.0, 127.7, 128.3, 143.8, 140.4,
142.3/142.4p.
20
2H), 3.79 (q, 1H, Jˆ6.6 Hz). [a]D ˆ141 (2.0, MeOH).
2.1.10.
(R)-(1)-N-ethyl-N-propargyl-1-phenyl-ethyl-
amine 9. The procedure described for 6 was followed
from (R)-(1)-N-ethyl-1-phenyl-ethylamine (11.51 g, 77.3
mmol). Yield: 12.88 g (90%); colorless oil. bp1 mmHgˆ808C.
1H NMR (400 MHz, CDCl3) dˆ1.03 (t, 3H, H4, Jˆ7.2 Hz),
1.38 (d, 3H, H2, Jˆ6.6 Hz), 2.20 (t, 1H, H7, Jˆ2.2 Hz), 2.56
0
0
(m, 2H, H3 and H3 ), 3.39 and 3.63 (2 dd, 2H, H5 and H5 ,
Jˆ17.7 and 2.2 Hz), 3.72 (q, 1H, H1), 7.27±7.39 (m, 5H,
Har). 13C NMR (50 MHz, CDCl3) dˆ12.9 (C4), 21.2 (C2),
38.2 (C5), 44.5 (C3), 61.1 (C1), 72.5 (C7), 79.2 (C6), 126.9±
2.1.6. (S)-(1)-N-methyl-1-cyclohexylethylamine. The
typical procedure described for (R)-N-methyl-1-phenylethyl-
amine was followed using (S)-(1)-1-cyclohexylethylamine
(5 g, 39.3 mmol). Yield: 3.54 g (64%), colorless oil. 1H NMR
(100 MHz, CDCl3) dˆ0.95 (d, 3H, Jˆ7.3 Hz), 0.95±1.73
20
127.4±128.4±145.4 (Car). [a]D ˆ1102 (2.4, CHCl3).
2.1.11. N-ethyl-N-(3-methyl-2-methylene-pent-4-enyl)-
(R)-1-phenylethylamine 10. The typical procedure
described for 8 was followed using (R)-(1)-N-ethyl-N-
propargyl-1-phenyl-ethylamine (374 mg, 2 mmol). The
20
(m, 11H), 2.35 (m, 4H). [a]D ˆ19 (6.3, CHCl3).
2.1.7. (S)-(1)-N-methyl-N-propargyl-1-cyclohexylethyl-

2482
H. Rezaei et al. / Tetrahedron 57 (2001) 2477±2483
reaction mixture was hydrolyzed after stirring 8 h at 2258C.
Flash chromatography on SiO2 (cyclohexane/AcOEt: 95/5)
of the crude product yielded: 427 mg (89%) of a clear
1.8 Hz), 3.58 (dd, 1H), 3.72 (q, 1H, Jˆ6.7 Hz), 5.08 (dt,
1H, Jˆ10.1, 1.5 Hz), 5.33 (dt, 1H, Jˆ16.9, 1.5 Hz), 5.86
(m, 1H), 7.27±7.38 (m, 5H). 13C NMR (100 MHz, CDCl3)
dˆ13.2, 21.6, 22.1, 30.1, 38.9, 44.6, 61.4, 77.4, 86.8, 114.2,
127.2,127.8, 128.7, 145.9, 140.2.
1
liquid. d.r.ˆ90/10. H NMR (400 MHz, CDCl3) dˆ0.99
(t, 3H, H4, Jˆ7.1 Hz), 1.10 (d, 3H, H11, Jˆ7.0 Hz), 1.35
(d, 3H, H2, Jˆ6.8 Hz), 2.38±2.59 (m, 2H, H3), 2.92±3.06
(m, 3H, H5 and H8), 3.91 (q, 1H, H1), 4.88±5.07 (m, 4H, H7
and H10), 5.73±5.82 (m, 1H, H9), 7.24±7.41 (m, 5H, Har).
13C NMR (100 MHz, CDCl3) dˆ12.4 (C4), 15.1/16.0p (C11),
18.8 (C2), 40.3 (C8), 43.1 (C3), 54.5 (C5), 57.6/57.9p (C1),
110.9 and 113.1 (C7 and C10), 126.6±128.0±128.1 (Car),
143.1 (C9), 144.4 (Car), 152.1 (C6). IR (neat): nˆ3090,
2.1.15. (S)-N-isopropyl-1-phenylethylamine. To a solu-
tion of S-(2)-1-phenyl-ethylamine (5 g, 41.3 mmol) in
methanol (40 mL), was added acetone (7.6 mL 2.5 equiv.)
and platinium (IV) oxide (120 mg). The mixture was stirred
under atmospheric pressure of hydrogen for 11 h. After a
®ltration on celite with Et2O, the solvents were evaporated
to give a pure product. Yield: 6.7 g (,100%); colorless oil.
1H NMR (400 MHz, CDCl3) dˆ0.98 and 1.01 (2d, 6H,
Jˆ6.3 Hz), 1.32 (d, 3H, Jˆ6.6 Hz), 2.62 (hept, 1H), 3.87
(q, 1H), 7.17±7.28 (m, 5H). 13C NMR (100 MHz, CDCl3)
dˆ22.4, 24.2, 25.1, 45.6, 55.2, 126.5, 126.8, 128.5, 146.3.
3020, 2990, 2850, 1680, 1595, 700 cm21
.
2.1.12. Crystal structure of the hydrochloride of 10.
Crystal data: C17H26N1Cl1, AcOEt, Mwˆ279.86, orthor-
hombic, space group P212121, Zˆ4, aˆ7.192 (3), cˆ
Ê
Ê 3
13.376 (6), cˆ17.933 (9) A, Vˆ1725 (1) A , dcalc
ˆ
1.08 g cm23, l (MoKa)ˆ0.71069 A, mˆ2.09 cm21. 1973
collected re¯exions, 1950 unique of which 994 were consid-
ered as observed having I$1.7 s(I). Hydrogen atoms ®tted
2.1.16. (S)-(2)-N-isopropyl-N-propargyl-1-phenylethyl-
amine. The procedure described for 9 was followed from
(S)-(2)-N-isopropyl-1-phenyl-ethylamine (6.7 g, 41.3 mmol).
Yield: 7.1 g (86%); colorless oil. Bp10 mmHgˆ1258C. 1H
NMR (400 MHz, CDCl3) dˆ1.08 (m, 6H), 1.42 (d, 3H,
Jˆ6.6 Hz), 2.19 (t, 1H, Jˆ2.4 Hz), 3.09 (m, 1H), 3.32
(dd, 1H, Jˆ18.2 Hz), 3.48 (dd, 1H), 4.07 (q, 1H), 7.24±
7.40 (m, 5H). 13C NMR (100 MHz, CDCl3) dˆ18.8, 20.7,
21.4, 34.0, 49.0, 58.3, 72.1, 83.3, 127.0, 127.5, 128.5, 146.1.
Ê
the theorical positions. A molecule of AcOEt was not
observed. Re®nement minimizing the function iFou2uFc/
P
P
Fo, Rˆ0.067 and Rwˆ0.073, goodness of ®tˆ0.82. The
residual electron density in the ®nal difference map was
Ê 23
located between 20.31 and 0.38 e A
.
20
2.1.13. N-ethyl-N-(3-ethoxy-2-methylene-pent-4-enyl)-
(R)-1-phenylethylamine 11. According to Sato et al.11 to
a cooled (2508C) solution of diethylacrolein acetal
(520 mg, 4 mmol) and titanium tetraisopropoxide (1.2 ml,
4.1 mmol) in dry ether (10 mL) was added a 1.4 M ethereal
solution of isopropylmagnesium chloride (4.1 mL,
8.2 mmol). After 2 h of further stirring at 2408C, a red±
black solution was obtained. At 2408C a solution of
lithiated 6 (2 mmol), prepared as for8, was added followed
by an ethereal solution of zinc bromide (1 M, 6 mL,
6 mmol). After stirring for 8 h at 2108C, the resulting
mixture was hydrolyzed with a solution of NH3/NH4Cl: 1/
2. After the usual work-up described for 8, Flash chroma-
tography on SiO2 (cyclohexane/AcOEt: 95/5) of the crude
product yielded: 302 mg (58%) of a clear liquid. d.r.ˆ93/7.
1H NMR (400 MHz, CDCl3) dˆ0.99 (t, 3H, Jˆ7.2 Hz),
1.16 (t, 3H, Jˆ7.2 Hz), 1.33 (d, 3H, Jˆ6.8 Hz), 2.39 and
2.58 (2m, 3H), 2.98 (s, 2H), 3.33±3.45 (m, 2H), 3.88 (q,
1H), 4.27 (d, 1H), 5.10±5.21 (m, 4H), 5.74 (m, 1H), 7.20±
7.37 (m, 5H). 13C NMR (100 MHz, CDCl3) dˆ12.6p/13.0,
15.8, 16.7, 43.4, 52.3, 57.6/58.2p, 64.3, 81.6, 113.2/113.5p,
116.3/116.5p, 126.9, 128.2, 128.3, 144.4, 138.3, 146.9/
147.7p.
[a]D ˆ2 77 (2.4, CHCl3).
2.1.17. N-isopropyl-N-(3-methyl-2-methylene-pent-4-enyl)-
(S)-1-phenylethylamine. The typical procedure described
for 10 was followed using (S)-(2)-N-isopropyl-N-pro-
pargyl-1-phenylethylamine (402 mg, 2 mmol). The reaction
mixture was hydrolyzed after stirring 6 h at 2258C. Flash
chromatography on SiO2 (cyclohexane/AcOEt: 95/5) of the
crude product yielded: 293 mg (57%) of a clear liquid.
1
d.r.ˆ75/25. H NMR (400 MHz, CDCl3) dˆ0.86p/0.89 (d,
3H, Jˆ6.6 Hz), 0.99 (d, 3H, Jˆ6.6 Hz), 1.05p and 1.13 (d,
3H, Jˆ7.0 Hz), 1.35 (d, 3H, Jˆ6.8 Hz), 2.96±3.18 (m, 4H),
3.94 (q, 1H), 4.91±5.24 (m, 4H), 5.83 (m, 1H), 7.23±7.43
(m, 5H). 13C NMR (100 MHz, CDCl3) dˆ18.6, 18.9, 19.0,
20.7, 40.8, 47.6/47.8p, 49.5, 57.2/57.6p, 110.5, 113.1, 126.4,
127.7, 128.1, 145.9, 143.2, 153.3.
2.1.18. (S)-N-methyl-1-naphth-1-yl-ethylamine. The
typical procedure described for 6 was followed using (S)-
(2)-1-naphth-1-yl-ethylamine (5 g, 29.2 mmol). Yield:
1
3.4 g (63%); colorless oil. H NMR (400 MHz, CDCl3)
dˆ1.54 (d, 3H, Jˆ6.6 Hz), 1.88 (s, 1H), 2.45 (s, 3H), 4.55
(q, 1H), 7.49±8.21 (m, 7H).
2.1.14. N-ethyl-N-(4-methyl-hex-5-en-2-ynyl)-(R)-1-phenyl-
ethylamine. The typical procedure of carbometalation
described for 9 was followed using (R)-(1)-N-ethyl-N-
propargyl-1-phenylethylamine (375 mg, 2 mmol). After
8 h stirring at 2258C, pure NIS was added at 2258C. The
mixture was then warm to rt, stirred overnight and hydro-
lyzed with a solution of NH3/NH4Cl: 1/2. After the usual
work-up, ¯ash chromatography on SiO2 (cyclohexane/
AcOEt: 90/10) offered: 97 mg (20%) of a pure product as
2.1.19. (S)-(2)-N-methyl-N-propargyl-naphth-1-yl-ethyl-
amine. The procedure described for 9 was followed from
(S)-N-methyl-1-naphth-1-yl-ethylamine (1.53 g, 8.27 mmol).
1
Yield: 1.48 g (81%); colorless oil. H NMR (400 MHz,
CDCl3) dˆ1.51 (d, 3H, Jˆ6.6 Hz), 2.29 (t, 1H, Jˆ
2.4 Hz), 2.40 (s, 3H), 3.41 (dd, 1H, Jˆ17.2 Hz), 3.66 (dd,
1H, Jˆ17.2 Hz), 4.37 (q, 1H), 7.45±8.48 (m, 7H). 13C NMR
(100 MHz, CDCl3) dˆ20.5, 40.1, 44.1, 59.5, 73.4, 79.2,
124.9, 125.5, 125.7, 128.8, 127.6, 128.9, 131.6, 134.2,
1
20
a clear liquid. H NMR (400 MHz, CDCl3) dˆ1.03 (t, 3H,
140.8. [a]D ˆ2110 (4.0, CHCl3).
Jˆ7.1 Hz), 1.31 (d, 3H, Jˆ7.0 Hz), 1.38 (d, 3H, Jˆ6.6 Hz),
2.50±2.61 (m, 2H), 3.22 (m, 1H), 3.40 (dd, 1H, Jˆ17.4,
2.1.20. N-methyl-N-(3-methyl-2-methylene-pent-4-enyl)-

H. Rezaei et al. / Tetrahedron 57 (2001) 2477±2483
2483
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp 271±337.
(S)-naphth-1-yl-ethylamineThe
typical
procedure
described for 10 was followed using (S)-(2)-N-methyl-N-
propargyl-naphth-1-yl-ethylamine (223 mg, 1 mmol). The
reaction mixture was hydrolyzed after stirring 5 h at
2158C. Flash chromatography on SiO2 (cyclohexane/
AcOEt: 90/10) of the crude product yielded: 165 mg
5. Funk, R. L.; Bolton, G. L.; Brummond, K. M.; Ellestad, K. E.;
Stallman, J. B. J. Am. Chem. Soc. 1993, 115, 7023±7024.
6. Hirai, A.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc.
1999, 121, 8665±8666.
1
7. (a) Bernardou, F.; Miginiac, L. Tetrahedron Lett. 1976, 3083±
3086. (b) Marek, I.; LefrancËois, J. M.; Normant, J. F. J. Org.
Chem. 1994, 59, 4154±4161.
(60%) of a clear liquid. d.r.ˆ82/18. H NMR (400 MHz,
CDCl3) dˆ0.95p/1.01 (d, 3H, Jˆ6.9 Hz), 1.50 (d, 3H, Jˆ
6.7 Hz), 2.19p/2.20 (s, 3H, H3), 2.90 (m, 2H, H4 and H7),
0
8. For such involvement of (mis)matched dimers in asymmetric
catalysis, see: Noyori, R. In Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994; Chapter 5.
3.05 (d, 1H, H4 , Jˆ13.3 Hz), 4.33 (q, 1H, H1), 4.85±5.01
(m, 4H), 5.65±574 (m, 1H), 7.43±8.45 (m, 7H). 13C NMR
(100 MHz, CDCl3) dˆ16.3, 18.7, 38.2p/38.71, 38.7, 58.9/
59.6p, 111.1, 113.0, 124.1, 124.8, 125.3, 125.4, 127.5, 128.7,
132.0, 134.2, 140.8, 143.0, 151.4.
9. (a) Brasseur, D.; Rezaei, H.; Fuxa, A.; Alexakis, A.; Mange-
ney, P.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1998, 39,
4821±4824. (b) Brasseur, D.; Marek, I.; Normant, J. F. C.R.
Â
Acad. Sci. Paris, t.1, Serie IIc 1998, 621±625.
10. Marek, I.; Schreiner, P.; Normant, J. F. Org. Lett. 1999, 1,
929±931.
References
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12. White, E. H.; Field, K. W.; Hendrickson, W. H.; Dzadzic, P.;
Roswell, D. F.; Paik, S.; Mullen, P. W. J. Am. Chem. Soc.
1992, 114, 8023±8031.
2. Creton, I.; Marek, I.; Normant, J.-F. Synthesis 1996, 1499±
1508.
13. Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.;
Hernandez, A. E.; Vickers, D.; Fluckiger, E.; Patterson,
R. G.; Reddy, K. V. Tetrahedron 1993, 49, 965±986.
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2000, 2, 419±421.
4. Marek, I.; Normant, J. F. In Metal-Catalyzed Cross-Coupling