Synthesis of enantiomerically enriched propargylamines by copper-catalyzed addition of alkynes to enamines

Article abstract of DOI:10.1002/chem.200204691

The first copper(I) bromide/Quinap-catalyzed synthesis of enantiomerically enriched propargylamines by addition of alkynes to enamines is reported. Various functionalized terminal alkynes add smoothly to N-protected enamines to afford the corresponding am

Full text of DOI:10.1002/chem.200204691

FULL PAPER
Synthesis of Enantiomerically Enriched Propargylamines by
Copper-Catalyzed Addition of Alkynes to Enamines
Christopher Koradin, Nina Gommermann, Kurt Polborn, and Paul Knochel*[a]
Abstract: The first copper(i) bromide/
Quinap-catalyzed synthesis of enantio-
merically enriched propargylamines by
addition of alkynes to enamines is re-
ported. Various functionalized terminal
alkynes add smoothly to N-protected
enamines to afford the corresponding
amines in good to high yields and
moderate to good enantiomeric excess-
es. The influence of the metal salt,the
ligand,and the protecting group on the
conversion,the reaction rate,and the
stereoselectivity of the reaction are
investigated. The scope of the reaction
and further transformations of the re-
sulting propargylamines (deprotection,
Pauson Khand reaction) are also de-
scribed.
Keywords: alkynes
asymmetric catalysis
activation ¥ copper catalysis
¥
amines
¥
À
¥
C H
Introduction
Results and Discussion
One of the most challenging tasks in organic synthesis is the
efficient preparation of complex molecules starting from
easily available raw materials. Therefore,the development of
In our previous investigations we reported that only copper
salts satisfactorily catalyze the addition of alkynes 2 to
enamines 1 to afford propargylamines of type 3 (Scheme 1).[11]
À
new C C bond coupling reactions which proceed with good
atom economy is of great importance.[1] The selective elab-
oration of stereogenic centers and the chemoselective intro-
duction of functional groups are especially of fundamental
importance.[2] Amines and their derivatives are very wide-
spread functional groups which are found in various natural
products,pharmaceuticals,and fine biologically important
chemicals.[3] Propargylamines are both biologically relevant
and useful synthetic intermediates for the preparation of
polyfunctional amino derivatives.[4] Several diastereoselective
and enantioselective syntheses of propargylamines have been
Scheme 1. Synthesis of propargylamines of type 3 by the addition of
alkynes 1 to enamines 2.
reported,[5] but a metal-catalyzed enantioselective prepara-
The use of other transition metal salts,for example,
AgOAc,AuI,AuBr 3,Sc(OTf) 3,Yb(OTf) 3,La(OTf) 3,Ru-
[7]
tion has not yet been described.[6] Recently,Li
and our
group[8] independently reported an enantioselective copper-
catalyzed addition of alkynes[9] to imines and enamines,
respectively.[10] In this paper we disclose detailed studies on
the different parameters influencing the outcome of this
asymmetric reaction. Furthermore,we demonstrate its broad
scope and synthetic utility.
(acac)3,Rh(acac) ,Rh(acac)cod,and Zn(OTf) 2,gave in all
3
cases no or inferior conversions to the desired propargyl-
amines. Among all the copper salts tested,copper( i) and
copper(ii) bromide (max. 5 mol%) proved to be the most
active catalysts for this transformation. The solvent of choice
is toluene and its use resulted in higher conversions to the
desired products compared with Et2O,THF, N-methylpyrro-
lidinone (NMP),or others. We chose enamines with readily
removable protecting groups as substrates. The substituents
attached to the enamine nitrogen atom play a crucial role in
the success of the reaction (Table 1). Only bisalkylated
enamines (R3, R4 ˆ alkyl) yielded the propargylamines 3,
whereas the replacement of one alkyl group by a trimethyl-
[a] Prof. Dr. P. Knochel,Dr. C. Koradin,
Dipl.-Chem. N. Gommermann,Dr. K. Polborn
Department Chemie,Ludwig-Maximilians-Universit‰t
Butenandtstrasse 5 13,Haus F,81377 M¸nchen (Germany)
Fax : (‡49)89-2180-7680
E-mail: paul.knochel@cup.uni-muenchen.de
Chem. Eur. J. 2003, 9,2797 2811
DOI: 10.1002/chem.200204691
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P. Knochel et al.
FULL PAPER
Table 1. Propargylamines of type 3 obtained by the copper(i) bromide-catalyzed addition of alkynes 2 to enamines 1.
Entry
1
a
2
a
R5
3
a
treaction [h]
Yield [%][a]
1
Ph
16
98
2
3
4
b
b
b
a
b
c
Ph
nHex
H
b
c
d
16
4
4
82
75
69
5
6
7
c
a
a
a
Ph
Ph
Ph
e
f
21
73
85
78
d
e
9
g
44
8
f
a
Ph
h
20
91
9
10
11
12
13
14
15
16
g
g
g
g
g
g
g
g
a
d
e
f
g
h
i
Ph
i
j
27
20
5
67
3
24
16
4
75
77
82[b]
78
84
93
70
66
1-cyclohexenyl
(CH2)3CN
(CH2)3Cl
CH2OMe
CH2OTBDPS
TMS
k
l
m
n
o
p
j
CH(OEt)2
2798
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Chem. Eur. J. 2003, 9,2797 2811

Enantiomerically Enriched Propargylamines
2797 2811
Table 1 (continued).
Entry
17
1
2
a
R5
Ph
3
treaction [h]
Yield [%][a]
99
h
q
5
18
19
i
i
a
k
Ph
nBu
r
s
18
24
91
89
20
21
22
j
j
j
a
l
m
Ph
TIPS
(CH3)2OTMS
t
u
v
24
7
20
99
88[b]
85[b]
23
24
k
k
a
n
Ph
pBrPh
w
x
27
18
94[b]
90[b]
25
26
l
b
b
nHex
nHex
y
z
24
15
80[b]
m
82
27
n
a
Ph
aa
24
75[b]
28
29
o
p
a
Ph
ab
ac
3
86[c]
b
nHex
18
79[c]
[a] Isolated yield of analytically pure product. [b] The reaction was performed at 608C. [c] The reaction was performed at 808C.
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P. Knochel et al.
FULL PAPER
silyl,acetyl,or tosyl group (R,R ˆ H,R 1 ˆ Me or
2
O
3
4
Pr,R ˆ Bn,R ˆ TMS,[12] C(O)CH3,[13] or Ts[14]
)
O
O
PPh2
PPh2
PPh2
PPh2
NH HN
leads to no formation of 3.
By increasing the steric hindrance of the pro-
Ph2P
PPh2
Tf NH HN Tf
tecting groups,the rate of the addition decreased
((All)2 > (All)Bn > Bn2). Furthermore,the sub-
(1R, 2R)- Trost ligand
(1R)-trans-(CF3SO2NH)2C6H1
(R)-Binap
(R)-Binap(O)
stituents at the enamine double bond had a strong
influence on the reaction rate. Disubstituted en-
amines were usually more reactive than trisubsti-
N
O
O
N
OMe
PPh2
PPh2
N
N
tuted ones (compare entries 9 and 20 or 23) and
b,b'-trisubstituted enamines needed less activation
(R)-Quinap (5)
(R)-Mop
(R)-Pybox
than a,a'-trisubstituted enamines (compare en-
tries 26 and 27). Also,electronic effects influence
Scheme 3. Ligands for the chiral addition reaction.
the outcome of the reaction. For example,the
conjugated,disubstituted enamine 1p is less reactive than the
unconjugated trisubstituted enamine 1m. As can be seen from
Table 1,various functionalized alkynes undergo the addition.
The reaction tolerates the presence of a double bond,
different protected alcohols,a cyano,a chloride,silyl groups,
and an acetal moiety. In the case of the cyclic enamine 1o,
which is in equilibrium with a dimeric structure,[15] the
reaction was carried out at 808C (3 h; entry 28 of Table 1).
Remarkably,acetylene itself ( 2c) reacted with good selectiv-
ity (>9:1) to give the monopropargylamine 3d in good yield
(entry 4,69%). For a second addition higher temperatures
were required (Scheme 2). We were able to combine a whole
Generally,an added chiral ligand decreased the reactivity
enormously. In most cases there was no detectable conversion
to the amine 3r at room temperature. Only (R)-Quinap (5),[16]
using one equivalent relative to copper(i) bromide,was
suitable to induce good enantioselectivity with very good
conversion. Interestingly,with two equivalents of the catalyst
5,conversion to the propargylamine 3r was first achieved at
608C but without any enantioselectivity. We have investigated
the influence of the copper salt on the selectivity and the rate
of the reaction with the same enamine 1i (Table 3).
The counterion had a dramatic effect on both parameters.
The most reactive copper source (CuBr) is also the most
selective one. Except for CuCl,
all other tested copper salts gave
poorer results. We have exam-
ined the effect of the protecting
groups on the enamine nitrogen
atom by using phenylacetylene
(2a) as the alkyne under these
optimized conditions (Table 4).
As in the case of the racemic
reaction,increasing the steric
1) 2i
CuBr (5 mol%)
toluene, rt
NAll2
H
1i
CuBr (5 mol%)
NBn2
Pr
Pr
Pr
toluene, 80 °C
2) TBAF
THF, rt
NBn2
NBn2
1g
3ad
4: 74 % overall yield
d.r. = 1:1
Scheme 2. Synthesis of 1,4-diamines.
range of different enamines 1 leading to 1,4-diamines like 4 as
1:1 mixtures of diastereoisomers in good to very good yields.
After these studies,we turned our attention to the
enantioselective addition reaction. Firstly,we screened vari-
ous chiral ligands,for example,diphosphanes,aminophos-
phanes,and diamines (Table 2,Scheme 3).
bulk of the protecting group leads to a drop of reactivity. In
some cases partial decomposition of the enamines 1c e was
observed during the reaction,and the corresponding prop-
argylamines 3c e could only be isolated in low yields.
Initially,the enantioselectivity (% ee) increased with the size
of the protecting group. For example,the ee increased from
diallyl (77%ee,entry 1) to allyl benzyl (82% ee,entry 2) to
Table 2. Ligand screening for the chiral addition reaction.
CuBr (5 mol%)
L* (5.5 mol%)
Ph
Table 3. Influence of the copper salt on the enantioselectivity and the
reaction rate.
NBn2
Ph
+
toluene, rt
NBn2
3r
Cu salt
Conversion [%][a]
t [h]
ee [%][b]
1i
2a
CuCl
CuBr
CuI
CuOTf ¥ 0.5C6H6
CuOTf2
CuTc[c]
CuOAc2
CuCN
90
100
75
70
40
50
40
0
28
18
81
85
62
16
28
40
12
Ligand
(R)-Binap
(R)-Binap(O)
(R)-Binap(O)[c]
(1R,2R)-Trost ligand
(R)-Quinap (5)
(1R)-trans-(CF3SO2NH)2C6H10
(R)-Pybox
Conversion [%][a]
ee [%][b]
168
168
120
144
120
120
240
0
0
40
0
100
100
55
87
0
85
0
32
0
Cu(MeCN)4PF6
3
(R)-MOP
[a] Conversions determined by GC analysis with n-decane as an internal
standard. [b] Enantiomeric excess determined by HPLC with a Chiracel
OD column (n-heptane/iPrOH). [c] CuTC: copper(i) thiophene-2-carbox-
ylate.
[a] Conversions determined by GC analysis with n-decane as an internal
standard. [b] Enantiomeric excess determined by HPLC with a Chiracel
OD column (n-heptane/iPrOH). [c] [Cu]:L* ˆ 1:2.
2800
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Enantiomerically Enriched Propargylamines
2797 2811
Table 4. Influence of the protecting group on the enantioselectivity.
the easy separation of the corresponding propargylamines by
chiral HPLC analysis (Table 5).
R3
Ph
CuBr (5 mol%)
(R)-Quinap (5.5 mol%)
N
As shown in Table 5,polyfunctional propargylamines can
be prepared in 54 90%ee and in moderate to high yields. In
general,the heteroatom-functionalized alkynes afforded low-
er ee values than the unfunctionalized alkynes. Surprisingly,
both 2- and 3-pyridinylacetylene (2o, 2p) yielded the amines
3ae and 3af,respectively,with 70% ee (entries 7 and 8). A
second substituent at the b-carbon of the enamine (entries 11
and 12) raised the enantioselectivity further. Enamine 1k and
1-bromo-4-ethynylbenzene (2n) yielded propargylamine 3x
with the highest enantioselectivity (90%ee,83% yield). The
absolute (S)-configuration of 3x was established by X-ray
analysis (Figure 1).[17]
Pr
R4
Ph
+
Pr
toluene, rt
N
R3
3a-q
R4
1a-h
2a
Entry
1
a
3
a
Yield [%][a]
ee [%][b]
1
99
77[c]
2
3
4
5
6
7
b
c
d
e
f
b
e
f
91
10
30
35
99
78
82[d]
76[e]
50[c]
68[f]
86[d]
83
g
h
i
Figure 1. Structure of the propargylamine 3x in the solid state. Selected
À
À
À
bond lengths [ä] and angles [8]: C1 C2 1.481(4),C1 C10 1.541(4),C1 N1
À
À
1.479(4),C2 C3 1.189(5),C7 Br1 1.895(3); N1-C1-C10 113.4(3),C2-C1-
C10 112.9(2),N1-C1-C2 111.6(3),C3-C2-C1 175.2(3),C2-C3-C4 178.0(4).
g
The propargylamines 3 obtained can be selectively depro-
tected by known literature methods (Scheme 4). Thus,treat-
ment of the mixed (allyl)propargylamine 3b with thiosalicylic
acid (6) in the presence of a palladium(0) catalyst (5 mol%
[Pd(dba)2] and 5 mol% dppb) led to the monoprotected
propargylamine 7a in 90% yield.[18] With the same catalyst,
the monoallylated amine 7d was obtained in 75% yield
starting from 3a. Treatment of 3 f with an excess of
triethylsilane (5 equiv) in refluxing trifluoroacetic acid also
yielded the monoallylated amine 7d in 88% yield.[19] By using
8
h
q
99
66[g]
[a] Isolated yield of analytically pure product. [b] Enantiomeric excess
determined by HPLC with a Chiracel OD-H column (n-heptane/iPrOH).
[c] Enantiomeric excess determined after deprotection to 7d. [d] Enantio-
meric excess determined after deprotection to 7a. [e] Enantiomeric excess
determined after deprotection to 7b. [f] Enantiomeric excess determined
after transformation to 10. [g] Enantiomeric excess determined after
complexation with Co2(CO)8 (1.1 equiv,90% yield).
¬
Guibe×s method (5 mol% [Pd(PPh3)4],1,3-dimethylbarbituric
acid (8,3 equiv)), 3e was converted into the monoprotected
amine 7b in 99% yield.[20] Furthermore,the absolute config-
uration of the propargylic amine 3a was determined by its
transformation into the amine 7c (91%) and comparison of its
optical rotation with literature data.[5e] Primary amines can be
obtained by hydrogenation of dibenzyl-protected propargyl-
amines in good yields. For example,the amine 3w is hydro-
genated to the amine 7e in 70% yield. To demonstrate further
synthetic application,the allyl-protected amines 3b and 3g
were used in Pauson Khand reactions (Scheme 5).[21] Treat-
dibenzyl (83%ee,entry 7). The exchange of the allyl group in
1b by a methallyl group in 1 f furnished the highest ee
(86%ee,entry 6). In contrast,the mixed enamines 1c e gave
only moderate ee values,perhaps due to the degradation of
these enamines.
For further investigations of the scope of the enantioselec-
tive reaction,we chose the dibenzyl group as the protecting
group,because of its availability,good ee of the products,and
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P. Knochel et al.
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Table 5. Enantioselective synthesis of propargylamines 3 by the copper(i) bromide/(R)-Quinap (5)-catalyzed addition of alkynes 2 to enamines 1.
Entry
1
2
R5
3
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
g
g
g
g
g
g
g
g
d
e
f
g
h
i
1-cyclohexenyl
(CH2)3CN
(CH2)3Cl
CH2OMe
CH2OTBDPS
TMS
j
k
l
m
n
o
ae
af
84
50
58
76
85
73
73
57
74
54
60
55
72
86[c]
70
70
o
p
2-pyr
3-pyr
9
10
i
i
a
k
Ph
nBu
r
s
99
56
85
76
11
j
a
Ph
t
64
87
12
13
k
k
a
n
Ph
pBrPh
w
x
79
83
88
90
[a] Isolated yield of analytically pure product. [b] Enantiomeric excess determined by HPLC with a Chiracel OD-H or OD column (n-heptane/iPrOH).
I
[c] Enantiomeric excess determined after conversion to 3i {i) TBAF; ii) PhI,Pd 0 cat.,Cu cat.; 77% overall yield}.
Ph
structure with the typical planar
four-membered Cu2(m-Br)2 ring.
The coordination spheres of
both copper atoms are distorted
tetrahedral,but they are not
identical. The Cu1 N1 distance
(2.348 ä) is much shorter than
the Cu2 N2 distance (2.725 ä).
Ph
Ph
ii)
i)
Bu
HN
Bu
All
Bu
HN
90 %
99 %
N
Bn
7a
R4
CH2Fc
7b
3b: R4 = Bn
3e: R4 = CH2Fc
Ph
Ph
Ph
Ph
i)
ii)
91 %
iii)
Bu
All
Bu
Bu
All
Bu
HN
In both cases the long Cu
N
88 %
75 %
N
Ph
N
NH2
All
All
distances indicate the absence of
direct bonding,but they are
shorter than the sum of the
van der Waals radii of Cu and
N. Interestingly,the P and the
N atoms of the two Quinap mol-
ecules are cisoid-orientated,in
Ph
7c
3a
7d
3f
NBn2
NH2
iv)
Ph
70 %
Ph
3w
7e
contrast to monodentate P
complexes of CuBr.[24]
Preliminary mechanistic stud-
ies showed that the acetylenic
N
Scheme 4. Deprotection of propargylamines 3 to primary and secondary amines: i) [Pd(dba)2] (5 mol%),dppb
(5 mol%), 6 (1.2 equiv),THF; ii) [Pd(PPh 3)4] (5 mol%), 8 (3 equiv per allyl group),CH 2Cl2; iii) Et3SiH (5 equiv),
CF3CO2H; iv) Pd/C (10%),H (1 atm),MeOH.
2
deuterium of [D1]phenylacety-
ment of 3b and 3g with Co2(CO)8 (1.1 equiv),followed by
oxidation with Me3NO (5 equiv) afforded the bicyclic com-
pounds 9 and 10 as single diastereoisomers in 50 and 38%
lene (2q) is transferred to the b-position of the enamine 1g
(>90% deuterium incorporated),leading to 12 in 91% yield
(Scheme 6).
We suggest the tentative mechanism described in Scheme 7.
The dimeric copper complex 11 dissociates first affording the
monomeric copper species 13,which after successive com-
plexation of alkyne 2 and enamine 1 results in the zwitterionic
[22]
yield,respectively.
We were able to isolate the complex [BrCu(Quinap)]2 (11)
as a yellow,air-stable solid,which was characterized by X-ray
crystallography (Figure 2).[23] Complex 11 has a dimeric
2802
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Enantiomerically Enriched Propargylamines
2797 2811
of the propargylamine products illustrate the good synthetic
utility of this method.
1) Co2(CO)8 (1.1 equiv)
Ph
H
Et2O or pentane, rt
Bu
O
R
N
2) Me3NO (5 equiv)
CH2Cl2 / MeCN 1:1, rt
N
R
Ph
Bu
3b
3g
9: R = Bn: 50 %
10: R = PMB: 38 %
Experimental Section
Scheme 5. Pauson Khand reaction of propargylamines 3.
General methods: Unless otherwise indicated all reactions were carried out
under argon and with dried solvents (THF,Et 2O,toluene,dichloromethane,
pentane,acetonitrile,methanol). Reactions were monitored by gas
chromatography (GC,GC-MS) or thin-layer chromatography (TLC)
analysis of hydrolyzed aliquots.
Starting materials: The following starting materials were prepared accord-
13]
ing to literature procedures: enamines 1a p,[11
4-bromophenylacety-
lene,[25] and tert-butyl(diphenyl)(2-propynyloxy)silane.[26]
N,N-Diallyl-1-phenyl-1-heptyn-3-amine (3a)
Typical procedure A (racemic reaction): CuBr (22 mg,0.15 mmol,
5.0 mol%) was suspended in toluene (3 mL) in a 25 mL Schlenk tube. A
solution of enamine 1a (0.645 g,3.90 mmol,1.3 equiv),phenylacetylene
(2a) (0.306 g,3.00 mmol),and n-decane (0.300 g,2.11 mmol) as an internal
standard in toluene (3 mL) was added at room temperature. The reaction
mixture was stirred for 16 h at room temperature. Standard workup and
column chromatographic purification (silica gel,pentane/Et 2O 98:2)
afforded 3a as a colorless oil (0.790 g,2.95 mmol,98%).
Typical procedure B (chiral reaction): CuBr (3.6 mg,0.025 mmol,
5.0 mol%) and (R)-(‡)-Quinap (12.1 mg,0.0275 mmol,5.5 mol%) were
suspended in toluene (2 mL) in a 10 mL Schlenk tube. After 30 min,a
solution of enamine 1a (124 mg,0.75 mmol,1.5 equiv),phenylacetylene
(2a) (51 mg,0.50 mmol),and n-decane (50 mg,0.35 mmol) as an internal
standard in toluene (2 mL) was added at room temperature. After stirring
for 20 h,standard workup and column chromatographic purification (silica
gel,pentane/Et 2O 98:2) yielded 3a (133 mg,0.50 mmol,99%, ee deter-
mined as 10) as a colorless oil. [a]2D0 ˆ À112 (c ˆ 0.80 in CHCl3); 1H NMR
(CDCl3,300 MHz): d ˆ 7.38 7.30 (m,2H),7.24 7.15 (m,3H),5.86 5.70
Figure 2. Structure of the complex [BrCu(Quinap)]2 (11) in the solid state
(the hydrogen atoms and crystallized solvent molecules are omitted for
À
clarity). Selected bond lengths [ä] and angles [8]: Cu1 Br1 2.4728(8),
À
À
À
Cu2 Br2 2.4150(8),Cu1 P1 2.199(2),Cu2 P2 2.1827(13); P2-Cu2-Br2
129.28(4),P2-Cu2-Br1 122.75(4),Br2-Cu2-Br1 104.18(3).
D
Ph
CuBr (5 mol%)
toluene, rt, 14 h
NBn2
+
Ph
D
Pr
Pr
(m,2H),5.20 5.00 (m,4H),3.64 (t,
J ˆ 7.6 Hz,1H),3.31 3.22 (m,2H),
NBn2
12: 91 %, > 90 % D
2.91 (dd, J ˆ 14.3,7.8 Hz,2H),1.68 1.56 (m,2H),1.45 1.20 (m,4H),
0.84 ppm (t, J ˆ 7.3 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 136.7,131.7,
128.2,127.7,123.6,117.0,88.4,85.0,54.0,53.1,33.6,28.8,22.4,14.0 ppm; IR
1g
2q
Scheme 6. Deuterium incorporation in propargylamines.
(film): nÄ ˆ 3079 (m),2957 (s),2932 (s),2861 (m),2815 (m),1642 (m),1598
‡
(w),1490 (s),919 (s),755 (vs),691 cm À1 (s); MS: m/z (%): 210 (100) [M
À
11
H
Ph
R
H
C4H9],167 (4),141 (6),128 (11),115 (22),91 (5),77 (2); HRMS (EI):
calcd for C19H24N [M À H]: 266.1909; found: 266.1929; elemental analysis
m/z:
2
‡
R
NHR2
calcd (%) for C19H24N: C 85.34,H 9.42,N 5.24; found: C 84.89,H 9.80,N
5.17.
P
N
Cu
Br
3
N-Allyl-N-benzyl-1-phenyl-1-heptyn-3-amine (3b): The reaction was car-
ried out according to procedure A with enamine 1b (0.711 g,3.30 mmol,
13
P
Br
Cu
P
N
Br
H
NHR2
1.1 equiv),phenylacetylene
0.15 mmol,5.0 mol%),and
(
2a) (0.306 g,3.00 mmol),CuBr (22 mg,
n-decane (0.300 g,2.11 mmol) in toluene
N
Cu
R
R
(6 mL) at room temperature for 16 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 3b
(0.784 g,2.47 mmol,82%) as a colorless oil.
15
H
R
R
Br
Cu
P
N
R
NR2
The reaction was carried out according to procedure B with enamine 1b
(162 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
1
R2N
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
H
R
(4 mL) at room temperature for 24 h. Standard workup and column
14
chromatographic purification (silica gel,pentane/Et 2O 98:2) yielded 3b
Scheme 7. Proposed mechanism.
(132 mg,0.42 mmol,83%, ee determined as 7) as a colorless oil. [a]D20
ˆ
1
À128 (c ˆ 1.07 in CHCl3); H NMR (CDCl3,300 MHz): d ˆ 7.42 7.34 (m,
2H),7.33 7.27 (m,2H),7.26 7.18 (m,5H),7.17 7.10 (m,1H),5.86 5.72
intermediate 14. After intramolecular transfer of the alkyne
moiety to the imminium ion,the copper-complexed product
15 is formed. Decomplexation produces the free propargylic
amine 3 and regenerates the catalyst 13.
In summary,we have reported the first copper( i)/Quinap-
catalyzed addition of functionalized alkynes to enamines with
up to 90%ee and high yields. The mild reaction conditions,
the broad scope of the reaction,and the selective deprotection
(m,1H),5.22 5.13 (m,1H),5.07 5.00 (m,1H),3.84 (d,
J ˆ 13.9 Hz,1H),
3.58 (t, J ˆ 7.8 Hz,1H),3.37 (d, J ˆ 13.9 Hz,1H),3.30 3.18 (m,1H),3.00
2.90 (dd, J ˆ 14.1,7.9 Hz,1H),1.69 1.59 (m,2H),1.41 1.30 (m,2H),1.21
(sext, J ˆ 7.1 Hz,2H),0.81 ppm (t, J ˆ 7.3 Hz,3H); 13C NMR (CDCl3,
75 MHz): d ˆ 140.0,136.8,131.8,128.8,128.2,128.1,127.8,126.8,123.6,
117.0,88.4,85.0,54.9,54.0,52.7,33.7,28.7,22.4,14.0 ppm; IR (film):
nÄ ˆ 3082
(w),3030 (w),2956 (m),2932 (s),1642 (w),1599 (w),1490 (s),1454 (s),918
(s),756 (vs),740 (s),691 cm À1 (vs); MS: m/z (%): 316 (0.1) [M À H],260
‡
‡
(100),128 (9),115 (21),91 (77); HRMS (EI): m/z: calcd for C23H26N [M
À
Chem. Eur. J. 2003, 9,2797 2811
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
2803

P. Knochel et al.
FULL PAPER
chromatographic purification (silica gel,pentane/Et 2O 99:1) afforded 3 f
(0.506 g,1.29 mmol,86%) as a light yellow oil.
H]: 316.2065; found: 316.2060; elemental analysis calcd (%) for C23H26N: C
87.02,H 8.57,N 4.41; found: C 87.06,H 8.13,N 4.36.
The reaction was carried out according to procedure B with enamine 1d
(219 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
N-Allyl-N-benzyl-6-tridecyn-5-amine (3c): The reaction was carried out
according to procedure A with enamine 1b (0.474 g,2.20 mmol,1.1 equiv),
1-octyne (2b) (0.220 g,2.00 mmol),CuBr (22 mg,0.15 mmol,5.0 mol%),
and n-decane (0.200 g,1.41 mmol) in toluene (4 mL) at room temperature
for 4 h. Standard workup and column chromatographic purification (silica
gel,pentane/Et 2O 98:2) afforded 3c (0.500 g,1.54 mmol,74%) as a
colorless oil. 1H NMR (CDCl3,300 MHz): d ˆ 7.30 7.14 (m,5H),5.85
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
(4 mL) at room temperature for 96 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 99:1) yielded 3e
(60 mg,0.15 mmol,30%,
ee determined as 7d) as a light yellow oil.
1H NMR (300 MHz,CDCl ): d ˆ 7.51 7.16 (m,15H),6.05 5.92 (m,1H),
3
5.65 (m,1H),5.20 5.08 (m,1H),5.00 (d,
J ˆ 9.8 Hz,1H),3.74 (d, J ˆ
5.04 4.93 (m,2H),5.02 (s,1H),3.76 (t, J ˆ 7.5 Hz,1H),3.48 (ddt, J ˆ 15.9,
6.5,1.3 Hz,1H),3.24 (ddt, J ˆ 15.9,6.1,1.3 Hz,1H),1.86 1.63 (m,2H),
14.2 Hz,1H),3.37 3.25 (m,1H),3.27 (d, J ˆ 13.9 Hz,1H),3.19 3.06 (m,
1H),2.85 (dd, J ˆ 14.1,8.0 Hz,1H),2.16 (td, J ˆ 6.9,2.0 Hz,2H),1.62 1.10
(m,14H),0.84 (t, J ˆ 6.7 Hz,3H),0.79 ppm (t, J ˆ 7.3 Hz,3H); 13C NMR
(CDCl3,75 MHz): d ˆ 140.3,137.1,128.8,128.1,126.6,116.6,84.8,78.2,54.8,
53.9,52.3,33.9,31.4,29.2,28.7,28.5,22.6,22.4,18.7,14.1,14.0 ppm; IR
1.49 1.22 (m,4H),0.90 ppm (t,
J ˆ 7.5 Hz,3H); 13C NMR (75 MHz,
CDCl3): d ˆ 143.5,142.9,138.6,131.7,128.5,128.4,128.3,128.2,128.2,127.7,
127.0,126.8,123.7,114.9,89.6,85.3,72.1,53.4,51.8,34.8,28.8,22.4,
‡
14.0 ppm; MS: m/z (%): 393 (1) [M ],337 (10),336 (35),168 (15),167
(100),165 (16),152 (10); HRMS (EI):
(film): nÄ ˆ 3064 (w),3028 (w),2927 (vs),2853 (s),1495 (w),1450 (s),918
‡
m/z: calcd for C29H31N [M ]:
À1
‡
(m),738 (s),698 cm
(s); MS: m/z (%): 268 (100) [M À C4H9],196 (1),
393.2456; found: 393.2483; IR (film): nÄ ˆ 2956 (s),2930 (s),2860 (m),1490
(s),1453 (m),756 (vs),705 (vs),692 cm À1 (vs); elemental analysis calcd (%)
for C29H31N: C 88.50,H 7.94,N 3.56; found: C 88.06,H 8.08,N 3.55.
‡
131 (2),91 (36); HRMS (EI): m/z: calcd for C23H34N [M À H]: 324.2691;
found: 324.2678; elemental analysis calcd (%) for C23H34N: C 84.86,H
10.84,N 4.30; found: C 85.16,H 10.51,N 3.96.
N-Allyl-N-(4-methoxybenzyl)-1-phenyl-1-heptyn-3-amine (3g): The reac-
tion was carried out according to procedure A with enamine 1e (0.638 g,
2.60 mmol,1.3 equiv),phenylacetylene ( 2a) (0.204 g,2.00 mmol),CuBr
N-Allyl-N-benzyl-1-heptyn-3-amine (3d): Acetylene was bubbled through
a solution of CuBr (43 mg,0.30 mmol) in toluene (6 mL). After 5 min a
solution of enamine 1b (1.29 g,6.00 mmol) and
n-decane (1.00 g,
(14 mg,0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in
7.03 mmol) in toluene (6 mL) was added. The reaction mixture was stirred
with a constant acetylene flow at room temperature for 4 h. Standard
workup and purification by column chromatography (silica gel,pentane/
Et2O 98:2) afforded 3d (1.07 g,4.27 mmol,69%) as a colorless oil. 1H NMR
(CDCl3,300 MHz): d ˆ 7.30 7.10 (m,5H),5.82 5.66 (m,1H),5.22 5.10
toluene (4 mL) at room temperature for 44 h. Standard workup and
column chromatographic purification (silica gel,pentane/Et 2O 95:5)
afforded 3g (0.542 g,1.56 mmol,78%) as a light yellow oil.
The reaction was carried out according to procedure B with enamine 1e
(244 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
(m,1H),5.05 4.95 (m,1H),3.77 (d,
J ˆ 14.0 Hz,1H),3.38 (td, J ˆ 7.6,
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
2.2 Hz,1H),3.27 (d, J ˆ 14.1 Hz,1H),3.20 3.10 (m,1H),2.85 (dd,
14.4,8.3 Hz,1H),2.17 (d, J ˆ 2.2 Hz,1H),1.66 1.48 (m,2H),1.38 1.10
J ˆ
(4 mL) at room temperature for 120 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 95:1) yielded 3e
(m,4H),0.79 ppm (t, J ˆ 7.2 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ
139.9,136.7,128.7,128.2,126.8,117.0,82.4,72.2,54.7,53.8,51.9,33.5,28.5,
22.3,14.0 ppm; IR (film): nÄ ˆ 3304 (s),3029 (w),2957 (vs),2934 (vs),2861
(60 mg,0.17 mmol,35%,
ee determined as 10) as an light yellow oil.
1H NMR (300 MHz,CDCl 3): d ˆ 7.49 7.46 (m,2H),7.33 7.29 (m,5H),
6.87 (d, J ˆ 8.8 Hz,2H),5.95 5.81 (m,1H),5.27 (d, J ˆ 17.3 Hz,1H),5.13
(s),1643 (w),1495 (m),1454 (s),920 (s),738 (s),698 (vs),643 cm
À1 (s); MS:
‡
m/z (%): 184 (100) [M À C4H9],146 (5),131 (5),115 (2),91 (84); HRMS
‡
(d, J ˆ 10.2 Hz,1H),3.86 (d, J ˆ 13.8 Hz,1H),3.80 (s,3H),3.67 (t,
7.6 Hz,1H),3.40 (d, J ˆ 13.6 Hz,1H),3.32 (ddt, J ˆ 14.2,4.4,1.8 Hz,1H),
3.02 (dd, J ˆ 14.7,8.0 Hz,1H),1.73 (qd, J ˆ 7.1,3.0 Hz,2H),1.50 1.40 (m,
2H),1.31 (sext, J ˆ 7.8 Hz,2H),0.91 ppm (t, J ˆ 7.0 Hz,3H); 13C NMR
(75 MHz,CDCl 3): d ˆ 158.5,137.0,132.0,131.8,129.9,128.2,127.7,123.6,
116.8,113.6,88.4,84.9,55.2,54.3,53.8,52.5,33.6,28.7,22.4,14.0 ppm; MS:
J ˆ
(EI): m/z: calcd for C17H22N [M À H]: 240.1752; found: 240.1725;
elemental analysis calcd (%) for C17H22N: C 84.59,H 9.60,N 5.80; found:
C 84.13,H 9.79,N 5.75.
N-Allyl-N-ferrocenylmethyl-1-phenyl-1-heptyn-3-amine (3e): The reac-
tion was carried out according to procedure A with enamine 1c (0.905 g,
2.80 mmol,1.4 equiv),phenylacetylene ( 2a) (0.204 g,2.00 mmol),CuBr
‡
m/z (%): 347 (1) [M ],291 (12),290 (54),122 (10),121 (100); HRMS (EI):
‡
(14 mg,0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in
m/z: calcd for C24H29NO [M ]: 347.2249; found: 347.2209; IR (film): nÄ ˆ
toluene (4 mL) at room temperature for 21 h. Standard workup and
column chromatographic purification (silica gel,pentane/Et 2O 15:1)
afforded 3e (0.624 g,1.47 mmol,73%) as an orange-brown oil.
2955 (s),2933 (s),1612 (m),1512 (vs),1464 (m),1249 (vs),1038 (m),756 (s),
691 cmÀ1 (m); elemental analysis calcd (%) for C24H29NO: C 82.95,H 8.41,
N 4.03; found: C 82.92,H 8.38,N 4.03.
The reaction was carried out according to procedure B with enamine 1c
(242 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
N-Benzyl-N-(2-methyl-2-propenyl)-1-phenyl-1-heptyn-3-amine (3h): The
reaction was carried out according to procedure A with enamine 1 f
(0.642 g,2.80 mmol,1.4 equiv),phenylacetylene ( 2a) (0.204 g,2.00 mmol),
CuBr (14 mg,0.10 mmol,5.0 mol%),and n-decane (0.200 g,1.41 mmol) in
toluene (4 mL) at room temperature for 20 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 99:1) afforded 3h
(0.602 g,1.82 mmol,91%) as a colorless oil.
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
(4 mL) at room temperature for 72 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 15:1) yielded 3e
(20 mg,0.05 mmol,10%, ee determined as 7b) as an orange-brown oil.
1H NMR (300 MHz,CDCl 3): d ˆ 7.48 7.45 (m,2H),7.35 7.31 (m,3H),
5.92 5.79 (m,1H),5.27 (dd, J ˆ 17.2,1.3 Hz,1H),5.14 (d, J ˆ 10.2 Hz,1H),
4.23 (d, J ˆ 9.7 Hz,2H),4.12 (s,7H),3.72 3.65 (m,2H),3.39 3.28 (m,
2H),2.98 (dd, J ˆ 14.2,7.9 Hz,1H),1.68 (q, J ˆ 7.1 Hz,2H),1.48 1.25 (m,
4H),0.90 ppm (t, J ˆ 7.0 Hz,3H); 13C NMR (75 MHz,CDCl 3): d ˆ 137.0,
The reaction was carried out according to procedure B with enamine 1 f
(172 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
(4 mL) at room temperature for 72 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 99:1) yielded 3h
131.7,128.2,127.7,123.7,116.8,88.6,85.11,85.08,70.2,69.6,68.5,68.0,67.4,
‡
53.8,52.7,50.5,33.6,28.8,22.4,14.1 ppm; MS:
m/z (%): 425 (21) [M ],200
(164 mg,0.49 mmol,99%, ee determined as 7d) as a colorless oil. [a]D20
ˆ
(25),199 (100),170 (13),121 (70); HRMS (EI): m/z: calcd for C27H31NFe
1
À201 (c ˆ 0.84 in CHCl3); H NMR (300 MHz,CDCl ): d ˆ 7.37 7.34 (m,
3
‡
[M ]: 425.1806; found: 425.1820; IR (film): nÄ ˆ 2955 (s),2932 (s),1490 (m),
2H),7.28 7.26 (m,2H),7.22 7.11 (m,6H),4.90 (s,1H),4.76 (s,1H),3.78
(d, J ˆ 14.2 Hz,1H),3.50 (t, J ˆ 7.4 Hz,1H),3.28 (d, J ˆ 14.0 Hz,1H),3.04
(d, J ˆ 13.8 Hz,1H),2.86 (d, J ˆ 13.1 Hz,1H),1.65 (s,3H),1.64 1.55 (m,
2H),1.39 1.27 (m,2H),1.17 (sext, J ˆ 7.2 Hz,2H),0.77 ppm (t, J ˆ 7.2 Hz,
3H); 13C NMR (75 MHz,CDCl 3): d ˆ 143.7,140.1,131.8,128.8,128.2,128.1,
127.7,126.8,123.7,113.0,88.2,84.9,57.4,54.8,52.1,33.5,28.7,22.4,20.8,
1106 (m),818 (m),756 (vs),691 (s),484 cm À1 (m); elemental analysis calcd
(%) for C27H31NFe: C 76.23,H 7.35,N 3.29; found: C 76.03,H 7.53,N 3.26.
N-Allyl-N-benzhydryl-1-phenyl-1-heptyn-3-amine (3 f): The reaction was
carried out according to procedure A with enamine 1d (0.874 g,3.00 mmol,
1.5 equiv),phenylacetylene
0.08 mmol,5.0 mol%),and
(
2a) (0.153 g,1.50 mmol),CuBr (11 mg,
n-decane (0.200 g,1.41 mmol) in toluene
‡
14.0 ppm; MS: m/z (%): 331 (1) [M ],275 (23),274 (100),115 (10),91 (39).
‡
(4 mL) at room temperature for 9 h. Standard workup and column
HRMS (EI): m/z: calcd for C24H28N [M À H]: 330.2222; found: 330.2207;
2804
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9,2797 2811

Enantiomerically Enriched Propargylamines
2797 2811
IR (film): nÄ ˆ 2956 (s),2934 (s),2860 (m),1490 (m),1454 (m),1444 (m),898
tr (min) ˆ 17.2 (À),21.2 ( ‡); 1H NMR (CDCl3,300 MHz): d ˆ 7.35 7.10 (m,
10H),3.72 (d, J ˆ 13.7 Hz,2H),3.26 (d, J ˆ 13.7 Hz,2H),3.32 3.22 (m,
1H),2.45 (t, J ˆ 7.1 Hz,2H),2.39 (td, J ˆ 6.8,2.0 Hz,2H),1.82 (quint, J ˆ
À1
(m),756 (vs),741 (m),691 cm
(m); elemental analysis calcd (%) for
C24H28N: C 86.96,H 8.82,N 4.23; found: C 86.82,H 8.95,N 4.33.
7.2 Hz,2H),1.70 1.42 (m,2H),1.40 1.20 (m,2H),1.16 1.04 (sext,
J ˆ
N,N-Dibenzyl-1-phenyl-1-heptyn-3-amine (3i): The reaction was carried
out according to procedure A with enamine 1g (0.557 g,2.10 mmol,
7.2 Hz,2H),0.76 ppm (t, J ˆ 7.0 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ
139.8,128.7,128.1,126.8,119.1,81.8,80.3,54.8,51.6,33.7,28.5,25.0,22.2,
17.9,16.1,13.9 ppm; IR (film): nÄ ˆ 3062 (w),3028 (w),2955 (m),2934 (m),
1.1 equiv),phenylacetylene
0.05 mmol,2.50 mol%),and
(
2a) (0.204 g,2.00 mmol),CuBr (7.2 mg,
n-decane (0.250 g,1.76 mmol) in toluene
2248 (w),1603 (w),1494 (m),1454 (s),1122 (s),747 (s),699 cm
À1 (vs); MS:
(4 mL) at room temperature for 24 h and at 608C for 3 h. Standard workup
and purification by column chromatographic purification (silica gel,
pentane/Et2O 98:2) afforded 3i (0.550 g,1.50 mmol,75%) as a colorless oil.
‡
m/z (%): 301 (100) [M À C4H9],181 (6),91 (66),65 (4); HRMS (EI): m/z:
‡
calcd for C25H29N2 [M À H]: 357.2331; found: 357.2329; elemental analysis
calcd (%) for C25H29N2: C 83.75,H 8.43,N 7.81; found: C 83.41,H 8.30,N
8.21.
The reaction was carried out according to procedure B with enamine 1g
(173 mg,0.65 mmol,1.3 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
N,N-Dibenzyl-10-chloro-6-decyn-5-amine (3l): The reaction was carried
out according to procedure A with enamine 1g (0.690 g,2.60 mmol,
1.3 equiv),5-chloro-1-pentyne ( 2 f) (0.205 g,2.00 mmol),CuBr (14 mg,
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
(4 mL) at room temperature for 24 h. Standard workup and purification by
column chromatographic purification (silica gel,pentane/Et 2O 98:2)
0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in toluene
(4 mL) at room temperature for 67 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 3l
(0.575 g,1.56 mmol,78%) as a colorless oil.
yielded 3i (144 mg,0.39 mmol,78%,83%
ee) as a colorless oil. [a]D20
ˆ
À239 (c ˆ 1.00 in CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,
1
0.2 mLminÀ1): tr (min) ˆ 45.4 (‡),53.8 ( À); H NMR (CDCl3,300 MHz):
d ˆ 7.44 7.10 (m,15H),3.80 (d, J ˆ 13.7 Hz,2H),3.51 (t, J ˆ 7.4 Hz,1H),
3.40 (d, J ˆ 13.8 Hz,2H),1.78 1.56 (m,2H),1.46 1.23 (m,2H),1.14 (sext,
J ˆ 7.2 Hz,2H),0.78 ppm (t, J ˆ 7.1 Hz,3H); 13C NMR (CDCl3,75 MHz):
d ˆ 139.9,131.8,128.8,128.3,128.2,127.8,126.8,123.6,88.1,85.2,55.0,52.2,
33.6,28.6,22.3,13.5 ppm; IR (film): nÄ ˆ 3062 (w),3029 (w),2955 (s),2932
The reaction was carried out according to procedure B with enamine 1g
(173 mg,0.65 mmol,1.3 equiv),5-chloro-1-pentyne
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
(
2 f) (51 mg,
R)-(‡)-Quinap
(12.1 mg,0.0275 mmol,5.5 mol%),and
n-decane (50 mg,0.35 mmol) in
toluene (4 mL) at room temperature for 64 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) yielded 3l
(107 mg,0.29 mmol,58%,60% ee) as a colorless oil. [a]2D0 ˆ À100 (c ˆ 0.86
in CHCl3). HPLC (OD-H,99% n-heptane/1% isopropanol,0.2 mLmin À1):
tr (min) ˆ 58.2 (‡),66.3 ( À); 1H NMR (CDCl3,300 MHz): d ˆ 7.34 7.08
(m,10H),3.72 (d, J ˆ 13.7 Hz,2H),3.65 (t, J ˆ 6.4 Hz,2H),3.28 (d, J ˆ
14.2 Hz,2H),3.29 3.20 (m,1H),2.40 (td, J ˆ 6.7,2.1 Hz,2H),1.93 (quint,
(s),1599 (m),1490 (s),1454 (s),755 (vs),698 cm À1 (vs); MS: m/z (%): 310
‡
(100) [M À C4H9],218 (3),128 (2),115 (7),91 (57); HRMS (EI):
m/z:
‡
calcd for C27H28N [M À H]: 366.2222; found: 366.2215; elemental analysis
calcd (%) for C27H28N: C 88.24,H 7.95,N 3.81; found: C 87.85,H 7.84,N
3.73.
N,N-Dibenzyl-1-(1-cyclohexen-1-yl)-1-heptyn-3-amine (3j): The reaction
was carried out according to procedure A with enamine 1g (0.690 g,
2.60 mmol,1.3 equiv),1-ethinyl-1-cyclohexene ( 2d) (0.212 g,2.00 mmol),
CuBr (14 mg,0.10 mmol,5.0 mol%),and n-decane (0.200 g,1.41 mmol) in
toluene (4 mL) at room temperature for 20 h. Standard workup and
purification by column chromatographic purification (silica gel,pentane/
Et2O 98:2) afforded 3j (0.570 g,1.53 mmol,77%) as a colorless oil.
J ˆ 6.7 Hz,2H),1.68 1.41 (m,2H),1.40 1.10 (m,4H),0.76 ppm (t,
J ˆ
nÄ ˆ
7.3 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 140.0,128.8,128.1,126.8,
82.8,79.3,54.9,51.7,43.7,33.8,31.9,28.6,22.3,16.2,14.0 ppm; IR (film):
3063 (w),3028 (w),2956 (m),2932 (m),1494 (m),1454 (s),1028 (m),746 (s),
‡
698 cmÀ1 (vs); MS: m/z (%): 310 (100) [M À C4H9],196 (2),181 (4),91
‡
(67); HRMS (EI): m/z: calcd for C24H29ClN [M À H]: 366.1989; found:
366.1952; elemental analysis calcd (%) for C24H29ClN: C 78.34,H 8.22,N
3.81; found: C 78.40,H 8.25,N 3.75.
The reaction was carried out according to procedure B with enamine 1g
(173 mg,0.65 mmol,1.3 equiv),1-ethinyl-1-cyclohexene
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
(
2d) (53 mg,
R)-(‡)-Quinap
N,N-Dibenzyl-1-methoxy-1-octyn-4-amine (3m): The reaction was carried
out according to procedure A with enamine 1g (0.690 g,2.60 mmol,
1.3 equiv),3-methoxy-1-propyne ( 2g) (0.140 g,2.00 mmol),CuBr (14 mg,
(12.1 mg,0.0275 mmol,5.5 mol%),and
n-decane (50 mg,0.35 mmol) in
toluene (4 mL) at room temperature for 44 h. Standard workup and
purification by column chromatographic purification (silica gel,pentane/
Et2O 98:2) yielded 3j (156 mg,0.42 mmol,84%,74% ee) as a colorless oil.
[a]2D0 ˆ À172 (c ˆ 1.03 in CHCl3). HPLC (OD-H,99% n-heptane/1%
isopropanol,0.2 mLmin À1): tr (min) ˆ 30.3 (‡),35.1 ( À); 1H NMR (CDCl3,
300 MHz): d ˆ 7.36 7.10 (m,10H),6.08 6.00 (m,1H),3.73 (d, J ˆ 14.2 Hz,
2H),3.39 (t, J ˆ 7.5 Hz,1H),3.31 (d, J ˆ 13.6 Hz,2H),2.17 1.98 (m,4H),
1.70 1.44 (m,6H),1.40 1.18 (m,2H),1.10 (sext, J ˆ 7.3 Hz,2H),0.76 ppm
(t, J ˆ 7.3 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 140.1,133.8,128.8,
128.1,126.7,120.8,86.9,85.0,54.9,52.1,33.7,29.9,28.6,25.6,22.4,22.3,21.6,
14.0 ppm; IR (film): nÄ ˆ 3063 (w),3028 (m),2932 (vs),1604 (w),1494 (s),
1454 (s),1261 (m),1028 (m),802 (m),746 (s),698 cm À1 (vs); MS: m/z (%):
0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in toluene
(4 mL) at room temperature for 3 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et O 98:2) afforded 3m
2
(0.564 g,1.68 mmol,84%) as a colorless oil.
The reaction was carried out according to procedure B with enamine 1g
(173 mg,0.65 mmol,1.3 equiv),3-methoxy-1-propyne
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
(
2g) (35 mg,
R)-(‡)-Quinap
(12.1 mg,0.0275 mmol,5.5 mol%),and
n-decane (50 mg,0.35 mmol) in
toluene (4 mL) at room temperature for 20 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) yielded 3m
(128 mg,0.38 mmol,76%,55% ee) as a colorless oil. [a]2D0 ˆ À98 (c ˆ 0.98
in CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,0.2 mLmin À1):
tr (min) ˆ 75.4 (‡),91.9 ( À); 1H NMR (CDCl3,300 MHz): d ˆ 7.34 7.10
(m,10H),4.14 (d, J ˆ 1.8 Hz,2H),3.75 (d, J ˆ 13.8 Hz,2H),3.37 (s,3H),
3.32 (d, J ˆ 13.8 Hz,2H),3.40 3.31 (m,1H),1.72 1.45 (m,2H),1.41 1.00
(m,4H),0.76 ppm (t, J ˆ 7.3 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ
139.8,128.8,128.2,126.8,84.9,80.3,60.1,57.4,54.9,51.7,33.5,28.5,22.2,
‡
314 (100) [M À C4H9],236 (1),222 (2),91 (45); HRMS (EI): m/z: calcd for
‡
C25H33N [M ]: 371.2613; found: 371.2589; elemental analysis calcd (%) for
C25H33N: C 87.28,H 8.95,N 3.77; found: C 87.02,H 9.10,N 3.72.
7-(Dibenzylamino)-5-undecynenitrile (3k): The reaction was carried out
according to procedure A with enamine 1g (0.345 g,1.30 mmol,1.3 equiv),
5-hexynenitrile (2e) (0.093 g,1.00 mmol),CuBr (7 mg,0.05 mmol,
5.0 mol%),and n-decane (0.100 g,0.70 mmol) in toluene (2 mL) at 60 8C
for 5 h. Standard workup and column chromatographic purification (silica
gel,pentane/Et 2O 19:1 then 4:1) afforded 3k (0.295 g,0.82 mmol,82%) as
a colorless oil.
13.9 ppm; IR (film): nÄ ˆ 3063 (w),3029 (w),2955 (m),2819 (m),1604 (w),
1494 (m),1454 (s),1358 (m),1102 (vs),747 (s),698 cm À1 (vs); MS: m/z (%):
‡
278 (100) [M À C4H9],218 (3),196 (3),181 (4),91 (68); HRMS (EI): m/z:
‡
calcd for C23H29NO [M ]: 335.2249; found: 335.2213; elemental analysis
calcd (%) for C23H29NO: C 82.34,H 8.71,N 4.18; found: C 81.74,H 8.57,N
4.11.
The reaction was carried out according to procedure B with enamine 1g
(199 mg,0.75 mmol,1.5 equiv),5-hexynenitrile ( 2e) (47 mg,0.50 mmol),
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
(4 mL) at room temperature for 64 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 4:1) yielded 3k
(103 mg,0.29 mmol,51%,54% ee) as a colorless oil. [a]2D0 ˆ À91 (c ˆ 1.01
in CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,0.6 mLmin À1):
R)-(‡)-Quinap (12.1 mg,
N,N-Dibenzyl-1-{[tert-butyl(diphenyl)silyl]oxy}-2-octyn-4-amine
The reaction was carried out according to procedure A with enamine 1g
(0.345 g,1.30 mmol,1.3 equiv), tert-butyl(diphenyl)(2-propynyloxy)silane
(2h) (0.294 g,1.00 mmol),CuBr (7 mg,0.05 mmol,5.0 mol%),and
decane (0.300 g,2.11 mmol) in toluene (2 mL) at room temperature for
24 h. Standard workup and column chromatographic purification (silica
(3n):
n-
Chem. Eur. J. 2003, 9,2797 2811
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
2805

P. Knochel et al.
FULL PAPER
gel,pentane/Et 2O 98:2) afforded 3n (0.521 g,0.93 mmol,93%) as a
chromatographic purification (silica gel,pentane/Et 2O 4:1) afforded 3q
colorless oil.
(0.851 g,1.99 mmol,99%) as a light yellow oil.
The reaction was carried out according to procedure B with enamine 1g
(173 mg,0.65 mmol,1.3 equiv), tert-butyl(diphenyl)(2-propynyloxy)silane
(2h) (147 mg,0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),( R)-(‡)-
The reaction was carried out according to procedure B with enamine 1h
(244 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
R)-(‡)-Quinap (12.1 mg,
Quinap (12.1 mg,0.0275 mmol,5.5 mol%),and
n-decane (150 mg,
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
1.05 mmol) in toluene (4 mL) at room temperature for 48 h. Standard
workup and column chromatographic purification (silica gel,pentane/Et 2O
(4 mL) at room temperature for 96 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 4:1) yielded 3q
98:2) yielded 3n as a colorless oil (238 mg,0.43 mmol,85%,72%
ee);
(212 mg,0.49 mmol,99%,66%
ee,determined by complexation with
[a]2D0 ˆ À69 (c ˆ 0.90 in CHCl3); HPLC (OD-H,99% n-heptane/1%
Co2(CO)8 (1.1 equiv) in pentane (room temperature,45 min,silica gel,
isopropanol,0.2 mLmin À1): tr (min) ˆ 53.3 (À),57.8 ( ‡); 1H NMR (CDCl3,
pentane/Et2O 9:1,dark red oil,90%) as a light yellow oil. [ a]2D0 ˆ À171 (c ˆ
300 MHz): d ˆ 7.74 7.64 (m,4H),7.39 7.10 (m,16H),4.39 (d,
J ˆ 1.8 Hz,
0.53 in CHCl3). HPLC (OD-H,99%
n-heptane/1% isopropanol,
2H),3.67 (d, J ˆ 13.8 Hz,2H),3.25 (d, J ˆ 13.8 Hz,2H),3.30 3.20 (m,
0.15 mLminÀ1): tr ˆ 33.1 (À),34.1 ( ‡); 1H NMR (300 MHz,CDCl 3): d ˆ
7.53 7.50 (m,2H),7.36 7.31 (m,7H),6.87 (d, J ˆ 8.7 Hz,4H),3.82 (d, J ˆ
1H),1.64 1.20 (m,6H),1.02 (s,9H),0.75 ppm (t,
J ˆ 7.4 Hz,3H);
13C NMR (CDCl3,75 MHz): d ˆ 140.0,135.6,133.5,129.8,128.8,128.1,
127.7,126.8,83.5,83.1,54.8,52.9,51.6,33.4,28.5,26.7,22.2,19.2,14.0 ppm;
IR (film): nÄ ˆ 3070 (w),3029 (w),2957 (m),2859 (m),1494 (m),1454 (m),
13.4 Hz,2H),3.81 (s,6H),3.59 (t,
J ˆ 7.4 Hz,1H),3.40 (d, J ˆ 13.1 Hz,
2H),1.86 1.65 (m,2H),1.53 1.34 (m,2H),1.30 1.18 (m,2H),0.88 ppm
(t, J ˆ 7.3 Hz,3H); 13C NMR (75 MHz,CDCl 3): d ˆ 158.5,131.9,131.8,
129.9,128.2,127.8,123.7,113.6,88.3,85.0,55.2,54.1,51.9,33.5,28.6,22.3,
1428 (m),1113 (vs),1075 (s),739 (s),700 cm À1 (vs); MS: m/z (%): 559 (0.2)
‡
‡
[M ],502 (90),307 (20),229 (10),199 (36),91 (100); HRMS (EI):
m/z:
14.0 ppm; MS: m/z (%): 425 (0.1) [M À 2H],371 (13),371 (13),370 (45),
‡
‡
calcd for C38H45NOSi [M ]: 559.3270; found: 559.3247; elemental analysis
calcd (%) for C38H45NOSi: C 81.52,H 8.10,N 2.50; found: C 81.27,H 8.31,N
2.48.
121 (100); HRMS (EI): m/z: calcd for C29H33NO2 [M ]: 427.2511; found:
427.2522; IR (film): nÄ ˆ 2954 (s),2933 (s),2834 (m),1612 (s),1512 (vs),1464
(m),1301 (m),1249 (s),1171 (m),1038 (s),757 cm À1 (s); elemental analysis
calcd (%) for C29H33NO2: C 81.46,H 7.78,N 3.28; found: C 81.17,H 8.16,N
3.25.
N,N-Dibenzyl-1-(trimethylsilyl)-1-heptyn-3-amine (3o): The reaction was
carried out according to procedure A with enamine 1g (0.345 g,1.30 mmol,
1.3 equiv),trimethylsilylacetylene ( 2i) (0.098 g,1.00 mmol),CuBr (7 mg,
N,N-Dibenzyl-5-methyl-1-phenyl-1-hexyn-3-amine (3r): The reaction was
carried out according to procedure A with enamine 1i (0.583 g,2.20 mmol,
0.05 mmol,5.0 mol%),and
n-decane (0.100 g,0.70 mmol) in toluene
(2 mL) at room temperature for 16 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 3o
(0.267 g,0.73 mmol,73%) as a colorless oil.
1.1 equiv),phenylacetylene
0.10 mmol,5.0 mol%),and
(4 mL) at room temperature for 18 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 3r
(0.671 g,1.83 mmol,91%) as a colorless oil.
(
2a) (0.204 g,2.00 mmol),CuBr (14 mg,
n-decane (0.200 g,1.41 mmol) in toluene
The reaction was carried out according to procedure B with enamine 1g
(199 mg,0.75 mmol,1.5 equiv),trimethylsilylacetylene
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),and
(
2i) (49 mg,
n-decane (50 mg,
The reaction was carried out according to procedure B with enamine 1i
(199 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
CuBr (3.6 mg,0.025 mmol,5.0 mol%),( R)-Quinap (12.1 mg,0.0275 mmol,
5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene (4 mL) at room
temperature for 19 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 98:2) yielded 3r (182 mg,0.49 mmol,
99%,85% ee) as a colorless oil. [a]2D0 ˆ À237 (c ˆ 1.09 in CHCl3); HPLC
0.35 mmol) in toluene (4 mL) at room temperature for 24 h. Standard
workup and column chromatographic purification (silica gel,pentane/Et 2O
98:2) yielded 3o (128 mg,0.35 mmol,70%, ee determined as 3i) as a
colorless oil. [a]D20 ˆ À164 (c ˆ 0.97 in CHCl3); 1H NMR (CDCl3,
300 MHz): d ˆ 7.22 7.00 (m,10H),3.62 (d, J ˆ 13.7 Hz,2H),3.19 (d, J ˆ
13.7 Hz,2H),3.21 3.15 (m,1H),1.59 1.35 (m,2H),1.30 1.10 (m,2H),
1.10 0.94 (sext, J ˆ 7.3 Hz,2H),0.66 (t, J ˆ 7.3 Hz,3H),0.07 ppm (s,9H);
13C NMR (CDCl3,75 MHz): d ˆ 139.5,128.4,127.7,126.4,104.3,88.6,54.4,
(OD,99% n-heptane/1% isopropanol,0.1 mLmin À1): tr (min) ˆ 94.8 (À),
1
112.0 (‡); H NMR (300 MHz,CDCl ): d ˆ 7.44 7.41 (m,2H),7.35 7.32
3
51.9,32.9,28.0,21.8,13.5,0.00 ppm; IR (film):
nÄ ˆ 3064 (w),3029 (w),2958
(m,4H),7.28 7.21 (m,7H),7.17 7.13 (m,2H),3.81 (d,
J ˆ 13.7 Hz,2H),
(s),2159 (m),1495 (m),1454 (m),1250 (s),842 (vs),698 cm
À1 (s); MS: m/z
3.60 (t, J ˆ 7.1 Hz,1H),3.40 (t, J ˆ 13.7 Hz,2H),1.84 (sept, J ˆ 6.7 Hz,1H),
‡
(%): 348 (5) [M À CH3],306 (100),214 (4),91 (85),73 (12); HRMS (EI):
1.70 1.61 (m,1H),1.51 1.42 (m,1H),0.74 (d,
J ˆ 6.7 Hz,3H),0.62 ppm
‡
m/z: calcd for C24H32NSi [M À H]: 362.2304; found: 362.2333; elemental
(d, J ˆ 6.7 Hz,3H); 13C NMR (75 MHz,CDCl 3): d ˆ 135.8,131.8,128.9,
analysis calcd (%) for C24H32NSi: C 79.28,H 9.15,N 3.85; found: C 79.19,H
9.15,N 3.83.
128.3,128.2,127.8,126.9,123.6,88.2,85.1,55.0,50.2,43.0,24.6,22.8,
‡
21.9 ppm; MS: m/z (%): 365 (1) [M À 2H],311 (23),310 (100),91 (64);
‡
HRMS (EI): m/z: calcd for C27H29N [M À H]: 366.2222; found: 366.2224;
N,N-Dibenzyl-1,1-diethoxy-2-octyn-4-amine (3p): The reaction was carried
out according to procedure A with enamine 1g (0.345 g,1.30 mmol,
1.3 equiv),33, -diethoxy-1-propyne ( 2j) (0.128 g,1.00 mmol),CuBr (7 mg,
IR (film): nÄ ˆ 2954 (s),2932 (m),1490 (s),1454 (s),755 (vs),698 cm À1 (vs);
elemental analysis calcd (%) for C27H29N: C 88.24,H 7.95,N 3.81; found: C
88.03,H 8.33,N 3.81.
0.05 mmol,5.0 mol%),and
n-decane (0.130 g,2.11 mmol) in toluene
(2 mL) at room temperature for 4 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 19:1) afforded 3p
(0.260 g,0.66 mmol,66%) as a colorless oil. 1H NMR (C6D6,300 MHz):
d ˆ 7.55 7.45 (m,4H),7.32 7.15 (m,6H),5.59 (d, J ˆ 1.4 Hz,1H),4.02 (d,
N,N-Dibenzyl-2-methyl-5-decyn-4-amine (3s): The reaction was carried
out according to procedure A with enamine 1i (0.583 g,2.20 mmol,
1.1 equiv),1-hexyne ( 2k) (0.164 g,2.00 mmol),CuBr (14 mg,0.10 mmol,
5.0 mol%),and n-decane (0.200 g,1.41 mmol) in toluene (4 mL) at room
temperature for 24 h and at 608C for 1 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 3s
(0.618 g,1.78 mmol,89%) as a colorless oil.
J ˆ 12.8 Hz,2H),4.10 3.90 (m,2H),3.77 3.64 (m,3H),3.64 (d,
J ˆ
13.7Hz,2H),1.88 1.62 (m,2H),1.42 (quint,
J ˆ 7.5 Hz,2H),1.30 (t, J ˆ
7.1 Hz,3H),1.29 (t, J ˆ 7.3 Hz,3H),1.16 (sext, J ˆ 7.5 Hz,2H),0.85 ppm (t,
J ˆ 7.3 Hz,3H); 13C NMR (C6D6,75 MHz): d ˆ 140.1,129.2,128.6,127.3,
The reaction was carried out according to procedure B with enamine 1i
(80 mg,0.30 mmol,1.2 equiv),1-hexyne ( 2k) (21 mg,0.25 mmol),CuBr
92.1,83.7,81.7,60.8,55.5,52.0,33.8,28.8,22.5,15.4,14.1 ppm; IR (film):
3063 (w),3029 (w),2932 (m),2874 (m),2236 (w),1495 (m),1454 (m),1132
nÄ ˆ
(1.8 mg,0.0125 mmol,5.0 mol%),(
R)-Quinap (6.0 mg,0.01375,
(s),1053 (vs),747 (s),699 cm À1 (vs); MS: m/z (%): 348 (12) [M À C2H5O],
‡
5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene (3 mL) at room
temperature for 120 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 98:2) yielded 3s (47 mg,0.14 mmol,
56%,76% ee) as a colorless oil. [a]2D0 ˆ À124 (c ˆ 1.03 in CHCl3); HPLC
(OD-H,99% n-heptane/1% isopropanol,0.1 mLmin À1): tr (min) ˆ 47.2
(À),50.6 ( ‡); 1H NMR (300 MHz,CDCl 3): d ˆ 7.40 7.38 (m,4H),7.33
7.20 (m,6H),3.80 (d, J ˆ 13.7 Hz,2H),3.44 (tt, J ˆ 7.8,2.2 Hz,1H),3.37 (d,
J ˆ 13.7 Hz,2H),2.30 (td, J ˆ 7.2,2.3 Hz,2H),1.86 (sept, J ˆ 6.6 Hz,1H),
‡
336 (100) [M À C4H9],234 (62),91 (85); HRMS (EI): m/z: calcd for
‡
C22H26NO2 [M À C4H9]: 336.1964; found: 336.1964; elemental analysis
calcd (%) for C22H26NO2: C 79.35,H 8.96,N 3.56; found: C 79.12,H 8.82,N
3.55.
N,N-Bis-(4-methoxybenzyl)-1-phenyl-1-heptyn-3-amine (3q): The reaction
was carried out according to procedure A with enamine 1h (1.300 g,
4.00 mmol,2.0 equiv),phenylacetylene ( 2a) (0.204 g,2.00 mmol),CuBr
(14 mg,0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in
1.67 1.36 (m,6H),0.98 (t,
J ˆ 7.0 Hz,3H),0.78 (d,
J ˆ 6.6 Hz,3H),
toluene (4 mL) at room temperature for 5 h. Standard workup and column
0.66 ppm (d, J ˆ 6.6 Hz,3H); 13C NMR (75 MHz,CDCl 3): d ˆ 140.1,128.9,
2806
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9,2797 2811

Enantiomerically Enriched Propargylamines
2797 2811
128.1,126.7,84.8,78.1,54.8,49.7,43.3,31.4,24.6,22.8,22.0,21.9,18.4,
The reaction was carried out according to procedure B with enamine 1k
(219 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
‡
13.6 ppm; MS: m/z (%): 291 (22) [M À C4H9],290 (100),91 (61); HRMS
‡
(EI): m/z:calcd for C25H32N [M À H]: 346.2583; found: 346.2543; IR
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
(film): nÄ ˆ 2956 (vs),2932 (vs),2869 (m),1494 (m),1454 (s),745 (s),
698 cmÀ1 (vs); elemental analysis calcd (%) for C25H32N: C 86.40,H 9.57,N
4.03; found: C 86.18,H 9.70,N 4.00.
(4 mL) at room temperature for 96 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) yielded 3w
(155 mg,0.39 mmol,79%,88% ee) as a white solid. [a]2D0 ˆ À231 (c ˆ 0.50
in CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,0.2 mLmin À1):
tr (min) ˆ 41.3 (‡),46.2 ( À); 1H NMR (CDCl3,300 MHz): d ˆ 7.46 7.11
(m,15H),3.80 (d, J ˆ 13.7 Hz,2H),3.39 (d, J ˆ 13.8 Hz,2H),3.17 (d, J ˆ
10.3 Hz,1H),2.25 (d, J ˆ 12.9 Hz,1H),1.99 (d, J ˆ 12.80 Hz,1H),1.68
N,N-Dibenzyl-4-methyl-1-phenyl-1-pentyn-3-amine (3t):[27] The reaction
was carried out according to procedure A with enamine 1j (0.653 g,
2.60 mmol,1.3 equiv),phenylacetylene ( 2a) (0.204 g,2.00 mmol),CuBr
(14 mg,0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in
toluene (4 mL) at room temperature for 12 h and at 608C for 1 h. Standard
workup and column chromatographic purification (silica gel,pentane/Et 2O
99:1) afforded 3t (0.702 g,1.99 mmol,99%) as a colorless oil.
1.45 (m,4H),1.23 0.55 ppm (m,5H);
139.8,131.8,128.9,128.3,128.2,127.8,126.8,123.7,87.1,86.2,58.4,55.1,39.8,
13C NMR (CDCl3,75 MHz): d ˆ
31.4,30.3,26.6,26.2,26.0 ppm; IR (KBr): nÄ ˆ 3061 (w),3030 (w),2928 (vs),
2850 (s),1598 (w),1489 (m),1450 (m),756 (s),747 (s),698 (s),692 cm
À1 (s);
The reaction was carried out according to procedure B with enamine 1j
(189 mg,0.75 mmol,1.5 equiv),phenylacetylene ( 2a) (51 mg,0.50 mmol),
‡
MS: m/z (%): 310 (100) [M À C6H11],218 (3),191 (2),115 (5),91 (51);
‡
CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
0.0275 mmol,5.5 mol%),and n-decane (50 mg,0.35 mmol) in toluene
R)-(‡)-Quinap (12.1 mg,
HRMS (EI): m/z: calcd for C29H30N [M À H]: 392.2378; found: 392.2349.
N,N-Dibenzyl-3-(4-bromophenyl)-1-cyclohexyl-2-propyn-1-amine
(3x):
(4 mL) at room temperature for 120 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 99:1) yielded 3t
(113 mg,0.32 mmol,64%,87% ee) as a colorless oil. [a]2D0 ˆ À303 (c ˆ 0.58
in CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,0.2 mLmin À1):
tr (min) ˆ 21.2 (À),22.9 ( ‡); 1H NMR (300 MHz,CDCl 3): d ˆ 7.48 7.15 (m,
15H),3.84 (d, J ˆ 13.7 Hz,2H),3.42 (d, J ˆ 13.6 Hz,2H),3.07 (d, J ˆ
10.1 Hz,1H),2.01 1.87 (m,1H),0.97 (d, J ˆ 6.1 Hz,3H),0.96 ppm (d, J ˆ
6.2 Hz,3H); 13C NMR (75 MHz,CDCl 3): d ˆ 139.8,131.8,128.9,128.3,
The reaction was carried out according to procedure A with enamine 1k
(0.758 g,2.60 mmol,1.3 equiv),4-bromophenylacetylene (
2.00 mmol),CuBr (14 mg,0.10 mmol,5.0 mol%),and
2n) (0.362 g,
n-decane (0.360 g,
2.53 mmol) in toluene (4 mL) at room temperature for 14 h and at 608C for
4 h. Standard workup and column chromatographic purification (silica gel,
pentane/Et2O 98:2) afforded 3x (0.855 g,1.81 mmol,90%) as a white solid.
The reaction was carried out according to procedure B with enamine 1k
(219 mg,0.75 mmol,1.5 equiv),4-bromophenylacetylene
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
(
2n) (91 mg,
R)-(‡)-Quinap
128.2,127.8,126.8,123.7,87.4,86.0,59.7,55.1,30.8,21.0,20.0 ppm; MS:
m/z
‡
(%): 353 (1) [M ],311 (25),310 (100),91 (48).
(12.1 mg,0.0275 mmol,5.5 mol%),and n-decane (100 mg,0.70 mmol) in
toluene (4 mL) at room temperature for 44 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) yielded 3x
(197 mg,0.42 mmol,83%,90% ee) as a white solid. [a]2D0 ˆ À239 (c ˆ 0.80
in CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,0.2 mLmin À1):
tr (min) ˆ 21.1 (À),22.9 ( ‡); 1H NMR (CDCl3,300 MHz): d ˆ 7.41 7.11
(m,14H),3.80 (d, J ˆ 13.7 Hz,2H),3.36 (d, J ˆ 14.1 Hz,2H),3.15 (d, J ˆ
10.4 Hz,1H),2.30 2.16 (m,1H),2.10 1.88 (m,1H),1.68 1.48 (m,4H),
1.25 0.91 (m,3H),0.88 0.60 ppm (m,2H); 13C NMR (CDCl3,75 MHz):
d ˆ 139.7,133.3,131.5,128.8,128.2,126.9,122.6,121.9,88.5,85.2,58.4,55.1,
N,N-Dibenzyl-4-methyl-1-(triisopropylsilyl)-1-pentyn-3-amine (3u): The
reaction was carried out according to procedure A with enamine 1j
(1.510 g,6.00 mmol,1.5 equiv),triisopropylacetylene
4.00 mmol),CuBr (28 mg,0.20 mmol,5.0 mol%),and
(
2l) (0.720 g,
n-decane (0.200 g,
1.41 mmol) in toluene (4 mL) at room temperature for 14 h and at 608C for
7 h. Standard workup and column chromatographic purification (silica gel,
pentane/Et2O 98:2) afforded 3u (1.530 g,3.52 mmol,88%) as a colorless oil
which slowly crystallized. M.p. 438C; 1H NMR (300 MHz,CDCl 3): d ˆ
7.33 7.30 (m,4H),7.25 7.12 (m,6H),3.75 (d,
J ˆ 13.7 Hz,2H),3.34 (d,
J ˆ 13.7 Hz,2H),2.85 (d, J ˆ 10.1 Hz,1H),1.90 1.77 (m,1H),1.22 1.18
39.7,31.3,30.3,26.6,26.1,26.9 ppm; IR (KBr):
nÄ ˆ 3062 (w),3028 (w),2932
(m,3H),1.08 (s,18H),0.93 (d,
J ˆ 6.6 Hz,3H),0.92 ppm (d, J ˆ 6.6 Hz,
(vs),2850 (m),1603 (w),1485 (vs),1452 (m),1070 (m),827 (s),747 (s),
3H); 13C NMR (75 MHz,CDCl 3): d ˆ 139.8,128.8,128.2,126.8,105.5,85.4,
‡
698 cmÀ1 (vs); MS: m/z (%): 310 (100) [M À C6H11],218 (3),191 (2),115
‡
59.9,55.1,30.2,20.9,19.9,18.8,11.4 ppm; MS:
m/z (%): 433 (1) [M ],391
‡
(5),91 (51); HRMS (EI): m/z: calcd for C29H29BrN [M À H]: 470.1483;
‡
(33),390 (100),91 (26); HRMS (EI): m/z: calcd for C29H42NSi [M À H]:
432.3087; found: 432.3054; IR (KBr): nÄ ˆ 2942 (vs),2865 (vs),2157 (m),
1494 (m),1454 (s),1383 (m),1365 (m),1070 (m),1017 (s),883 (m),746 (s),
697 (vs),676 (s),659 cm À1 (m); elemental analysis calcd (%) for C29H42NSi:
C 80.30,H 9.99,N 3.23; found: C 80.47,H 9.80,N 3.05.
found: 470.1495; elemental analysis calcd (%) for C29H29BrN: C 73.72,H
6.40,N 2.96; found: C 73.52,H 6.55,N 2.94.
N-Allyl-N-benzyl-1-cyclohexyl-2-nonyn-1-amine (3y): The reaction was
carried out according to procedure A with enamine 1l (0.531 g,2.60 mmol,
1.3 equiv),1-octyne ( 2b) (0.220 g,2.00 mmol),CuBr (7 mg,0.05 mmol,
2.5 mol%),and n-decane (0.200 g,1.41 mmol) in toluene (4 mL) at 60 8C
for 24 h. Standard workup and column chromatographic purification (silica
gel,pentane/Et 2O 98:2) afforded 3y (0.570 g,1.62 mmol,80%) as a
colorless oil. 1H NMR (CDCl3,300 MHz): d ˆ 7.32 7.10 (m,5H),5.82
N,N-Dibenzyl-2,6-dimethyl-6-[(trimethylsilyl)oxy]-4-heptyn-3-amine (3v):
The reaction was carried out according to procedure A with enamine 1j
(0.754 g,3.00 mmol,1.5 equiv),[(11, -dimethyl-2-propynyl)oxy](trimethyl)-
silane (2m) (0.313 g,2.00 mmol),CuBr (14 mg,0.10 mmol,5.0 mol%),and
n-decane (0.200 g,1.41 mmol) in toluene (4 mL) at room temperature for
14 h and at 608C for 20 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 97:3) afforded 3v (0.691 g,1.70 mmol,
85%) as a colorless oil which slowly crystallized. M.p. 598C; 1H NMR
(300 MHz,CDCl 3): d ˆ 7.33 7.30 (m,4H),7.25 7.12 (m,6H),3.74 (d, J ˆ
13.7 Hz,2H),3.30 (d, J ˆ 13.8 Hz,2H),2.83 (d, J ˆ 10.7 Hz,1H),1.91 1.71
(m,1H),1.51 (d, J ˆ 2.0 Hz,6H),0.93 (d, J ˆ 6.6 Hz,3H),0.89 (d, J ˆ
5.64 (m,1H),5.19 5.09 (m,1H),5.04 4.95 (m,1H),3.74 (d,
J ˆ 13.8 Hz,
J ˆ 6.8,2.0 Hz,2H),2.15
1H),3.25 (d, J ˆ 13.7 Hz,1H),3.17 3.05 (m,1H),2.97 (dt, J ˆ 10.1,2.3 Hz,
1H),2.81 (dd, J ˆ 14.5,8.1 Hz,1H),2.17 (td,
2.05 (m,1H),1.98 1.85 (m,1H),1.68 0.66 (m,17H),0.84 ppm (t,
6.9 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 140.4,137.3,128.7,128.1,
126.6,116.5,85.6,77.1,58.2,54.9,53.7,40.2,31.4,31.3,30.4,29.3,28.5,26.7,
J ˆ
26.2,26.0,22.6,18.7,14.1 ppm; IR (film):
nÄ ˆ 3065 (w),3029 (w),2957 (s),
6.7 Hz,3H),0.17 ppm (s,9H);
13C NMR (75 MHz,CDCl 3): d ˆ 139.8,
À1
2932 (vs),2859 (m),1494 (w),1455 (m)9,18 (m),737 (m),698 cm
(m);
‡
128.8,128.2,126.8,91.2,80.4,66.7,59.1,55.1,33.9,30.6,20.9,19.9,2.1 ppm;
MS: m/z (%): 268 (100) [M À C6H11],196 (2),146 (2),131 (2),91 (45);
‡
‡
MS: m/z (%): 407 (1) [M ],365 (29),364 (100),91 (39); HRMS (EI): m/z:
HRMS (EI): m/z: calcd for C23H33N [M À C2H4]: 323.2613; found:
‡
calcd for C26H35NOSi [M À H]: 406.2566; found: 406.2561; IR (KBr): nÄ ˆ
323.2598.
2981 (s),2959 (s),1454 (m),1248 (s),1161 (s),1033 (vs),842 (vs),746 (s),
698 cmÀ1 (s); elemental analysis calcd (%) for C26H35NOSi: C 76.60,H 9.15,
N 3.44; found: C 76.33,H 9.21,N 3.39.
N,N-Diallyl-1-cyclohexyl-2-nonyn-1-amine (3z): The reaction was carried
out according to procedure A with enamine 1m (0.631 g,3.30 mmol,
1.1 equiv),1-octyne ( 2b) (0.331 g,3.00 mmol),CuBr (22 mg,0.15 mmol,
5.0 mol%),and n-decane (0.300 g,2.11 mmol) in toluene (4 mL) at room
temperature for 15 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 98:2) afforded 3z (0.754 g,2.50 mmol,
82%) as a colorless oil. 1H NMR (CDCl3,300 MHz): d ˆ 5.86 5.72 (m,
2H),5.23 5.20 (m,1H),5.17 5.14 (m,1H),5.10 5.07 (m,1H),5.06 5.03
N,N-Dibenzyl-1-cyclohexyl-3-phenyl-2-propyn-1-amine (3w): The reaction
was carried out according to procedure A with enamine 1k (1.049 g,
3.60 mmol,1.2 equiv),phenylacetylene ( 2a) (0.306 g,3.00 mmol),CuBr
(22 mg,0.15 mmol,5.0 mol%),and
n-decane (0.300 g,2.11 mmol) in
toluene (6 mL) at room temperature for 24 h and at 608C for 3 h. Standard
workup and column chromatographic purification (silica gel,pentane/Et 2O
98:2) afforded 3w (1.115 g,2.83 mmol,94%) as a white solid.
(m,1H),3.60 3.14 (m,2H),3.09 (dt,
J ˆ 14.4,8.1 Hz,2H),2.21 (td, J ˆ 6.9,2.2 Hz,2H),2.10 1.90 (m,2H),
J ˆ 10.1,2.0 Hz,1H),2.83 (dd,
Chem. Eur. J. 2003, 9,2797 2811
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
2807

P. Knochel et al.
FULL PAPER
1.77 1.02 (m,16H),0.98 0.74 (m,1H),0.88 ppm (t,
J ˆ 6.9 Hz,3H);
(300 MHz,CDCl 3): d ˆ 7.32 7.30 (m,4H),7.25 7.12 (m,6H),3.75 (d, J ˆ
13C NMR (CDCl3,75 MHz): d ˆ 137.3,116.4,85.4,77.2,58.3,53.9,40.3,31.3,
13.7 Hz,2H),3.34 3.28 (m,3H),2.23 (d,
J ˆ 2.2 Hz,1H),1.72 1.49 (m,
31.2,30.4,29.2,28.5,26.7,26.2,26.0,22.6,18.7,14.0 ppm; IR (film):
nÄ ˆ 3079
2H),1.39 1.22 (m,2H),1.17 1.05 (m,2H),0.76 ppm (d,
J ˆ 7.4 Hz,3H);
(w),2925 (vs),2853 (s),1839 (w),1643 (m),1448 (s)9, 18 cm
À1 (s); MS: m/z
13C NMR (75 MHz,CDCl ): d ˆ 139.7,128.8,128.2,126.9,82.2,72.4,54.7,
3
‡
‡
(%): 300 (1) [M À H],218 (100),192 (3),162 (6),146 (2),120 (8),106 (7),
51.4,33.4,28.4,22.2,13.9 ppm; MS:
m/z (%): 290 (1) [M À H],235 (22),
‡
91 (8); HRMS (EI): m/z: calcd for C21H36N [M ‡H]: 302.2848; found:
234 (98),181 (11),92 (100),65 (10); HRMS (EI): m/z: calcd for C21H24N
‡
302.2860; elemental analysis calcd (%) for C21H36N: C 83.65,H 11.70,N
4.65; found: C 83.72,H 11.93,N 4.67.
[M À H]: 290.1909; found: 290.1885; IR (film): nÄ ˆ 3302 (m),2956 (s),
À1
2934 (s),2860 (m),1494 (m),1454 (s),746 (s),698 cm
(vs); elemental
analysis calcd (%) for C21H24N: C 86.55,H 8.65,N 4.81; found: C 86.84,H
8.80,N 4.97.
N,N-Diallyl-1-(phenylethynyl)cyclohexanamine (3aa): The reaction was
carried out according to procedure A with enamine 1n (0.585 g,3.30 mmol,
1.1 equiv),phenylacetylene
0.15 mmol,5.0 mol%),and
(
2a) (0.306 g,3.00 mmol),CuBr (22 mg,
n-decane (0.200 g,1.41 mmol) in toluene
N,N-Dibenzyl-1-(2-pyridinyl)-1-heptyn-3-amine (3ae): The reaction was
carried out according to procedure A with enamine 1g (0.318 g,1.20 mmol,
1.2 equiv),2-pyridinylacetylene ( 2o) (0.103 g,1.00 mmol),CuBr (7 mg,
(6 mL) at 608C for 24 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 98:2) afforded 3aa (0.626 g,
2.24 mmol,75%) as a colorless oil. 1H NMR (CDCl3,300 MHz): d ˆ
0.05 mmol,5.0 mol%),and
n-decane (0.100 g,0.70 mmol) in toluene
(2 mL) at 608C for 48 h. Standard workup and column chromatographic
7.37 7.30 (m,2H),7.25 7.17 (m,3H),5.90 (m,2H),5.07 (dd,
J ˆ 1.8,
purification (silica gel,pentane/Et 2O 9:1,then pentane/Et O 1:1) afforded
2
17.3 Hz,2H),4.98 (dd, J ˆ 1.8,10.2 Hz,2H),3.29 (d, J ˆ 6.3 Hz,4H),2.04
3ae (0.173 g,0.47 mmol,47%) as a yellow oil.
1.92 (m,2H),1.68 1.40 (m,7H),1.22 0.80 ppm (m,1H);
13C NMR
The reaction was carried out according to procedure B with enamine 1g
(CDCl3,75 MHz): d ˆ 137.7,131.5,128.2,127.6,123.8,115.7,92.5,85.4,59.1,
(199 mg,0.75 mmol,1.5 equiv),2-pyridinylacetylene
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
(
2o) (52 mg,
R)-(‡)-Quinap
51.8,37.3,25.6,23.1 ppm; IR (film): nÄ ˆ 3077 (w),2933 (vs),2856 (m),1642
(w),1598 (w),1490 (m),1444 (m),915 (s),755 (vs),690 cm
À1 (m); MS: m/z
(12.1 mg,0.0275 mmol,5.5 mol%),and
n-decane (50 mg,0.35 mmol) in
‡
(%): 278 (100) [M À H],264 (48),250 (62),236 (55),222 (24),208 (72),115
toluene (4 mL) at room temperature for 76 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 9:1 then 1:1) yielded
3ae (135 mg,0.37 mmol,73%,70% ee) as a yellow oil. [a]2D0 ˆ À174 (c ˆ
‡
(48),91 (19); HRMS (EI): m/z: calcd for C20H24N [M À H]: 278.1909;
found: 278.1902; elemental analysis calcd (%) for C20H24N: C 85.97,H 9.02,
N 5.01; found: C 85.83,H 8.96,N 5.02.
0.98 in CHCl3); HPLC (OD-H,99%
n-heptane/1% isopropanol,
1-Benzyl-2-(phenylethynyl)piperidine (3ab): The reaction was carried out
according to procedure A with enamine 1o (0.347 g,2.00 mmol),phenyl-
acetylene (2a) (0.225 g,2.20 mmol,1.1 equiv),CuBr (14 mg,0.10 mmol,
5.0 mol%),and n-decane (0.200 g,1.41 mmol) in toluene (4 mL) at 80 8C
for 3 h. Standard workup and column chromatographic purification (silica
gel,pentane/Et 2O 9:1) afforded 3ab (0.476 g,1.73 mmol,86%) as a
colorless oil. 1H NMR (CDCl3,300 MHz): d ˆ 7.43 7.11 (m,10H),3.64 (d,
0.5 mLminÀ1): tr (min) ˆ 17.3 (À),18.8 ( ‡); 1H NMR (CDCl3,300 MHz):
d ˆ 8.54 8.50 (m,1H),7.55 (td, J ˆ 7.7,1.8 Hz,1H),7.42 7.30 (m,4H),
7.25 7.19 (m,4H),7.17 7.09 (m,4H),3.83 (d, J ˆ 13.6 Hz,2H),3.56 (t, J ˆ
7.6 Hz,1H),3.50 (d, J ˆ 13.6 Hz,2H),1.81 1.60 (m,2H),1.42 1.22 (m,
2H),1.12 (sext, J ˆ 7.4 Hz,2H),0.76 ppm (t, J ˆ 7.3 Hz,3H); 13C NMR
(CDCl3,75 MHz): d ˆ 149.9,143.6,139.7,136.0,128.8,128.1,127.4,126.8,
122.5,88.6,84.8,54.9,52.0,33.3,28.4,22.2,13.9 ppm; IR (film):
nÄ ˆ 3062
J ˆ 13.3 Hz,1H),3.64 3.55 (m,1H),3.56 (d,
(m,1H),2.48 2.34 (m,1H),1.80 1.38 ppm (m,6H);
75 MHz): d ˆ 138.6,131.7,129.2,128.2,128.1,127.8,126.9,123.6,87.5,86.7,
60.5,51.7,49.2,31.4,25.8,20.8 ppm; IR (film):
J ˆ 13.4 Hz,1H),2.60 2.49
(m),3029 (m),2955 (s),2932 (s),2860 (m),2214 (w),1582 (vs),1463 (vs),
13C NMR (CDCl3,
À1
‡
1427 (s),779 (s),740 (s),690 cm
(vs); MS: m/z (%): 311 (100) [M
À
C4H9],219 (6),194 (9),130 (5),91 (65); HRMS (EI):
m/z: calcd for
nÄ ˆ 3063 (w),3028 (w),2955
‡
C22H19N2 [M À C4H9]: 311.1548; found: 311.1522; elemental analysis calcd
(m),2934 (m),2248 (m),1603 (w),1494 (s),1454 (s),1028 (m),747 (s),
(%) for C22H19N2: C 84.74,H 7.66,N 7.60; found: C 84.28,H 7.61,N 7.43.
‡
699 cmÀ1 (vs); MS: m/z (%): 275 (82) [M ],246 (37),184 (100),156 (19),
N,N-Dibenzyl-1-(3-pyridinyl)-1-heptyn-3-amine (3af): The reaction was
carried out according to procedure A with enamine 1g (0.318 g,1.20 mmol,
1.2 equiv),3-pyridinylacetylene ( 2p) (0.103 g,1.00 mmol),CuBr (7 mg,
‡
128 (52),115 (39),91 (87); HRMS (EI): m/z: calcd for C20H21N [M ]:
275.1674; found: 275.1663. elemental analysis calcd (%) for C20H21N: C
87.23,H 7.69,N 5.09; found: C 87.28,H 7.97,N 5.08.
0.05 mmol,5.0 mol%),and
n-decane (0.100 g,0.70 mmol) in toluene
N,N-Diallyl-1-phenyl-3-decyn-2-amine (3ac): The reaction was carried out
according to procedure A with enamine 1p (0.518 g,2.60 mmol,1.3 equiv),
1-octyne (2b) (0.220 g,2.00 mmol),CuBr (14 mg,0.10 mmol,5.0 mol%),
and n-decane (0.200 g,1.41 mmol) in toluene (4 mL) at 60 8C for 20 h.
Standard workup and column chromatographic purification (silica gel,
pentane/Et2O 98:2) afforded 3ac (0.489 g,1.58 mmol,79%) as a colorless
oil. 1H NMR (300 MHz,CDCl 3): d ˆ 7.37 7.23 (m,5H),5.93 5.79 (m,
2H),5.28 5.25 (m,1H),5.22 5.20 (m,1H),5.18 5.16 (m,1H),5.15 5.12
(m,1H),3.84 3.76 (m,1H),3.42 3.33 (m,2H),3.10 2.86 (m,4H),2.25
(2 mL) at 608C for 48 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 9:1,then pentane/Et O 1:1) afforded
2
3af (0.215 g,0.58 mmol,58%) as a yellow oil.
The reaction was carried out according to procedure B with enamine 1g
(199 mg,0.75 mmol,1.5 equiv),3-pyridinylacetylene
0.50 mmol),CuBr (3.6 mg,0.025 mmol,5.0 mol%),(
(
2p) (52 mg,
R)-(‡)-Quinap
(12.1 mg,0.0275 mmol,5.5 mol%),and
n-decane (50 mg,0.35 mmol) in
toluene (4 mL) at room temperature for 48 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 9:1 then 1:1) yielded
3af (104 mg,0.28 mmol,57%,70% ee) as a yellow oil. [a]2D0 ˆ À190 (c ˆ
(td, J ˆ 6.9,2.3 Hz,2H),1.60 1.28 (m,8H),0.98 ppm (t,
J ˆ 6.9 Hz,3H);
13C NMR (75 MHz,CDCl 3): d ˆ 139.1,136.6,129.4,127.9,126.1,116.9,86.0,
0.91 in CHCl3); HPLC (OD-H,99%
n-heptane/1% isopropanol,
77.4,54.7,53.9,40.6,31.3,29.0,28.5,22.2,18.6,14.0 ppm; MS:
m/z (%): 218
0.5 mLminÀ1): tr (min) ˆ 17.3 (‡),18.5 ( À); 1H NMR (CDCl3,300 MHz):
d ˆ 8.65 (brs,1H),8.43 (d, J ˆ 4.0 Hz,1H),7.66 (dt, J ˆ 7.8,2.0 Hz,1H),
7.36 7.10 (m,11H),3.81 (d, J ˆ 13.7 Hz,2H),3.54 (t, J ˆ 7.7 Hz,1H),3.38
‡
(100) [M À C7H8],162 (3),146 (3),128 (3),106 (3),91 (13); HRMS (EI):
‡
m/z: calcd for C22H32N [M ‡H]: 310.2535; found: 310.2557; IR (film): nÄ ˆ
3079 (w),2956 (vs),2930 (s),2858 (m),1642 (w),1496 (w),1454 (m),919 (s),
698 cmÀ1 (s); elemental analysis calcd (%) for C22H32N: C 85.38,H 10.10,N
4.53; found: C 85.22,H 10.45,N 4.51.
(d, J ˆ 13.7 Hz,2H),1.80 1.56 (m,2H),1.46 1.22 (m,2H),1.13 (sext,
7.3 Hz,2H),0.78 ppm (t, J ˆ 7.3 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ
152.5,148.2,139.6,138.6,128.7,128.2,127.1,126.9,122.9,91.8,81.9,54.9,
52.2,33.3,28.4,22.2,13.9 ppm; IR (film): nÄ ˆ 3062 (w),3028 (m),2955 (m),
J ˆ
N,N-Dibenzyl-1-heptyn-3-amine (3ad): The reaction was carried out
according to procedure A with enamine 1g (1.274 g,4.80 mmol,1.2 equiv),
trimethylsilylacetylenene (2i) (0.392 g,4.00 mmol),CuBr (28 mg,
À1
2932 (m),2228 (vw),1604 (w),1494 (s),1454 (s),804 (m),747 (s),699 cm
‡
(vs); MS: m/z (%): 311 (100) [M À C4H9],219 (3),194 (4),116 (3),91 (67);
0.20 mmol,5.0 mol%),and
n-decane (0.400 g,2.81 mmol) in toluene
‡
HRMS (EI): m/z: calcd for C22H19N2 [M À C4H9]: 311.1548; found:
(8 mL) at room temperature for 20 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 3o
(1.142 g,3.14 mmol,79%) as a colorless oil. Propargylamine 3o (0.909 g,
2.5 mmol) was dissolved in THF (10 mL) and TBAF (1m in THF,2.75 mL,
2.75 mmol,1.1 equiv) was added dropwise at room temperature. The
reaction mixture was stirred for 30 min,hydrolyzed,and extracted with
Et2O. The combined organic layers were dried over MgSO4 and the crude
product purified by column chromatography (silica gel,pentane/Et 2O 98:2)
to afford 3ad (0.694 g,2.40 mmol,95%) as a light yellow oil. 1H NMR
311.1558.
N4,N4-Diallyl,N7,N7-dibenzyl-2-methyl-5-undecyne-4,7-diamine (4): The
reaction was carried out according to procedure A with enamine 1i
(0.149 g,0.90 mmol,1.2 equiv),
N,N-dibenzyl-1-heptyn-3-amine (3ad)
(0.219 g,0.75 mmol),CuBr (5.4 mg,0.0375 mmol,5.0 mol%),and n-decane
(0.100 g,0.70 mmol) in toluene (2 mL) at 60 8C for 19 h. Standard workup
and column chromatographic purification (silica gel,pentane/Et 2O 93:7)
afforded 4 (0.342 g,0.74 mmol,99%,diastereomeric ratio 1:1) as a
2808
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9,2797 2811

Enantiomerically Enriched Propargylamines
2797 2811
1
colorless oil. H NMR (400 MHz,CDCl 3): d ˆ 7.32 7.30 (m,4H),7.23 (t,
6.00 mmol,6 equiv),and 3a (0.267 g,1.00 mmol) in CH 2Cl2 (3 mL) at room
temperature for 90 min. Purification of the crude product (solution in
Et2O) was achieved by extraction with HCl solution (2m),then treatment
with saturated K2CO3 solution (pH > 8),extraction of the aqueous layers
with CH2Cl2 and drying over MgSO4 to yield 7c (0.170 g,0.91 mmol,91%)
as a yellow oil.
J ˆ 8.0 Hz,4H),7.17 7.13 (m,2H),5.85 5.75 (m,2H),5.18 (d, J ˆ 17.0 Hz,
2H),5.06 (d, J ˆ 10.0 Hz,2H),3.75 (d, J ˆ 13.7 Hz,2H),3.63 (t, J ˆ 7.6 Hz,
1H),3.33 (d, J ˆ 13.7 Hz,2H),3.34 3.24 (m,3H),2.90 (dd,
J ˆ 14.0,
J ˆ
6.1 Hz,2H),1.82 (sept, J ˆ 6.8 Hz,1H),1.67 1.51 (m,2H),1.48 (t,
7.1 Hz,2H),1.40 1.24 (m,2H),1.18 1.08 (m,2H),0.89 (d,
J ˆ 6.7 Hz,
3H),0.86 (d, J ˆ 6.8 Hz,3H),0.78 ppm (t,
J ˆ 7.3 Hz,3H); 13C NMR
The chiral reaction was similarly performed with [Pd(PPh3)4] (11 mg,
(75 MHz,CDCl 3): d ˆ 140.0,136.9,128.8,128.2,126.8,116.9,82.9,82.5,
0.009 mmol,5 mol%), 8 (175 mg,1.12 mmol,6 equiv),and
3a (50 mg,
55.0,54.2,51.8,50.8,43.4,33.9,28.6,25.2,22.8,22.5,22.3,14.0 ppm; MS:
0.19 mmol) in CH2Cl2 (2 mL) at room temperature for 90 min and yielded
7c (28 mg,0.15 mmol,80%) as a yellow oil. [ a]2D0 ˆ ‡5 (c ˆ 1.02 in CHCl3);
1H NMR (CDCl3,300 MHz): d ˆ 7.35 7.28 (m,2H),7.23 7.15 (m,3H),
‡
m/z (%): 400 (19) [M À C4H9],399 (62),266 (10),234 (27),166 (10),134
‡
(22),91 (100); HRMS (EI): m/z: calcd for C32H45N [M ‡H]: 457.3583;
found: 457.3607; IR (film): nÄ ˆ 2955 (vs),2932 (vs),2870 (m),2812 (m),1454
3.68 (t, J ˆ 6.5 Hz,1H),1.70 1.10 (m,6H),0.86 ppm (t,
J ˆ 7.2 Hz,3H);
À1
(m),919 (m),698 cm
(s); elemental analysis calcd (%) for C32H45N: C
13C NMR (CDCl3,75 MHz): d ˆ 131.5,128.2,127.8,123.3,93.1,82.4,44.0,
84.16,H 9.71,N 6.11; found: C 84.09,H 10.09,N 6.03.
38.0,28.2,22.4,14.0 ppm; IR (film): nÄ ˆ 3370 (w),3057 (w),2931 (s),2957
À1
N-Benzyl-1-phenyl-1-heptyn-3-amine (7a)
(vs),2859 (m),1682 (w),1598 (m),1490 (s),756 (vs),692 cm
(vs); MS:
‡
m/z (%): 186 (1) [M À H],130 (100),115 (3),103 (11),77 (7); HRMS (EI):
Typical procedure C: Pd(dba)2 (29 mg,0.05 mmol,5 mol%) and dppb
(21 mg,0.05 mmol,5 mol%) were dissolved in THF (1 mL) and the
reaction mixture was stirred at room temperature for 15 min. In a second
flask,thiosalicylic acid ( 6) (0.170 g,1.10 mmol,1.1 equiv) was dissolved in
THF (2 mL),propargylamine 3b (0.317 g,1.00 mmol) was added and the
reaction mixture stirred for 15 min. The catalyst solution was then added
dropwise to the amine solution and stirred at room temperature for 5 h.
After dilution with Et2O,extraction with saturated Na 2CO3 solution,and
drying over MgSO4,the crude product was purified by column chromatog-
raphy (silica gel,pentane/Et 2O 4:1) to afford 7a (0.249 g,0.90 mmol,90%)
as a colorless oil.
‡
m/z: calcd for C13H16N [M À H]: 186.1283; found: 186.1281.
N-Allyl-1-phenyl-1-heptyn-3-amine (7d)
Starting from 3a: The reaction was carried out according to procedure C
with Pd(dba)2 (29 mg,0.05 mmol,5 mol%),dppb (21 mg,0.05 mmol,
5 mol%), 6 (0.185 g,1.2 mmol,1.2 equiv),and 3a (0.267 g,1.00 mmol) in
THF (3 mL) at 08C for 2 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 1:1) yielded 7d (0.170 g,0.75 mmol,
75%) as a colorless oil. The chiral reaction was similarly performed with
[Pd(dba)2] (5.4 mg,0.009 mmol,5 mol%),dppb (4.0 mg,0.009 mmol,
5 mol%), 6 (35 mg,0.22 mmol,1.2 equiv),and
3a (50 mg,0.19 mmol) in
The chiral reaction was similarly performed with Pd(dba)2 (12 mg,
0.021 mmol,5 mol%),dppb (9 mg,0.021 mmol,5 mol%),
THF (3 mL) at 08C for 2 h. Standard workup and column chromatographic
purification (silica gel,pentane/Et 2O 1:1) yielded 7d (25 mg,0.11 mmol,
62%,77% ee) as a colorless oil. [a]2D0 ˆ À46 (c ˆ 0.75 in CHCl3); HPLC
(OD-H,99% n-heptane/1% isopropanol,0.6 mLmin À1): tr (min) ˆ 8.6 (‡),
11.2 (À); 1H NMR (CDCl3,300 MHz): d ˆ 7.38 7.30 (m,2H),7.25 7.15
(m,3H),5.95 5.80 (m,1H),5.22 5.02 (m,2H),3.56 3.44 (m,2H),3.33
6 (96 mg,
0.62 mmol,1.5 equiv),and 3b (132 mg,0.42 mmol) at room temperature
for 2 h. Standard workup and column chromatographic purification (silica
gel,pentane/Et 2O 4:1) yielded 7a (105 mg,0.38 mmol,91%,82% ee) as a
colorless oil. [a]2D0 ˆ À66 (c ˆ 0.38 in CHCl3); HPLC (OD-H,99% n-
heptane/1% isopropanol,0.9 mLmin À1): tr (min) ˆ 30.6 (‡),41.8 ( À);
1H NMR (CDCl3,300 MHz): d ˆ 7.40 7.10 (m,10H),4.00 (d, J ˆ 12.8 Hz,
1H),3.80 (d, J ˆ 12.9 Hz,1H),3.50 (t, J ˆ 6.8 Hz,1H),1.73 1.55 (m,2H),
1.50 1.35 (m,3H),1.28 (sext, J ˆ 7.2 Hz,2H),0.83 ppm (t, J ˆ 7.3 Hz,3H);
13C NMR (CDCl3,75 MHz): d ˆ 140.1,131.6,128.34,128.32,128.2,127.8,
3.22 (m,1H),1.72 1.54 (m,2H),1.52 1.11 (m,4H),0.86 ppm (t,
7.2 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 136.5,131.6,128.2,127.9,
123.4,116.2,91.0,83.8,51.5,50.2,35.9,28.3,22.5,14.0 ppm; IR (film):
J ˆ
nÄ ˆ
3316 (m),3080 (w),2957 (s),2931 (s),1598 (w),1490 (m),918 (m),756 (vs),
‡
691 cmÀ1 (s); MS: m/z (%): 226 (1) [M À H],170 (100),128 (18),115 (11),
‡
126.9,123.4,91.1,83.9,51.5,50.0,35.8,28.3,22.5,13.9 ppm; IR (film):
3083 (w),3029 (w),2956 (s),2931 (s),2205 (vw),1622 (w),1599 (w),1490
(s),1454 (s),756 (vs),692 cm À1 (vs); MS: m/z (%): 277 (1) [M ],220 (100),
nÄ ˆ
91 (3),77 (2); HRMS (EI): m/z: calcd for C16H22N [M ‡H]: 228.1752;
found: 228.1759; elemental analysis calcd (%) for C16H22N: C 84.53,H 9.31,
N 6.16; found: C 84.76,H 9.74,N 6.09.
‡
‡
128 (3),115 (7),91 (39); HRMS (EI): m/z: calcd for C20H24N [M ‡H]:
Starting from 3 f: Propargylamine 3 f (78 mg,0.20 mmol) was dissolved in
CF3CO2H (3 mL). Et3SiH (116 mg,1.00 mmol,5 equiv) was added at room
temperature and then the reaction mixture was heated to 808C for 2 h. After
cooling to room temperature,the mixture was diluted with CH 2Cl2,
hydrolyzed and neutralized with saturated K2CO3 solution. The organic
278.1909; found: 278.1895; elemental analysis calcd (%) for C20H24N: C
86.59,H 8.36,N 5.05; found: C 86.27,H 8.26,N 5.10.
N-Ferrocenylmethyl-1-phenyl-1-heptyn-3-amine (7b)
Typical procedure D: Pd(PPh3)4 (17 mg,0.015 mmol,5 mol%) and
8
layer was separated,washed with saturated K CO3 solution and dried over
(140 mg,0.90 mmol,3 equiv) were dissolved in CH 2Cl2 (2.5 mL).
A
2
MgSO4. Column chromatographic purification (silica gel,pentane/Et 2O 4:1
then 1:1) afforded 7d (40 mg,0.18 mmol,88%) as a colorless oil. The chiral
reaction was similarly performed with 3 f (60 mg,0.15 mmol),CF 3CO2H
(2.5 mL),and Et 3SiH (87 mg,0.75 mmol,5 equiv) and yielded 7d (17 mg,
0.075 mmol,50%,50% ee). [a]D20 ˆ À25 (c ˆ 0.50 in CHCl3); HPLC (OD-H,
99% n-heptane/1% isopropanol,0.3 mLmin À1): tr (min)ˆ 18.8 (‡),23.7 ( À).
solution of 3e (0.128 g,0.30 mmol) in CH 2Cl2 (2.5 mL) was added at room
temperature and the reaction mixture was stirred for 2 h. After evaporation
of CH2Cl2 in vacuo,the residue was dissolved in Et O. The organic phase
2
was extracted with saturated K2CO3 solution and dried over MgSO4.
Column chromatographic purification (silica gel,pentane/Et 2O 2:1)
afforded 7b (0.116 g,0.30 mmol,99%) as an orange-brown oil.
1-Cyclohexyl-3-phenyl-propyl-1-amine (7e): Palladium on charcoal (10%,
0.550 g) was suspended in methanol (5 mL) under a hydrogen atmosphere
(1 atm). A solution of 3w (0.550 g,1.40 mmol) in methanol (5 mL) was
added at room temperature and the reaction mixture was stirred for 14 h.
After filtration over Celite and evaporation of the solvent in vacuo,the
crude product was purified by bulb-to-bulb destillation in vacuo to yield 7e
(0.213 g,0.98 mmol,70%) as a colorless oil which slowly crystallized. M.p.
<258C; 1H NMR (CDCl3,300 MHz): d ˆ 7.28 7.09 (m,5H),2.79 2.65
(m,1H),2.59 2.40 (m,2H),1.80 1.40 (m,7H),1.24 0.82 ppm (m,8H);
13C NMR (CDCl3,75 MHz): d ˆ 142.6,128.32,128.30,125.6,55.7,44.0,36.7,
The chiral reaction was similarly performed with [Pd(PPh3)4] (3.0 mg,
0.0025 mmol,5 mol%), 8 (23 mg,0.15 mmol,3 equiv) and
3e (21 mg,
0.05 mmol) in CH2Cl2 (2 mL). Standard workup and column chromato-
graphic purification (silica gel,pentane/Et 2O 2:1) yielded 7b (15 mg,
0.04 mmol,78%,76% ee) as an orange-brown oil. [a]2D0 ˆ ‡32 (c ˆ 0.55 in
CHCl3); HPLC (OD-H,99% n-heptane/1% isopropanol,0.2 mLmin À1): tr
(min) ˆ 61.8 (À),66.2 ( ‡); 1H NMR (300 MHz,CDCl 3): d ˆ 7.49 7.46 (m,
2H),7.35 7.30 (m,3H),4.27 4.24 (m,2H),4.15 (s,5H),4.12 4.11 (m,
2H),3.81 (d, J ˆ 13.0 Hz,1H),3.65 (t, J ˆ 6.8 Hz,1H),3.60 (t, J ˆ 12.8 Hz,
1H),1.77 1.68 (m,2H),1.58 1.35 (m,5H),0.94 ppm (t,
J ˆ 7.2 Hz,3H);
13C NMR (75 MHz,CDCl ): d ˆ 131.6,128.3,127.9,123.5,91.3,86.9,83.3,
33.0,29.6,27.8,26.63,26.55,26.42 ppm; IR (film):
nÄ ˆ 3083 (w),3029 (w),
3
2956 (s),2931 (s),2205 (vw),1622 (w),1599 (w),1490 (s),1454 (s),756 (vs),
68.6,68.4,68.0,67.7,67.6,50.3,46.4,35.8,28.3,22.5,14.0 ppm; MS:
m/z (%):
‡
692 cmÀ1 (vs); MS: m/z (%): 218 (2) [M ‡H],134 (100),117 (28),104 (4),
‡
385 (20) [M ],353 (19),352 (91),288 (16),287 (100),200 (15),199 (38),173
‡
‡
91 (62); HRMS (EI): m/z: calcd for C15H24N [M ‡H]: 218.1909; found:
(18),145 (22),121 (24); HRMS (EI): m/z: calcd for C24H27FeN [M ]:
385.1493; found: 385.1521; IR (film): nÄ ˆ 2956 (s),2931 (s),2859 (m),1490
218.1893; elemental analysis calcd (%) for C15H24N: C 82.89,H 10.67,N
6.44; found: C 82.46,H 10.77,N 6.08.
(m),1443 (m),1105 (m),818 (m),756 (vs),691 (vs),484 cm
À1 (m).
1-Phenyl-1-heptyn-3-amine (7c): The reaction was carried out according to
procedure D with Pd(PPh3)4 (58 mg,0.005 mmol,5 mol%), 8 (0.937 g,
2-Benzyl-1-butyl-6-phenyl-2,3,3a,4-tetrahydrocyclopenta[c]-pyrrol-5(1H)-
one (9)
Chem. Eur. J. 2003, 9,2797 2811
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
2809

P. Knochel et al.
FULL PAPER
Typical procedure E: Co2(CO)8 (135 mg,0.40 mmol,1.2 equiv) was dis-
solved in Et2O (3.5 mL). A solution of 3b (105 mg,0.33 mmol) in Et 2O
(1.5 mL) was added at room temperature (CO evolution observed) and
stirred for 1 h. After filtration over Celite,the solvent was evaporated and
the residue was dissolved in CH2Cl2 (5 mL). This solution was added to a
suspension of Me3NO (183 mg,1.65 mmol,5.0 equiv) in MeCN (5 mL) and
the reaction mixture was stirred for 14 h. Evaporation of the solvents in
vacuo and column chromatographic purification (silica gel,pentane/Et 2O
1:1) afforded 9 (57 mg,0.16 mmol,50%,diastereomeric ratio ˆ > 99:1) as
a yellow oil. 1H NMR (CDCl3,400 MHz): d ˆ 7.40 7.16 (m,10H),3.95 (d,
[1] a) B. M. Trost, Science 1991, 254,1471; b) B. M Trost, Angew. Chem.
1995, 107,259; Angew. Chem. Int. Ed. 1995, 34,285.
[2] a) G.-Q. Lin,Y.-M. Li,A. S. C. Chan, Principles and Applications of
¬
Asymmetric Synthesis,Wiley, 2001; b) R. E. Gawley,J. Aube , Princi-
ples of Asymmetric Synthesis,Pergamon, 1996.
[3] G. Habermehl,P. E. Hammann, Naturstoffchemie,Springer,Heidel-
berg, 1992.
[4] a) M. A. Huffman,N. Yasuda,A. E. DeCamp,E. J. J. Grabowski,
J.
Org. Chem. 1995, 60,1590; b) M. Konishi,H. Ohkuma,T. Tsuno,T.
Oki,G. D. VanDuyne,J. Clardy, J. Am. Chem. Soc. 1990, 112,3715.
[5] a) J. R. Hauske,P. Dorff,S. Julin,G. Martinelli,J. Bussolari,
Tetrahedron Lett. 1992, 33,3715; b) M. Kolb,J. Barth, Angew. Chem.
1980, 92,753; Angew. Chem. Int. Ed. 1980, 19,725; c) H. Braun,F. P.
Schmidtchen,A. Schneider,H. Simon, Tetrahedron 1991, 47,3329;
d) M. J. Burk,J. E. Feaster, J. Am. Chem. Soc. 1992, 114,6266; e) D.
Enders,J. Schankat, Helv. Chim. Acta 1995, 78,970; f) J. Blanchet,M.
Bonin,A. Chiaroni,L. Micouin,C. Riche,H.-P. Husson, Tetrahedron
Lett. 1999, 40,2935; g) C. Fischer,E. M. Carriera, Org. Lett. 2001, 3,
4319.
[6] R. Noyori, Asymmetric Catalysis in Organic Synthesis,Wiley,New
York, 1994.
[7] C. M. Wei,C. J. Li, J. Am. Chem. Soc. 2002, 124,5638.
[8] C. Koradin,K. Polborn,P. Knochel, Angew. Chem. 2002, 114,2651;
Angew. Chem. Int. Ed. 2002, 41,2535.
J ˆ 13.1 Hz,1H),3.68 3.60 (m,1H),3.48 3.40 (m,1H),3.40 (d.
14.0 Hz,1H),3.26 (t, J ˆ 7.5 Hz,1H),3.20 3.06 (m,1H),2.63 (dd,
J ˆ
J ˆ
17.9,6.4 Hz,1H),2.15 (dd, J ˆ 18.0,3.7 Hz,1H),1.88 (dd, J ˆ 10.5,8.4 Hz,
1H),1.75 1.58 (m,2H),1.54 1.40 (m,1H),1.25 1.15 (m,2H),0.78 ppm
(t, J ˆ 7.1 Hz,3H); 13C NMR (CDCl3,100 MHz): d ˆ 207.6,182.7,138.9,
135.1,131.6,128.7,128.4,128.32,128.30,127.9,127.1,63.7,59.3,57.9,42.6,
40.0,33.6,27.4,22.9,14.0 ppm; IR (film): nÄ ˆ 3060 (m),3029 (m),2958 (s),
À1
2930 (s),1713 (vs),1601 (m),1495 (s),1454 (s),1137 (s),756 (m),698 cm
‡
(s); MS: m/z (%): 345 (7) [M ],288 (100),168 (3),141 (3),115 (3),91 (52);
‡
HRMS (EI): m/z: calcd for C24H27NO [M ]: 345.2093; found: 345.2063.
1-Butyl-2-(4-methoxybenzyl)-6-phenyl-2,3,3a,4-tetrahydrocyclo-penta[c]-
pyrrol-5(1H)-one (10): The reaction was carried out according to proce-
dure E with Co2(CO)8 (113 mg,0.33 mmol,1.1 equiv) and
3g (104 mg,
0.30 mmol) in pentane (4 mL) at room temperature for 45 min. The
oxidation was performed with Me3NO (167 mg,1.50 mmol,5.0 equiv) in
CH2Cl2/MeCN (1:1,10 mL) at room temperature for 5 h. Standard workup
and column chromatographic purification (silica gel,pentane/Et 2O 1:1)
[9] For a very efficient Zn-catalyzed enantioselective addition of alkynes
to aldehydes,see: a) N. K. Anand,E. M. Carreira, J. Am. Chem. Soc.
2001, 123,9687; b) E. El-Sayed,N. K. Anand,E. M. Carreira,
Org.
Lett. 2001, 3,3017; c) D. E. Frantz,R. Faessler,C. S. Tomooka,E. M.
Carreira, Acc. Chem. Res. 2000, 33,373; d) D. E. Frantz,R. Faessler,
E. M. Carreira, J. Am. Chem. Soc. 2000, 122,1806.
afforded 10 (43 mg,0.11 mmol,38%,diastereomeric ratio
yellow oil.
> 99:1) as a
The chiral reaction was similarly performed with Co2(CO)8 (64 mg,
0.19 mmol,1.1 equiv), 3g (60 mg,0.19 mmol),and Me 3NO (94 mg,
ee).
[10] For a copper(i) chloride-catalyzed reaction of alkynes with enamines,
see: a) K. C. Brannock,R. D. Burpitt,J. G. Thweatt, J. Org. Chem.
1963, 28,1462; see also: b) J. J. McNally,M. A. Youngman,S. L. Dax,
Tetrahedron Lett. 1998, 39,967; c) M. A. Youngman,S. L. Dax,
Tetrahedron Lett. 1997, 38,6347.
[11] K. Taguchi,F. H. Westheimer, J. Org. Chem. 1971, 36,1570.
[12] E. O. D¸ber,H. Ahlbrecht, Synthesis 1980,630.
[13] J. R. Stille,G. R. Cook, Tetrahedron 1994, 50,4105.
[14] This enamine (95% yield) was prepared according to ref. [13] with
TsCl (1 equiv).
0.85 mmol,5.0 equiv) to yield 10 (20 mg,0.05 mmol,31%,68%
[a]2D0 ˆ À21 (c ˆ 0.55 in CHCl3); HPLC (OD-H,98% n-heptane/2%
isopropanol,0.6 mLmin À1): tr (min) ˆ 46.4 (‡),51.1
(
À); 1H NMR
(300 MHz,CDCl 3): d ˆ 7.38 7.22 (m,5H),7.17 (d, J ˆ 8.9 Hz,2H),6.79
(d, J ˆ 8.7 Hz,2H),3.88 (d, J ˆ 13.3 Hz,1H),3.74 (s,3H),3.61 (t,
3.5 Hz,1H),3.37 (d, J ˆ 13.0 Hz,1H),3.24 (t, J ˆ 7.5 Hz,1H),3.18 3.08
(m,1H),2.64 (dd, J ˆ 17.7,6.7 Hz,1H),2.15 (dd, J ˆ 18.0,3.3 Hz,1H),1.87
(dd, J ˆ 10.6,7.8 Hz,1H),1.74 1.59 (m,2H),1.54 1.40 (m,2H),1.27 1.11
(m,2H),0.78 ppm (t, J ˆ 7.4 Hz,3H); 13C NMR (75 MHz,CDCl 3): d ˆ
207.7,182.8,158.8,135.0,131.6,130.9,129.8,128.4,128.3,127.9,113.7,63.5,
J ˆ
[15] P. Beeken,F. W. Fowler, J. Org. Chem. 1980, 45,1336.
[16] a) J. M. Valk,G. A. Whitlock,T. P. Layzell,J. M. Brown, Tetrahedron:
Asymmetry 1995, 6,2593; b) E. Fernandez,K. Maeda,M. W. Hooper,
J. M. Brown, Chem. Eur. J. 2000, 6,1840.
58.6,57.8,55.3,42.5,40.1,33.7,27.4,22.9,14.0 ppm; MS:
m/z (%): 375 (6)
‡
‡
[M ],318 (26),121 (100); HRMS (EI): m/z: calcd for C25H29NO2 [M ]:
375.2198; found: 375.2177; IR (film): nÄ ˆ 2956 (s),2931 (s),2858 (m),1706
(vs),1612 (m),1512 (vs),1465 (m),1300 (m),1249 (vs),1175 (m),1136 (m),
1035 (m),697 cm À1 (m).
[17] Crystal data for 3x: Mr ˆ 472.45,monoclinic,space group P21, a ˆ
7.0422(8), b ˆ 18.9473(30), c ˆ 9.8262(18) ä, Vˆ 1243.1(4) ä3, Z ˆ 2,
1calcd ˆ 1.262 mgmÀ3,Mo
radiation (l ˆ 0.71073 ä), m ˆ 1.669mmÀ1
.
Ka
N,N-Dibenzyl-1-phenyl-1-heptyn-3-amine (12): The reaction was carried
out according to procedure A with enamine 1g (0.345 g,1.30 mmol,
Data were collected on a NONIUS MACH3 system at 295 K. The
structure was solved by direct methods and refined on Fo2 by full-
matrix least-squares methods (SHELXS-86,SHELXL-93). All non-
hydrogen atoms were refined anisotropically. R1 ˆ 0.0343, wR2 ˆ
0.0767 for all data with I > 2s(I). CCDC 199761 contains the
supplementary crystallographic data (excluding structure factors)
and can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road,Cambridge CB2 1EZ,UK; fax: ( ‡44)1223-336-033;
or deposit@ccdc.cam.uk).
1.3 equiv),phenylacetylene-
0.05 mmol,5.0 mol%),and
d
(2q) (0.102 g,1.00 mmol),CuBr (7 mg,
n-decane (0.100 g,0.70 mmol) in toluene
(2 mL) at room temperature for 14 h. Standard workup and column
chromatographic purification (silica gel,pentane/Et 2O 98:2) afforded 12
(0.334 g,0.91 mmol,91%, >90% deuterium incorporation) as a colorless
oil. 1H NMR (CDCl3,300 MHz): d ˆ 7.46 7.10 (m,15H),3.82 (d, J ˆ
13.7 Hz,2H),3.56 3.48 (m,1H),3.42 (d,
(m,1H),1.42 1.24 (m,2H),1.15 (sext,
J ˆ 13.7 Hz,2H),1.80 1.60
J ˆ 7.2 Hz,2H),0.79 ppm (t, J ˆ
7.3 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 139.9,131.8,128.8,128.3,
√
[18] a) S. Lemaire-Audoire,M. Savignac,J. P. Gene t, Tetrahedron Lett.
128.2,127.8,126.8,123.6,88.1,85.2,55.0,52.1 (t,
J ˆ 5.0 Hz),33.6,33.2 (t,
1995, 36,1267; b) S. Lemaire-Audoire,M. Savignac,C. Dupuis,J. P.
J ˆ 19.3 Hz),28.5 (t,
J ˆ 7.3 Hz),22.3 (t,
J ˆ 2.0 Hz),13.5 ppm; IR
√
Genet, Bull. Soc. Chim. Fr. 1995, 132,1167.
(film): nÄ ˆ 3024 (m),2924 (m),2858 (w),1639 (m),1606 (s),1488 (m),
[19] W. L. Neumann,M. M. Rogic,T. J. Dunn, Tetrahedron Lett. 1991, 32,
1443 (m),994 (s),913 (vs),790 (m),702 cm À1 (vs); MS: m/z (%): 310 (100)
5865.
‡
[M À C4H8D],218 (2),191 (2),115 (5),91 (56); HRMS (EI): m/z: calcd for
¬
[20] F. Garro-Helion,A. Mertouk,F. Guibe , J. Org. Chem. 1993, 58,6109.
‡
C27H26DN [M À 2H]: 365.2127; found: 365.2098.
[21] N. Jeong,in Transition Metals for Organic Synthesis, Vol. 1 (Eds.: M.
Beller,C. Bolm),Wiley-VCH,Weinheim, 1998,p. 560.
[22] The stereochemistry of 11 was established by analysis of NOE data.
[23] Crystal data for 5: Mr ˆ 1287.82,orthorhombic,space group C2221, a ˆ
15.549(3), b ˆ 16.989(2), c ˆ 42.706(7) ä, Vˆ 11281(3) ä3, Z ˆ 8,
Acknowledgements
1calcd ˆ 1.516 mgmÀ3,Mo Ka radiation (l ˆ 0.71073 ä), m ˆ 2.366 mmÀ1
.
We thank the Deutsche Forschungsgemeinschaft (Leibniz program). C.K.
Data were collected on a NONIUS MACH3 system at 295 K. The
structure was solved by direct methods and refined on Fo2 by full-
matrix least-squares methods (SHELXS-86,SHELXL-93). All non-
thanks BASF AG (Ludwigshafen) for
a fellowship. We thank also
Chemetall GmbH (Frankfurt) and BASF AG (Ludwigshafen) for the
generous gift of chemicals.
2810
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9,2797 2811

Enantiomerically Enriched Propargylamines
2797 2811
hydrogen atoms were refined anisotropically. R1 ˆ 0.0374, wR2 ˆ
0.0834 for all data with I > 2s(I). CCDC 182716 contains the
supplementary crystallographic data (excluding structure factors)
and can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road,Cambridge CB2 1EZ,UK; fax: ( ‡44)1223-336-033;
or deposit@ccdc.cam.uk).
[24] a) J. Qiong-Hua,L. De-Liang,W. Yu-Xian,X. Xin-Quan,
Acta
Crystallogr. 1998, C54,948; J. Zukerman-Schpector,E. E. Castellano,
A. E. Mauro,M. R. Roveri, Acta Crystallogr. 1986, C42,302.
[25] T. Kamikawa,T. Hayashi, J. Org. Chem. 1998, 63,8922.
[26] C. L. Branch,M. J. Pearson, J. Chem. Soc. Perkin Trans. 1 1986,1077.
[27] A. R. Kartritzky,J. K. Gallos,K. Yannakopoulou, Synthesis 1989,31.
Received: December 20,2002 [F4691]
Chem. Eur. J. 2003, 9,2797 2811
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
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