Preparation of functionalized primary chiral amines and amides via an enantioselective three-component synthesis of propargylamines

Article abstract of DOI:10.1016/j.tet.2005.08.064

A general preparation of functionalized primary chiral amines and amides from propargylamines has been developed. The chirality is established by an enantioselective three-component reaction of an aldehyde, a terminal alkyne and a secondary amine in the p

Full text of DOI:10.1016/j.tet.2005.08.064

Tetrahedron 61 (2005) 11418–11426
Preparation of functionalized primary chiral amines and
amides via an enantioselective three-component synthesis
of propargylamines
*
Nina Gommermann and Paul Knochel
¨ ¨ ¨
Department Chemie und Biochemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, D-81377 Munchen, Germany
Received 1 July 2005; revised 28 July 2005; accepted 17 August 2005
Available online 12 September 2005
Abstract—A general preparation of functionalized primary chiral amines and amides from propargylamines has been developed. The
chirality is established by an enantioselective three-component reaction of an aldehyde, a terminal alkyne and a secondary amine in the
presence of copper(I) bromide/Quinap as the catalytic system leading to chiral propargylamines in high yields and enantioselectivities.
Functionalization and reduction leads to various primary amines and amides.
q 2005 Published by Elsevier Ltd.
1. Introduction
generated imminium ions from aldehydes and secondary
amines in the presence of copper(I) bromide/Quinap8 as the
catalytic system (Scheme 1).
Multicomponent reactions play an important role in modern
organic chemistry, since they exhibit generally a higher
atom economy1 and selectivity, as well as lower level of by-
products compared to classical stepwise synthesis routes.
Furthermore, in many cases multicomponent reactions are
easy to perform leading to simpler experimental pro-
cedures2 as well as lower costs, time and energy. The
Strecker-reaction, developed in 1850, has been recognized
as the first multi-component reaction.3 This three-com-
ponent coupling of an amine, a carbonyl compound and
hydrogen cyanide giving a-aminonitriles establishes an
important indirect route to a-amino acids. The amine group
itself is one of the fundamental structures in organic
chemistry. In particular, optically active primary amines,
in which the nitrogen atom is attached to a stereogenic
center play a crucial role as characteristic structural features
in bioactive natural products and pharmaceutically impor-
tant compounds. Several methods have been developed for
their synthesis. One possibility, similar to the addition
of carbanions to a carbonyl group, is the addition of
organometallic reagents to the C]N double bonds of
imines and imine derivatives. A new stereogenic center and
a C–C– bond are formed during this addition reaction.4
Recently, we5 and others6 have developed an asymmetric
multicomponent one-pot synthesis7 for the preparation of
propargylamines by the addition of alkynes to in situ
Scheme 1. Asymmetric three-component synthesis of propargylamines.
In this article, we wish to describe the use of our
multicomponent asymmetric propargylamine synthesis for
the preparation of enantiomerically enriched functionalized
and primary amines.
2. Results and discussion
In a recent communication,5a we have described the
asymmetric three-component synthesis of propargylamines.
This method is superior to our previously reported method9
using a two-step sequence consisting of the preparation of
an enamine followed by the copper-catalyzed addition of a
terminal alkyne in a separate step. Using the multi-
component protocol, it was possible to improve the
enantioselectivity of the reaction and the use of aromatic
aldehydes was now possible. From these aldehydes, no
enamines could be obtained. Furthermore, the need to
prepare and purify sensitive enamines is abandoned. This
new multicomponent protocol allows the enantioselective
Keywords: Propargylamines; Chiral primary amines; Three-component.
*
Corresponding author. Tel.: C49 89 2180 77679; fax: C49 89 2180
77680; e-mail: paul.knochel@cup.uni-muenchen.de
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.08.064

N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
11419
preparation of propargylamines by simple mixing of the
commercially available starting materials (aldehyde,
terminal alkyne and secondary amine) with the catalyst
consisting of copper(I) bromide and Quinap at rt.
The resulting terminal propargylamines 5 could be further
functionalized using known methods (Scheme 4). For
example, deprotonation of 5a and 5d with n-BuLi in THF
at K78 8C and alkylation with either paraformaldehyde10 or
ethylene oxide in the presence of boron trifluoride–
etherate11 yielded the corresponding alcohols. These were
subsequently silylated with TIPSCl in the presence of
imidazole giving the protected aminoalcohols 6a–b in 58–
71% yield over two steps with 98 and 90% ee, respectively,
(Scheme 4). Sonogashira cross-coupling12 of 5b and 5d with
iodobenzene or ethyl 4-iodobenzoate in the presence of
PdCl2(PPh3)2 (2 mol%) and CuI (2 mol%) led to the
functionalized phenylacetylene derivatives 6c–e in 87–
90% yield and 90–98% ee (see Scheme 4). Finally, the
reaction of the alkynyllithiums derived from 5a, 5c and 5e
with ethyl chloroformiate provided the chiral alkynyl esters
6f–h in 85–96% yield and 88–97% ee (Scheme 4).
2.1. The preparation of enantiomerically enriched
propargylamines
During our studies, we have observed that the use of
dibenzylamine (1) leads to propargylamines with high
enantiomeric purity. As the alkyne component, we have
found trimethylsilylacetylene (2) to be the substrate of
choice. It is also leading to products with exceptionally high
enantiomeric excess. Furthermore, after removal of the
trimethylsilyl group, it is possible to convert the propargylic
amine to various substituted derivatives. A number of chiral
propargylamines 3 have been prepared using different
aldehydes 4 (Scheme 2 and Table 1).
Scheme 2. Asymmetric three-component synthesis of benzyl-protected
propargylamines.
Table 1. Asymmetric three-component synthesis of propargylamines
Entry
RCHO 4
Product of type 3
Yield
(%)a
ee
(%)b
1
2
3
4
5
6
4a: n-Pr
3a: RZn-Pr
98
75
97
97
92
76
90
90
88
98
97
88
4b: n-Bu
4c: n-Pent
4d: s-Pent
4e: c-Hex
3b: RZn-Bu
3c: RZn-Pent
3d: RZs-Pent
3e: RZc-Hex
Scheme 4. Preparation of chiral functionalized propargylamines 6.
4f: C6H5(CH2)2 3f: RZC6H5(CH2)2
2.3. Reduction to functionalized primary chiral amines
and amides
a Isolated yield of analytically pure product.
b Enantiomeric excess determined by HPLC using Chiracel OD-H column
(n-heptane/i-PrOH).
We have investigated the reduction of the propargylamines
5 and 6 in the presence of Pd on charcoal in methanol under
hydrogen atmosphere (1 bar) (Scheme 5).
Propargylamines 3a–f were obtained in good to excellent
yields and uniformly high enantioselectivities. The steri-
cally most hindered 2-ethylbutyraldehyde 4d furnished the
propargylamine 3d with the highest selectivity (98% ee, see
entry 4, Table 1). Similarly, the c-hexyl-substituted
propargylamine 3e was obtained with 97% ee (entry 5,
Table 1).
Scheme 5. Hydrogenation of propargylamines 5 and 6.
2.2. Functionalization of chiral propargylamines
Hydrogenation of the dihydrocinnamaldehyde derived
propargylamine 5f under the described conditions at rt
led to the desired primary amine 7a in 92% yield after
transformation to the hydrochloride (entry 1, Table 2).
The trimethylsilyl group was readily removed from the
propargylamines 3 using Bu4NF as solution in THF at 0 8C
giving terminal propargylamines 5 in very good yields
(generally O90%) (Scheme 3).
The unfunctionalized propargylamine 5e was succesfully
reduced to the chiral primary amine 7b in 84% yield and
97% ee (entry 2, Table 2). Hydrogenation of the TIPS-ether
substituted propargylamines 6a–b also leads to the
aminoalcohols 7c–d in 66 and 99% yield and 98
and 90% ee, respectively, (entries 3 and 4, Table 2).
Scheme 3. Removal of the trimethylsilyl group.

11420
N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
Table 2. Functionalized primary amines and amides
Entry
1
Propargylamine
Reduction product 7
Yield (%)/ee (%)a
92/88
7a
7b
5f
2
3
84/97
66/98
5e
7c: RZs-Pent, nZ1
7d: RZn-Pr, nZ2
6a
6b
4
5
99/90
72/90
7e: RZn-Bu, R1ZH
7f: RZs-Pent, R1ZH
7g: RZn-Bu, R1ZCO2Et
6c
6d
6e
6
7
88/98
72/90
8
9
10
6f
6g
6h
7h: RZn-Pr
7i: RZn-Pent
7j: RZc-Hex
75/90
87/88
85/97
a Isolated yield of analytically pure compound.
The phenylacetylene-derivatives 6c and 6d underwent
equally smooth reduction to the b-phenyl-substituted
amines 7e–f in good yields (entries 5 and 6, Table 2).
Furthermore, the ester functionality in 6e was perfectly
tolerated and the aminoester 7g was obtained in 72% yield
and 90% ee. Finally, reduction of the alkynyl esters 6f–h
under the standard conditions led directly to the cyclic
amides 7h–j in good yields (75–85%) and selectivities
(88–97% ee) (entries 8–10, Table 2).
Toluene was predried over KOH and continuously refluxed
and freshly distilled from sodium. THF was continuously
refluxed and freshly distilled from sodium benzophenone
ketyl under nitrogen. Preparative chromatography was
performed on silica gel 60 (0.063–0.200 mm) from Merck.
Yields refer to isolated yields of compounds estimated to be
1
O95% pure as determined by H NMR and capillary GC.
4.2. Typical procedure A (racemic propargylamine
synthesis)
3. Conclusion
In a dry and argon flushed 25 mL flask, equipped with a
magnetic stirrer and a septum, CuBr (0.075 mmol, 5 mol%)
˚
was suspended in dry toluene (3 mL). MS 4 A (750 mg) and
In summary, we have developed a convenient synthesis of
functionalized chiral primary amines and amides in 88–98%
ee. The key step and source of chirality is the asymmetric
one-pot three-component synthesis of propargylamines
from aldehydes, dibenzylamine and terminal alkynes like
trimethylsilylacetylene. This reaction leads to the desired
propargylamines in high yields and excellent selectivities
(88–98% ee). Functionalization and reduction with Pd on
charcoal under hydrogen atmosphere proceeds under mild
conditions and is compatible with functional groups, such as
silyl ethers and ester groups leading to functionalized
primary amines. Furthermore, the use of alkynyl esters in
the reduction reaction is leading directly to chiral cyclic
amides in good yields.
n-decane (100 mg) were added, followed by trimethylsilyl-
acetylene (1.5 mmol), the aldehyde (1.5 mmol) and
dibenzylamine (1.5 mmol). The reaction mixture was stirred
at rt until GC-analysis showed full conversion (12–48 h).
MS 4 A was filtered and washed with diethyl ether. The
crude product was concentrated in vacuo and purified by
column chromatography on silica gel.
˚
4.3. Typical procedure B (chiral propargylamine
synthesis)
In a dry and argon flushed 10 mL flask, equipped with a
magnetic stirrer and a septum, CuBr (0.015 mmol, 5 mol%)
and (R)-Quinap (0.017 mmol, 5.5 mol%) were suspended in
˚
dry toluene (1.5 mL) and stirred for 30 min at rt. MS 4 A
4. Experimental
4.1. General
(150 mg) and n-decane (30 mg) were added, followed by
trimethylsilylacetylene (0.3 mmol), the aldehyde
(0.3 mmol) and dibenzylamine (0.3 mmol). The reaction
mixture was stirred at rt until GC-analysis showed full
conversion (24 h–6 days). MS 4 A was filtered and washed
with diethyl ether. The crude product was concentrated in
vacuo and purified by column chromatography on silica gel.
˚
All reactions were carried out under an argon atmosphere in
dried glassware. All starting materials were purchased from
commercial sources and used without further purification.

N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
11421
4.3.1. N,N-Dibenzyl-1-(trimethylsilyl)-1-hexyn-3-amine
(3a). Prepared according to typical procedure A and B.
Column chromatographic purification: SiO2, pentane/ether
99:1. Yield (racemic): 90% (2.0 mmol scale, 628 mg);
(nonracemic): 98% (0.3 mmol scale, 103 mg) as a colorless
oil. [a]2D0K166 (c 0.96, CHCl3). 1H NMR (300 MHz,
CDCl3): dZ7.43–7.23 (m, 10H), 3.84 (d, JZ13.7 Hz, 2H),
3.43 (t, JZ7.6 Hz, 1H), 3.41 (d, JZ13.7 Hz, 2H), 1.79–1.34
(m, 4H), 0.82 (t, JZ7.5 Hz, 3H), 0.28 (s, 9H). 13C NMR
(75 MHz, CDCl3): dZ139.9, 128.8, 128.2, 126.8, 104.7,
89.0, 54.8, 52.1, 35.8, 19.5, 13.7, 0.4. MS (70 eV, EI): m/z
(%): 349 (MC, !1), 307 (25), 306 (100), 91 (33). HRMS
(EI): calcd for C23H31NSi [MC]: 349.2226, found:
349.2198. IR (film): 2958 (s), 2935 (m), 2158 (m), 1495
(m), 1454 (m), 1250 (s), 842 (vs), 698 (s). Anal. Calcd for
C23H31NSi: C, 79.02; H, 8.94; N, 4.01. Found: C, 79.01; H,
9.06; N, 3.96.
JZ13.5 Hz, 2H), 3.19 (d, JZ10.1 Hz, 1H), 1.75–1.27 (m,
5H), 0.81 (t, JZ7.9 Hz, 3H), 0.59 (t, JZ7.9 Hz, 3H), 0.29
(s, 9H). 13C NMR (75 MHz, CDCl3): dZ139.7, 129.1,
128.1, 126.8, 104.0, 90.0, 55.6, 55.0, 41.4, 22.1, 20.1, 10.6,
8.9, 0.5. MS (70 eV, EI): 362 (MCKMe, 1), 307 (30), 306
(100), 91 (29). HRMS (EI): calcd for C25H36NSi [MCCH]:
378.2617, found: 378.2617. IR (film): 2962 (s), 2158 (m),
1494 (m), 1454 (m), 1250 (s), 842 (vs), 747 (m), 698 (s).
Anal. Calcd for C25H36NSi: C, 79.51; H, 9.34; N, 3.71.
Found: C, 79.49; H, 9.37; N, 3.69.
4.3.5. N,N-Dibenzyl-1-cyclohexyl-3-(trimethylsilyl)-2-
propyn-1-amine (3e). Prepared according to typical
procedure A and B. Column chromatographic purification:
SiO2, pentane/ether 99:1. Yield (racemic): 99% (2.0 mmol
scale, 770 mg); (nonracemic): 92% (0.3 mmol scale,
107 mg) as a colorless solid. Mp 81–82 8C. [a]2D0K185 (c
1
0.89, CHCl3). H NMR (300 MHz, CDCl3): dZ7.44–7.42
4.3.2. N,N-Dibenzyl-1-(trimethylsilyl)-1-heptyn-3-amine
(3b). Prepared according to typical procedure A and B.
Column chromatographic purification: SiO2, pentane/ether
99:1. Yield (racemic): 82% (2.0 mmol scale, 596 mg);
(nonracemic): 75% (0.3 mmol scale, 82 mg) as a colorless
oil. [a]2D0K186 (c 0.69, CHCl3). 1H NMR (300 MHz,
CDCl3): dZ7.22–7.00 (m, 10H), 3.62 (d, JZ13.7 Hz, 2H),
3.19 (d, JZ13.7 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, JZ7.3 Hz, 2H),
0.66 (t, JZ7.3 Hz, 3H), 0.07 (s, 9H). 13C NMR (75 MHz,
CDCl3): dZ139.5, 128.4, 127.7, 126.4, 104.3, 88.6, 54.4,
51.9, 32.9, 28.0, 21.8, 13.5, 0.4. MS (70 eV, EI): m/z (%):
348 (5, MCKCH3), 306 (100), 214 (4), 91 (85), 73 (12).
HRMS (EI): calcd for C24H32NSi [MCKH]: 362.2304,
found: 362.2333. IR (film): 3064 (w), 3029 (w), 2958 (s),
2159 (m), 1495 (m), 1454 (m), 1250 (s), 842 (vs), 698 (s).
Anal. Calcd for C24H33NSi: C, 79.28; H, 9.15; N, 3.85.
Found: C, 79.19; H, 9.15; N, 3.83.
(m, 4H), 7.37–7.32 (m, 4H), 7.28–7.23 (m, 2H), 3.83 (d, JZ
13.6 Hz, 2H), 3.39 (d, JZ13.6 Hz, 2H), 3.06 (d, JZ
10.9 Hz, 1H), 2.32–2.28 (m, 1H), 2.04–2.00 (m, 1H), 1.73–
1.55 (m, 4H), 1.28–1.07 (m, 3H), 0.89–0.67 (m, 2H), 0.28
(s, 9H). 13C NMR (75 MHz, CDCl3): dZ139.8, 128.8,
128.2, 126.8, 103.5, 90.1, 58.6, 54.9, 39.5, 31.2, 30.3, 26.6,
26.2, 25.9, 0.5. MS (70 eV, EI): 307 (MCKc-Hex, 27), 306
(100), 91 (34). HRMS (EI): calcd for C26H35NSi [MC]:
389.2539, found: 389.2506. IR (KBr): 2924 (s), 2852 (m),
2160 (m), 1494 (m), 1451 (m), 1248 (s), 1006 (m), 844 (vs),
737 (s), 698 (s). Anal. Calcd for C26H35NSi: C, 80.14; H,
9.05; N, 3.59. Found: C, 79.90; H, 9.07; N, 3.54.
4.3.6. N,N-Dibenzyl-5-phenyl-1-(trimethylsilyl)-1-pen-
tyn-3-amine (3f). Prepared according to typical procedure
A and B. Column chromatographic purification: SiO2,
pentane/ether 99:1. Yield (racemic): 78% (1.0 mmol scale,
321 mg); (nonracemic): 76% (0.3 mmol scale, 94 mg) as a
colorless oil. [a]2D0K114 (c 0.38, CHCl3). 1H NMR
(300 MHz, CDCl3): dZ7.44–7.14 (m, 13H), 7.09–7.06
(m, 2H), 3.88 (d, JZ13.6 Hz, 2H), 3.50 (d, JZ7.6 Hz, 1H),
3.45 (d, JZ13.6 Hz, 2H), 2.85–2.75 (m, 1H), 2.69–2.59 (m,
1H), 2.12–1.88 (m, 2H), 0.28 (s, 9H). 13C NMR (75 MHz,
CDCl3): dZ141.9, 139.7, 128.9, 128.4, 128.3, 128.2, 126.9,
125.7, 104.2, 89.6, 55.0, 52.2, 35.6, 32.6, 0.4. MS (70 eV,
EI): 411 (MC, !1), 307 (25), 306 (100), 91 (60). HRMS
(EI): calcd for C28H33NSi [MC]: 411.2382, found:
411.2406. IR (film): 3027 (m), 2956 (m), 2158 (m), 1495
(s), 1454 (s), 1250 (s), 842 (vs), 746 (s), 698 (vs). Anal.
Calcd for C28H33NSi: C, 81.69; H, 8.08; N, 3.40. Found: C,
81.92; H, 8.56; N, 3.37.
4.3.3. N,N-Dibenzyl-1-(trimethylsilyl)-1-octyn-3-amine
(3c). Prepared according to typical procedure A and B.
Column chromatographic purification: SiO2, pentane/ether
99:1. Yield (racemic): 99% (10.0 mmol scale, 3.74 g);
(nonracemic): 97% (0.3 mmol scale, 110 mg) as a colorless
oil. [a]2D0K152 (c 0.45, CHCl3). 1H NMR (300 MHz,
CDCl3): dZ7.43–7.40 (m, 4H), 7.36–7.22 (m, 6H), 3.83 (d,
JZ13.8 Hz, 2H), 3.43–3.37 (m, 3H), 1.77–1.56 (m, 2H),
1.48–1.11 (m, 6H), 0.87 (t, JZ7.7 Hz, 3H), 0.27 (s, 9H). 13C
NMR (75 MHz, CDCl3): dZ139.9, 128.8, 128.2, 126.8,
104.7, 89.0, 54.8, 52.3, 33.5, 31.3, 25.9, 22.5, 14.0, 0.4. MS
(70 eV, EI): m/z (%): 377 (MC, !1), 307 (25), 306 (100),
91 (45). HRMS (EI): calcd for C25H34NSi [MCKH]:
376.2461, found: 376.2448. IR (film): 2957 (s), 2933 (s),
2159 (m), 1494 (m), 1454 (m), 1250 (s), 842 (vs), 698 (s).
Anal. Calcd for C25H35NSi: C, 79.51; H, 9.34; N, 3.71.
Found: C, 79.39; H, 9.40; N, 3.64.
4.4. Typical procedure C (TMS-deprotection)
The amine of type 3 (1.0 mmol) was dissolved in dry THF
(5 mL) and cooled to 0 8C. Bu4NF (0.3 mL, 0.3 mmol, 1 M
in THF) was added dropwise and the mixture was stirred at
this temperature for 15 min. Water (20 mL) was added and
the aq phase was extracted with diethyl ether (3!25 mL).
The combined organic fractions were dried over Na2SO4,
filtered and concentrated in vacuo and the crude product was
purified by column chromatography on silica gel.
4.3.4. N,N-Dibenzyl-4-ethyl-1-(trimethylsilyl)-1-hexyn-
3-amine (3d). Prepared according to typical procedure A
and B. Column chromatographic purification: SiO2,
pentane/ether 99:1. Yield (racemic): 99% (5.0 mmol scale,
1.87 g); (nonracemic): 97% (0.3 mmol scale, 110 mg) as a
colorless oil. [a]2D0K199 (c 0.41, CHCl3). 1H NMR
(300 MHz, CDCl3): dZ7.43–7.40 (m, 4H), 7.36–7.31 (m,
4H), 7.28–7.23 (m, 2H), 3.82 (d, JZ13.5 Hz, 2H), 3.37 (d,
4.4.1. N,N-Dibenzyl-1-hexyn-3-amine (5a). The reaction
was carried out according to typical procedure C. Column

11422
N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
chromatographic purification: SiO2, pentane/ether 99:1.
Yield: 98% (1.0 mmol scale, 272 mg) as a colorless oil.
dZ7.43–7.41 (m, 4H), 7.37–7.32 (m, 4H), 7.29–7.24 (m,
2H), 3.84 (d, JZ13.7 Hz, 2H), 3.40 (d, JZ13.7 Hz, 2H),
3.21 (dd, JZ10.1, 2.3 Hz, 1H), 2.38 (d, JZ2.3 Hz, 1H),
1.79–1.62 (m, 3H), 1.50–1.28 (m, 2H), 0.81 (t, JZ7.3 Hz,
3H), 0.60 (t, JZ7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3):
dZ139.6, 129.0, 128.2, 126.9, 81.3, 73.3, 55.0, 54.6, 41.4,
21.9, 19.9, 10.4, 8.9. MS (70 eV, EI): 235 (20), 234 (MCK
1-ethylpropyl, 100), 91 (74). HRMS (EI): calcd for C22H26N
[MCKH]: 304.2065, found: 304.2075. IR (film): 3302 (m),
2963 (s), 2937 (m), 1495 (m), 1454 (m), 748 (m), 698 (s).
Anal. Calcd for C22H27N: C, 86.51; H, 8.91; N, 4.59. Found:
C, 86.45; H, 9.07; N, 4.57. HPLC (OD-H, 100% n-heptane/
0% i-propanol, 0.2 mL/min): tr(min)Z28.4 (K), 31.9 (C).
1
[a]2D0K160 (c 0.77, CHCl3). H NMR (300 MHz, CDCl3):
dZ7.44–7.42 (m, 4H), 7.37–7.32 (m, 4H), 7.29–7.24 (m,
2H), 3.87 (d, JZ13.7 Hz, 2H), 3.45 (td, JZ8.1, 2.2 Hz, 1H),
3.43 (d, JZ13.7 Hz, 2H), 2.35 (d, JZ2.2 Hz, 1H), 1.83–
1.36 (m, 4H), 0.83 (t, JZ7.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dZ139.7, 128.8, 128.2, 126.9, 82.2, 72.3, 54.8,
51.2, 35.9, 19.5, 13.6. MS (70 eV, EI): m/z (%): 377 (MC,
!1), 235 (17), 234 (100), 91 (65). HRMS (EI): calcd for
C20H23N [MC]: 277.1830, found: 277.1838. IR (film): 3301
(m), 2958 (s), 2935 (m), 1495 (m), 1454 (s), 748 (s), 698
(vs). Anal. Calcd for C20H23N: C, 86.59; H, 8.36; N, 5.05.
Found: C, 86.52; H, 8.46; N, 5.02. HPLC (OD-H, 100%
n-heptane/0% i-propanol, 0.8 mL/min): tr(min)Z11.3 (C),
12.9 (K).
4.4.5. N,N-Dibenzyl-1-cyclohexyl-2-propyn-1-amine (5e).
The reaction was carried out according to typical procedure
C. Column chromatographic purification: SiO2, pentane/
ether 99:1. Yield: 93% (1.5 mmol scale, 442 mg) as a
colorless solid. Mp 75–76 8C. [a]2D0K157 (c 0.35, CHCl3).
1H NMR (300 MHz, CDCl3): dZ7.44–7.41 (m, 4H), 7.36–
7.31 (m, 4H), 7.27–7.23 (m, 2H), 3.85 (d, JZ13.7 Hz, 2H),
3.41 (d, JZ13.7 Hz, 2H), 3.07 (dd, JZ10.6, 2.2 Hz, 1H),
2.37 (d, JZ2.2 Hz, 1H), 2.35–2.28 (m, 1H), 2.06–2.00 (m,
1H), 1.72–1.59 (m, 4H), 1.31–1.07 (m, 3H), 0.91–0.72 (m,
2H). 13C NMR (75 MHz, CDCl3): dZ139.7, 128.8, 128.2,
126.8, 81.0, 73.4, 57.6, 54.8, 39.5, 31.2, 30.2, 26.5, 26.1,
25.9. MS (70 eV, EI): 235 (21), 234 (MCKc-Hex, 100), 91
(88). HRMS (EI): calcd for C23H27N [MC]: 317.2143,
found: 317.2139. IR (KBr): 3302 (s), 2926 (vs), 2851 (s),
1495 (m), 1448 (m), 746 (s), 698 (s). Anal. Calcd for
C23H27N: C, 87.02; H, 8.57; N, 4.41. Found: C, 86.74; H,
8.37; N, 4.32. HPLC (OD-H, 100% n-heptane/0%
i-propanol, 0.2 mL/min): tr(min)Z31.7 (K), 36.0 (C).
4.4.2. N,N-Dibenzyl-1-heptyn-3-amine (5b). The reaction
was carried out according to typical procedure C. Column
chromatographic purification: SiO2, pentane/ether 99:1.
Yield: 92% (1.0 mmol scale, 268 mg) as a colorless oil.
[a]2D0K190 (c 0.87, CHCl3). H NMR (600 MHz, CDCl3):
1
dZ7.41 (d, JZ7.7 Hz, 4H), 7.33 (t, JZ7.3 Hz, 4H), 7.25 (t,
JZ7.3 Hz, 2H), 3.85 (d, JZ13.8 Hz, 2H), 3.46–3.40 (m,
3H), 2.33 (d, JZ1.3 Hz, 1H), 1.83–1.73 (m, 1H), 1.71–1.63
(m, 1H), 1.50–1.33 (m, 2H), 1.25–1.17 (m, 2H), 0.87 (t, JZ
7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3): dZ139.7,
128.8, 128.2, 126.9, 82.2, 72.4, 54.7, 51.5, 33.4, 28.4,
22.2, 13.9. MS (70 eV, EI): m/z (%):290 (1, MCKH), 235
(22), 234 (98), 181 (11), 92 (100), 65 (10). HRMS (EI):
calcd for C21H25N [MCKH]: 290.1909, found: 290.1885.
IR (film): 3302 (m), 2956 (s), 2934 (s), 2860 (m), 1494 (m),
1454 (s), 746 (s), 698 (vs). Anal. Calcd for C21H25N: C,
86.55; H, 8.65; N, 4.81. Found: C, 86.84; H, 8.80; N, 4.97.
HPLC (OD-H, 100% n-heptane/0% i-propanol, 0.8 mL/
min): tr(min)Z11.3 (C), 12.9 (K).
4.4.6. N,N-Dibenzyl-5-phenyl-1-pentyn-3-amine (5f). The
reaction was carried out according to typical procedure C.
Column chromatographic purification: SiO2, pentane/ether
99:1. Yield: 98% (0.5 mmol scale, 166 mg) as a colorless
oil. [a]2D0K83 (c 0.46, CHCl3). 1H NMR (300 MHz,
CDCl3): dZ7.45–7.15 (m, 13H), 7.09–7.07 (m, 2H), 3.91
(d, JZ13.8 Hz, 2H), 3.52 (dd, JZ8.0, 2.2 Hz, 1H), 3.48 (d,
JZ13.8 Hz, 2H), 2.87–2.77 (m, 1H), 2.72–2.62 (m, 1H),
2.39 (d, JZ2.2 Hz, 1H), 2.16–1.93 (m, 2H). 13C NMR
(75 MHz, CDCl3): dZ141.7, 139.5, 128.9, 128.3, 128.3,
128.2, 126.9, 125.7, 81.7, 72.9, 54.9, 51.2, 35.5, 32.5. MS
(70 eV, EI): 339 (MC, 1), 235 (18), 234 (100), 91 (94).
HRMS (EI): calcd for C25H25N [MC]: 339.1987, found:
339.1975. IR (film): 3295 (m), 3027 (m), 1495 (s), 1454 (s),
746 (s), 698 (vs). Anal. Calcd for C25H25N: C, 88.45; H,
7.42; N, 4.13. Found: C, 88.30; H, 7.47; N, 4.01. HPLC
(OD-H, 99% n-heptane/1% i-propanol, 0.15 mL/min):
tr(min)Z38.6 (C), 42.5 (K).
4.4.3. N,N-Dibenzyl-1-octyn-3-amine (5c). The reaction
was carried out according to typical procedure C. Column
chromatographic purification: SiO2, pentane/ether 99:1.
Yield: 96% (9.8 mmol scale, 2.87 g) as a colorless oil.
1
[a]2D0K115 (c 0.41, CHCl3). H NMR (600 MHz, CDCl3):
dZ7.44 (d, JZ7.2 Hz, 4H), 7.35 (t, JZ7.2 Hz, 4H), 7.29–
7.26 (m, 2H), 3.87 (d, JZ13.7 Hz, 2H), 3.44 (d, JZ13.7 Hz,
2H), 3.44–3.43 (m, 1H), 2.35 (d, JZ2.3 Hz, 1H), 1.80–1.74
(m, 1H), 1.70–1.64 (m, 1H), 1.49–1.37 (m, 2H), 1.30 (sext,
JZ7.2 Hz, 2H), 1.20–1.15 (m, 2H), 0.88 (t, JZ7.2 Hz, 3H).
13C NMR (150 MHz, CDCl3): dZ139.7, 128.8, 128.2,
126.9, 82.2, 72.4, 54.7, 51.4, 33.6, 31.3, 25.9, 22.5, 14.0. MS
(70 eV, EI): m/z (%): 305 (MC, !1), 235 (18), 234 (93), 91
(100). HRMS (EI): calcd for C22H27N [MC]: 305.2143,
found: 305.2165. IR (film): 3304 (m), 2954 (s), 2933 (s),
1495 (m), 1454 (s), 746 (s), 698 (vs). Anal. Calcd for
C22H27N: C, 86.51; H, 8.91; N, 4.59. Found: C, 86.31; H,
8.99; N, 4.55. HPLC (after acylation with benzoyl
chloride)(OD-H, 99% n-heptane/1% i-propanol, 0.2 mL/
min): tr(min)Z22.6 (K), 25.9 (C).
4.4.7. N,N-Dibenzyl-5-ethyl-1-[(triisopropylsilyl)oxy]-2-
heptyn-4-amine (6a). Propargylamine 5d (305 mg,
1.0 mmol) was dissolved in dry THF (5 mL) and cooled to
K78 8C. n-BuLi (0.67 mL, 1.55 M in hexane, 1.05 mmol)
was added dropwise and the reaction was stirred for 10 min.
Paraformaldehyde (95 mg, 1.05 mmol) was suspended in
dry THF (7 mL) and added to the reaction mixture. Stirring
was continued for 30 min at K78 8C and then at rt
overnight. Water (20 mL) was added to the reaction mixture
and the aq phase was extracted with diethyl ether (3!
4.4.4. N,N-Dibenzyl-4-ethyl-1-hexyn-3-amine (5d). The
reaction was carried out according to typical procedure C.
Column chromatographic purification: SiO2, pentane/ether
99:1. Yield: 98% (4.0 mmol scale, 1.20 g) as a colorless oil.
1
[a]2D0K199 (c 0.41, CHCl3). H NMR (300 MHz, CDCl3):

N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
11423
25 mL). The combined organic fractions were dried over
Na2SO4, filtered and concentrated in vacuo and the crude
product was purified by column chromatography (SiO2,
pentane/ether 4:1) leading to the alcohol (83%, 278 mg).
The alcohol (268 mg, 0.8 mmol) was dissolved in dry DMF
(4 mL) and imidazole (65 mg, 1.0 mmol) and DMAP
(25 mg) were added as solids. The reaction mixture was
cooled to 0 8C and TIPSCl (170 mg, 0.9 mmol) was added.
The reaction was allowed to warm to rt overnight. Water
(20 mL) was added to the reaction mixture and the aq phase
was extracted with diethyl ether (3!25 mL). The combined
organic fractions were dried over Na2SO4, filtered and
concentrated in vacuo and the crude product was purified by
column chromatography (SiO2, pentane/ether 98:2) leading
to 6a (70%, 276 mg, 0.6 mmol) as a colorless oil. 1H NMR
(300 MHz, CDCl3): dZ7.38–7.36 (m, 4H), 7.32–7.27 (m,
4H), 7.24–7.19 (m, 2H), 4.54 (d, JZ1.7 Hz, 2H), 3.79 (d,
JZ13.8 Hz, 2H), 3.38 (d, JZ13.8 Hz, 2H), 3.18 (td, JZ
10.2, 1.8 Hz, 1H), 1.72–1.57 (m, 3H), 1.48–1.32 (m, 2H),
1.03 (s, 21H), 0.74 (t, JZ7.5 Hz, 3H), 0.56 (t, JZ7.5 Hz,
3H). 13C NMR (75 MHz, CDCl3): dZ139.8, 129.0, 128.1,
126.8, 84.5, 82.1, 55.0, 54.8, 52.3, 41.6, 22.0, 20.0,
18.0, 12.1, 10.4, 8.9. MS (70 eV, EI): m/z (%): 490
(MCKH, !1), 421 (32), 420 (100), 91 (30). HRMS (EI):
calcd for C32H48NOSi [MCKH]: 490.3505, found:
490.3545. IR (KBr): 2962 (vs), 2942 (vs), 2866 (vs), 1495
(m), 1454 (s), 1369 (m), 1119 (s), 1068 (s), 883 (m), 747 (s),
698 (s). Anal. Calcd for C32H49NOSi: C, 78.15; H, 10.04; N,
2.85. Found: C, 77.92; H, 10.07; N, 2.99.
After 10 min of stirring at rt, the iodobenzene-derivative
(1.1 mmol) was added. Propargylamine 5 (1 mmol) was
dissolved in THF (3.5 mL) and added in one portion. After
stirring at rt for 20 h, TLC-analysis showed full conversion
and the reaction mixture was quenched with water (25 mL)
and the aq layer was extracted with diethyl ether (3!
30 mL) and dried over Na2SO4. The solution was filtered
and concentrated in vacuo and the crude product was
purified by column chromatography on silica gel.
4.5.1. N,N-Dibenzyl-1-phenyl-1-heptyn-3-amine (6c). The
reaction was carried out according to typical procedure D
with iodobenzene. Column chromatographic purification:
SiO2, pentane/ether 99:1. Yield: 89% (1.0 mmol scale,
314 mg) as a light yellow oil. 1H NMR (CDCl3, 300 MHz):
dZ7.44–7.10 (m, 15H), 3.80 (d, JZ13.7 Hz, 2H), 3.51 (t,
JZ7.4 Hz, 1H), 3.40 (d, JZ13.8 Hz, 2H), 1.78–1.56 (m,
2H), 1.46–1.23 (m, 2H), 1.14 (sext, JZ7.2 Hz, 2H), 0.78 (t,
JZ7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): dZ139.9,
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. MS (70 eV, EI): m/z (%):
310 (100, MCKC4H9), 218 (3), 128 (2), 115 (7), 91 (57).
HRMS (EI): calcd for C27H33N [MCKH]: 366.2222, found:
366.2215. IR (film): 3062 (w), 3029 (w), 2955 (s), 2932 (s),
1599 (m), 1490 (s), 1454 (s), 755 (vs), 698 (vs). Anal. Calcd
for C27H34N: C, 88.24; H, 7.95; N, 3.81. Found: C, 87.85; H,
7.84; N, 3.73.
4.5.2. N,N-Dibenzyl-4-ethyl-1-phenyl-1-hexyn-3-amine
(6d). The reaction was carried out according to typical
procedure D with iodobenzene. Column chromatographic
purification: SiO2, pentane/ether 99:1. Yield: 90%
4.4.8. N,N-Dibenzyl-8-[(triisopropylsilyl)oxy]-5-octyn-4-
amine (6b). Propargylamine 5a (277 mg, 1.0 mmol) was
dissolved in dry THF (2 mL). The mixture was cooled to
K78 8C and n-BuLi (0.92 mL, 1.2 mmol, 1.3 M in hexane)
was added. After stirring at this temperature for 30 min,
oxirane (0.15 mL, 3.0 mmol,) followed by BF3$OEt2
(170 mg, 1.2 mmol) were added and the mixture was kept
at K78 8C for 2 h. Satd NH4Cl-solution was added and the
aq layer was extracted with diethyl ether and dried
(Na2SO4). Column chromatographic purification (SiO2,
pentane/diethyl ether 2:1) furnished the desired alcohol as
a colorless oil (244 mg, 76%). Silylation was carried out as
described for 6a leading to compound 6b (0.5 mm scale,
93%, 22 2mg) as a colorless oil. 1H NMR (300 MHz,
CDCl3): dZ7.40–7.37 (m, 4H), 7.32–7.19 (m, 6H), 3.86 (t,
JZ7.3 Hz, 2H), 3.79 (d, JZ13.8 Hz, 2H), 3.38 (d, JZ
13.8 Hz, 2H), 3.39–3.34 (m, 1H), 2.54 (td, JZ7.0, 2.2 Hz,
2H), 1.70–1.30 (m, 4H), 1.10 (s, 21H), 0.78 (t, JZ7.0 Hz,
3H). 13C NMR (75 MHz, CDCl3): dZ140.1, 128.8, 128.1,
126.7, 81.8, 79.0, 62.7, 54.8, 51.5, 36.3, 23.4, 19.6, 18.0,
13.7, 12.0. MS (70 eV, EI): m/z (%): 477 (MC, !1), 435
(25), 434 (100). HRMS (EI): calcd for C31H47NOSi [MC]:
477.3427, found: 477.3436. IR (film): 2942 (vs), 2867 (vs),
1495 (m), 1463 (s), 1454 (s), 1110 (s), 1071 (m), 883 (m),
745 (m), 698 (s). Anal. Calcd for C31H47NOSi: C, 77.93; H,
9.91; N, 2.93. Found: C, 78.10; H, 9.94; N, 2.88.
1
(1.0 mmol scale, 343 mg) as a light yellow oil. H NMR
(300 MHz, CDCl3): dZ7.59–7.56 (m, 2H), 7.48–7.46 (m,
4H), 7.42–7.34 (m, 7H), 7.31–7.26 (m, 2H), 3.93 (d, JZ
13.6 Hz, 2H), 3.51 (d, JZ13.6 Hz, 2H), 3.43 (d, JZ9.6 Hz,
1H), 1.83–1.69 (m, 3H), 1.57–1.37 (m, 2H), 0.87 (t, JZ
7.7 Hz, 3H), 0.66 (t, JZ7.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dZ142.5, 128.3, 128.3, 125.7, 52.1, 47.3, 36.7,
33.3, 22.4, 21.4, 12.2, 12.1. MS (70 eV, EI): m/z (%): 380
(MCKH, !1), 311 (22), 310 (100), 91 (23). HRMS (EI):
calcd for C28H30N [MCKH]: 380.2378, found: 380.2374.
IR (film): 2961 (s), 2935 (m), 2803 (m), 1489 (m), 1453 (m),
754 (s), 746 (s), 698 (vs), 690 (vs). Anal. Calcd for
C28H31N: C, 88.14; H, 8.19; N, 3.67. Found: C, 87.96; H,
8.18; N, 3.65.
4.5.3. Ethyl 4-[3-(dibenzylamino)-1-heptynyl]benzoate
(6e). The reaction was carried out according to typical
procedure D with ethyl 4-iodobenzoate. Column chromato-
graphic purification: SiO2, pentane/ether 98:2. Yield: 87%
1
(1.0 mmol scale, 382 mg) as a light yellow oil. H NMR
(600 MHz, CDCl3): dZ8.06 (d, JZ8.5 Hz, 2H), 7.59 (d,
JZ8.5 Hz, 2H), 7.46 (d, JZ7.8 Hz, 4H), 7.36 (t, JZ7.8 Hz,
4H), 7.29–7.27 (m, 2H), 4.44 (q, JZ7.1 Hz, 2H), 3.95 (d,
JZ13.5 Hz, 2H), 3.67 (t, JZ7.8 Hz, 1H), 3.53 (d, JZ
13.5 Hz, 2H), 1.89–18.3 (m, 1H), 1.80–1.74 (m, 1H), 1.55–
1.49 (m, 1H), 1.46 (t, JZ7.2 Hz, 3H), 1.48–1.40 (m, 1H),
1.30–1.24 (m, 2H), 0.91 (t, JZ7.8 Hz, 3H). 13C NMR
(150 MHz, CDCl3): dZ166.1, 139.7, 131.7, 129.5, 129.4,
128.8, 128.2, 128.1, 126.9, 91.6, 84.7, 61.1, 55.0, 52.3, 33.4,
28.5, 22.3, 14.3, 14.0. MS (70 eV, EI): m/z (%): 439 (!1,
MC), 383 (28), 382 (100), 91 (53). HRMS (EI): calcd for
4.5. Typical procedure D (Sonogashira-coupling)
PdCl2(PPh3)2 (14 mg, 0.02 mmol) and CuI (3.8 mg,
0.02 mmol) were charged in a 10 mL Schlenk-flask and
dried in vacuo. After 15 min, the catalyst was suspended in
dry THF (1.5 mL) and NEt3 (152 mg, 1.5 mmol) was added.

11424
N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
C30H32NO2 [MCKH]: 438.2433, found: 438.2405. IR
(film): 2956 (m), 2933 (m), 1720 (vs), 1606 (m), 1454
(m), 1367 (m), 1272 (vs), 1174 (m), 1106 (s), 769 (m), 747
(m), 698 (m).
found: 389.2347. IR (KBr): 2928 (s), 2852 (m), 2219 (m),
1712 (vs), 1495 (m), 1452 (m), 1366 (m), 1241 (vs), 749 (s),
699 (s).
4.7. Typical procedure F (hydrogenation)
4.6. Typical procedure E (alkynyl ester synthesis)
Propargylamine of type 5 or 6 (1.0 mmol) was dissolved in
MeOH (5 mL). KOH (3 drops of a 1 M soln) and Pd on
charcoal (100 mg, 10%) were added and the reaction
mixture was stirred under H2 (1 atm) until TLC-analysis
showed the disappearance of the starting material. Filtration
over celite (washing with EtOAc) and concentration in
vacuo furnished the crude product. Purification was carried
out as described for each compound.
Propargylamine of type 5 (1.0 mmol) was dissolved in dry
THF (2 mL) and cooled to K78 8C. n-BuLi (0.67 mL,
1.0 mmol, 1.5 M in hexane) was added. After stirring at this
temperature for 30 min, ethyl chloroformiate (217 mg,
2.0 mmol) was added and the mixture was allowed to
warm to rt. The reaction mixture was quenched with water
(25 mL) and the aq phase was extracted with diethyl ether
(3!30 mL) and dried (Na2SO4). Column chromatographic
purification (SiO2, pentane/diethyl ether 98:2) furnished the
desired alkynyl esters.
4.7.1. 1-Ethyl-3-phenylpropylamine hydrochloride (7a).
The reaction was carried out according to typical procedure
F from 5f. The crude product was taken up in diethyl ether
and HCl in Et2O was added dropwise. A light yellow
precipitate was formed and collected by filtration (1.0 mmol
scale, 183 mg, 0.92 mmol, 92%). 1H NMR (300 MHz,
D2O): dZ7.47–7.26 (m, 5H), 3.22 (quint, JZ6.4 Hz, 1H),
2.73 (t, JZ7.3 Hz, 2H), 2.07–1.87 (m, 2H), 1.83–1.62 (m,
2H), 0.97 (t, JZ7.6 Hz, 3H). 13C NMR (75 MHz, D2O): dZ
141.4, 129.2, 128.8, 126.8, 53.0, 33.6, 31.0, 25.1, 8.8. MS
(70 eV, EI): m/z (%): 163 (MCKHCl, 1), 146 (17), 134
(42), 117 (25), 106 (16), 91 (85), 58 (100). HRMS (EI):
calcd for C11H17N [MCKHCl]: 163.1361, found:
163.1330. IR (film): 3437 (s), 3029 (vs), 2970 (vs), 2933
(vs), 1602 (m); 1502 (m), 1455 (m), 700 (m).
4.6.1. Ethyl 4-(dibenzylamino)-2-heptynoate (6f). Pre-
pared according to typical procedure E from 5a. Yield: 96%
(2.0 mmol scale, 673 mg), colorless oil. 1H NMR
(600 MHz, CDCl3): dZ7.42–7.40 (m, 4H), 7.37–7.32 (m,
4H), 7.29–7.24 (m, 2H), 4.31 (q, JZ7.0 Hz, 2H), 3.90 (d,
JZ13.8 Hz, 2H), 3.57 (t, JZ8.0 Hz, 1H), 3.45 (d, JZ
13.8 Hz, 2H), 1.83–1.62 (m, 2H), 1.56–1.34 (m, 3H), 1.39
(t, JZ7.1 Hz, 3H), 0.82 (t, JZ7.5 Hz, 3H). 13C NMR
(150 MHz, CDCl3): dZ153.7, 139.1, 128.8, 128.3, 127.1,
86.8, 77.2, 62.0, 54.9, 51.3, 35.0, 19.4, 14.1, 13.5. MS
(70 eV, EI): 348 (MCKH, !1), 307 (19), 306 (100), 91
(45). HRMS (EI): calcd for C25H29NO2 [MCK2H]:
375.2198, found: 375.2166. IR (film): 2960 (m), 2936
(m), 2220 (m), 1713 (vs), 1454 (m), 1242 (vs), 750 (m),
699 (m).
4.7.2. 1-Cyclohexyl-1-propanamine (7b). The reaction
was carried out according to typical procedure F from 5e.
The crude product was already analytically pure, yielding
7b as a colorless liquid (2.0 mmol scale, 236 mg,
4.6.2. Ethyl 4-(dibenzylamino)-2-nonynoate (6g). Pre-
pared according to typical procedure E from 5c. Yield: 95%
(1.0 mmol scale, 390 mg), colorless oil. 1H NMR
(600 MHz, CDCl3): dZ7.42 (d, JZ7.7 Hz, 4H), 7.35 (t,
JZ7.7 Hz, 4H), 7.29–7.26 (m, 2H), 4.32 (q, JZ7.3 Hz, 2H),
3.90 (d, JZ13.8 Hz, 2H), 3.56 (t, JZ7.7 Hz, 1H), 3.45 (d,
JZ13.8 Hz, 2H), 1.84–1.67 (m, 2H), 1.51–1.43 (m, 2H),
1.40 (t, JZ7.3 Hz, 3H), 1.31–1.25 (m, 2H), 1.18–1.13 (m,
2H), 0.87 (t, JZ7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3):
dZ153.7, 139.1, 128.8, 128.3, 127.1, 86.9, 77.4, 62.0, 54.9,
51.5, 32.8, 31.1, 25.7, 22.4, 14.1, 14.0. MS (70 eV, EI): 375
(MCK2H!1), 307 (18), 306 (100), 91 (53). HRMS (EI):
calcd for C25H29NO2 [MCK2H]: 375.2198, found:
375.2166. IR (film): 2956 (m), 2933 (m), 2222 (m), 1713
(vs), 1454 (m), 1242 (vs), 749 (m), 699 (m).
1
1.67 mmol, 84%). H NMR (300 MHz, CDCl3): dZ2.40–
2.38 (m, 1H), 1.77–1.60 (m, 5H), 1.54–1.42 (m, 1H), 1.28–
0.98 (m, 8H), 0.90 (t, JZ7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dZ57.6, 43.3, 29.8, 27.9, 27.3, 26.7, 26.6, 26.5,
10.8. MS (70 eV, EI): m/z (%): 142 (MCCH, 2), 112 (31),
95 (14), 58 (100), 41 (10). HRMS (EI): calcd for C9H20N
[MCCH]: 142.1596, found: 142.1592. IR (KBr): 2924 (vs),
2852 (s), 1565 (m), 1463 (m), 1449 (m).
4.7.3. 5-Ethyl-1-[(triisopropylsilyl)oxy]-4-heptanamine
(7c). The reaction was carried out according to
typical procedure F from 6a. Distillation in Kugelrohr
(1.0!10K1 mbar, 150 8C) leads to the desired amine
(0.50 mmol scale, 104 mg, 0.33 mmol, 66%) as a colorless
oil, which solidified upon standing. Mp 67–69 8C 1H NMR
(300 MHz, CDCl3): dZ8.07 (br s, 2H), 3.79–3.58 (m, 2H),
3.28–3.19 (m, 1H), 1.91–1.33 (m, 9H), 1.03 (s, 21H), 0.93
(t, JZ7.0 Hz, 3H), 0.92 (t, JZ7.0 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dZ62.2, 53.9, 43.4, 29.2, 25.8, 21.8,
18.0, 12.0, 11.9, 11.8, 11.6. MS (70 eV, EI): m/z (%): 315
(MC, 8), 273 (19), 272 (81), 245 (21), 244 (100), 157 (15),
131 (18), 130 (40), 123 (14), 103 (23), 100 (26). HRMS
(EI): calcd for C18H41NOSi [MC]: 315.2957, found:
315.2957. IR (KBr): 2942 (vs), 2867 (vs), 1605 (w), 1521
(m), 1463 (m), 1100 (s), 883 (m), 678 (m).
4.6.3. Ethyl 4-cyclohexyl-4-(dibenzylamino)-2-butynoate
(6h). Prepared according to typical procedure E from 5e.
Yield: 85% (1.0 mmol scale, 393 mg), colorless oil. 1H
NMR (300 MHz, CDCl3): dZ7.43–7.41 (m, 4H), 7.37–7.32
(m, 4H), 7.29–7.24 (m 2H), 4.32 (q, JZ7.1 Hz, 2H), 3.90 (d,
JZ13.8 Hz, 2H), 3.44 (d, JZ13.8 Hz, 2H), 3.21 (d, JZ
10.5 Hz, 1H), 2.30 (d, JZ14.1 Hz, 1H), 1.99 (d, JZ
12.1 Hz, 1H), 1.75–1.61 (m, 4H), 1.40 (t, JZ7.1 Hz, 3H),
1.34–1.06 (m, 3H), 0.97–0.68 (m, 2H). 13C NMR (75 MHz,
CDCl3): dZ153.8, 139.0, 128.8, 128.3, 127.1, 86.1, 78.5,
61.9, 57.8, 55.0, 39.2, 31.0, 30.2, 26.4, 25.9, 25.7, 14.1. MS
(70 eV, EI): m/z (%): 389 (MC, !1), 307 (20), 306 (100),
91 (66). HRMS (EI): calcd for C26H31NO2 [MC]: 389.2355,
4.7.4. 1-Propyl-5-[(triisopropylsilyl)oxy]pentylamine
(7d). The reaction was carried out according to typical

N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
11425
procedure F from 6b. Kugelrohr distillation (160 8C, 7!
10K2 mbar) yielded the desired product 7d (3.0 mmol scale,
861 mg, 2.9 mmol, 99%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): dZ3.67 (t, JZ6.0 Hz, 2H), 2.70 (br s,
2H), 1.56–1.12 (m, 9H), 1.08–1.00 (m, 2H), 1.03 (s, 21H),
0.90 (t, JZ6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): dZ
63.3, 50.9, 40.2, 37.9, 33.1, 22.4, 19.3, 18.0, 14.2, 12.0. MS
(70 eV, EI): m/z (%): 299 (MCK2H, 23), 298 (100), 258
(75), 241 (21), 199 (51), 170 (66), 130 (35), 115 (20), 75
(20), 72 (20). IR (film): 2941 (vs), 2866 (vs), 1463 (m), 1105
(s). Anal. Calcd for C17H39NOSi: C, 67.70; H, 13.03; N,
4.64. Found: C, 67.61; H, 12.71; N, 4.36.
carried out according to typical procedure F from 6f.
Distillation in Kugelrohr (4.5!10K1 mbar, 160 8C) leads to
the desired amide (0.90 mmol scale, 95 mg, 0.68 mmol,
75%) as a colorless solid. Mp 48–50 8C. 1H NMR
(300 MHz, CDCl3): dZ6.96 (br s, 1H), 3.61 (quint, JZ
6.7 Hz, 1H), 2.33–2.14 (m, 3H), 1.72–1.59 (m, 1H), 1.54–
1.26 (m, 4H), 0.90 (t, JZ7.4 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dZ178.5, 54.5, 38.9, 30.3, 27.2, 19.1, 13.9. MS
(70 eV, EI): m/z (%): 127 (MC, 2), 84 (100), 41 (21).
HRMS (EI): calcd for C7H13NO [MC]: 127.0997, found:
127.1002. IR (KBr): 3194 (s), 2963 (s), 2931 (s), 2871 (s),
1707 (vs), 1662 (s), 1461 (m), 1390 (m), 1347 (m), 1318
(m), 1290 (m), 766 (m). Anal. Calcd for C7H13NO: C,
66.10; H, 10. 30; N, 11.01. Found: C, 66.27; H, 9.94; N,
10.75.
4.7.5. 1-(2-Phenylethyl)pentylamine (7e). The reaction
was carried out according to typical procedure F from 6c.
The crude product was already analytically pure (0.90 mmol
scale, 123 mg, 0.64 mmol, 72%) and obtained as a colorless
oil, which slowly solidified upon standing. Mp 152–154 8C.
1H NMR (300 MHz, CDCl3): dZ8.56 (br s, 2H), 7.35–7.16
(m, 5H), 3.21 (quint, JZ6.3 Hz, 1H), 2.93–2.74 (m, 2H),
2.17–1.96 (m, 2H), 1.85–1.67 (m, 2H), 1.51–1.23 (m, 4H),
0.88 (t, JZ7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): dZ
140.3, 128.5, 128.4, 126.2, 52.0, 34.5, 32.5, 31.4, 27.3, 22.3,
13.7. MS (70 eV, EI): m/z (%): 190 (MCKH, 1), 134 (68),
117 (36), 104 (11), 91 (92), 86 (100). HRMS (EI): calcd for
C13H20N [MCKH]: 190.1596, found: 190.1591. IR (KBr):
3436 (m), 3027 (s), 2932 (vs), 1602 (m), 1498 (m), 1455
(m), 747 (w), 699 (m).
4.7.9. 5-Pentyl-2-pyrrolidinone (7i). The reaction was
carried out according to typical procedure F from 6g.
Distillation in Kugelrohr (1.0!10K1 mbar, 170 8C) leads to
the desired amide (0.75 mmol scale, 100 mg, 0.65 mmol,
1
87%) as a colorless oil. H NMR (300 MHz, CDCl3): dZ
6.86 (br s, 1H), 3.59 (quint, JZ6.2 Hz, 1H), 2.32–2.14 (m,
3H), 1.71–1.59 (m, 1H), 1.54–1.37 (m, 2H), 1.33–1.25 (m,
6H), 0.85 (t, JZ7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3):
dZ178.4, 54.7, 36.6, 31.6, 30.3, 27.2, 25.4, 22.4, 13.9. MS
(70 eV, EI): m/z (%): 154 (MC, 100), 110 (70), 100 (32), 97
(65), 84 (55), 69 (32), 43 (23), 41 (28). HRMS (EI): calcd
for C9H16NO [MCKH]: 154.1232, found: 154.1222. IR
(KBr): 3208 (m), 2956 (m), 2928 (s), 2859 (m), 1698 (vs),
1463 (m), 1284 (m).
4.7.6. 4-Ethyl-1-phenyl-3-hexanamine (7f). The reaction
was carried out according to typical procedure F from 6d.
Distillation in Kugelrohr (1.0!10K1 mbar, 120–140 8C)
leads to the desired amine (0.85 mmol scale, 150 mg,
4.7.10. 5-Cyclohexyl-2-pyrrolidinone (7j). The reaction
was carried out according to typical procedure F from 6h.
The crude product was dissolved in EtOH (3 mL) and concd
H2SO4 (3 drops) was added. After stirring overnight, the
reaction was quenched with NaHCO3 (30 mL) and the aq
phase was extracted with EtOAc (3!40 mL) and dried over
Na2SO4. Concentration under reduced pressure leads to the
amide 7j (1.4 mmol scale, 202 mg, 1.2 mmol, 85%) as a
yellow solid. Mp 110–112 8C. 1H NMR (300 MHz, CDCl3):
dZ6.23 (br s, 1H), 3.35 (q, JZ6.7 Hz, 1H), 2.49–2.34 (m,
1H), 2.21–2.09 (m, 1H), 1.86–1.62 (m, 6H), 1.56–1.42 (m,
1H), 1.30–1.13 (m, 4H), 1.05–0.83 (m, 2H). 13C NMR
(75 MHz, CDCl3): dZ178.3, 59.5, 43.4, 30.3, 29.4, 28.6,
26.3, 25.8, 25.7, 25.0. MS (70 eV, EI): m/z (%): 167 (MC,
!1), 85 (7), 84 (100), 55 (3), 40 (7). HRMS (EI): calcd for
C10H17NO [MC]: 167.1310, found: 167.1295. IR (KBr):
3182 (m), 2923 (s), 2855 (s), 1689 (vs), 1453 (m), 1279 (m),
1264 (m), 808 (m).
1
0.75 mmol, 88%) as a colorless oil. H NMR (300 MHz,
CDCl3): dZ7.33–7.28 (m, 2H), 7.24–7.17 (m, 3H), 2.82–
2.78 (m, 2H), 2.67–2.57 (m, 1H), 1.82–1.71 (m, 1H), 1.65–
1.53 (m, 1H), 1.46–1.13 (m, 7H), 0.91 (t, JZ7.5 Hz, 6H).
13C NMR (75 MHz, CDCl3): dZ142.5, 128.3, 128.3, 125.7,
52.1, 47.3, 36.7, 33.3, 22.4, 21.4, 12.2, 12.1. MS (70 eV,
EI): m/z (%): 206 (MCCH, 2), 134 (100), 117 (11), 91 (23).
HRMS (EI): calcd for C14H24N [MCCH]: 206.1909, found:
206.1901. IR (film): 2961 (vs), 2931 (s), 2874 (m), 1454
(m), 699 (m). Anal. Calcd for C14H23N: C, 81.89; H, 11.29;
N, 6.82. Found: C, 81.32; H, 11.19; N, 6.69.
4.7.7. Ethyl 4-(3-aminoheptyl)benzoate (7g). The reaction
was carried out according to typical procedure F from 6e.
The crude product was washed with diethyl ether and dried
in vacuo. Aminoester 7g (0.30 mmol scale, 57 mg,
0.22 mmol, 72%) was obtained as a colorless solid. Mp
1
136–138 8C. H NMR (300 MHz, CDCl3): dZ8.55 (br s,
2H), 7.90 (d, JZ8.4 Hz, 2H), 7.28 (d, JZ8.3 Hz, 2H), 4.35
(q, JZ7.4 Hz, 2H), 3.18 (quint, JZ6.0 Hz, 1H), 2.96–2.77
(m, 2H), 2.14–1.94 (m, 2H), 1.82–1.59 (m, 2H), 1.34 (t, JZ
7.4 Hz, 3H), 1.31–1.19 (m, 4H), 0.84 (t, JZ7.3 Hz, 3H). 13C
NMR (75 MHz, CDCl3): dZ166.4, 145.5, 129.7, 128.7,
128.4, 60.8, 52.1, 34.2, 32.6, 31.4, 27.3, 22.2, 14.3, 13.7. MS
(70 eV, EI): m/z (%): 263 (MC, 2), 207 (11), 206 (94), 163
(42), 86 (100). HRMS (EI): calcd for C16H25NO2 [MC]:
263.1885, found: 263.1882. IR (KBr): 3436 (s), 2959 (vs),
2931 (vs), 1716 (vs), 1612 (m), 1279 (vs), 1111 (m).
Acknowledgements
We thank the Fonds der Chemischen Industrie and Merck
Research Laboratories (MSD) for financial support. We
¨
thank the DFG (SPP 1118 ‘Sekundare Wechselwirkungen
als Steuerungsprinzip zur gerichteten Funktionalisierung
¨
reaktionstrager Substrate’) for a fellowship for N.G. and
Chemetall GmbH (Frankfurt) and BASF AG (Ludwigs-
hafen) for generous gifts of chemicals.
4.7.8. 5-Propyl-2-pyrrolidinone (7h). The reaction was

11426
N. Gommermann, P. Knochel / Tetrahedron 61 (2005) 11418–11426
S.; Kubo, T.; Ishii, Y. Angew. Chem., Int. Ed. 2001, 40, 2534.
References and notes
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