Intramolecular hydroamination of conjugated enynes

Article abstract of DOI:10.1016/j.tet.2008.09.045

An intramolecular hydroamination of conjugated enyne was developed using commercially available n-BuLi as a precatalyst. This hydroamination reaction led to products with allene and pyrrolidine functional groups. One of the enyne hydroamination products w

Full text of DOI:10.1016/j.tet.2008.09.045

Tetrahedron 65 (2009) 3090–3095
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular hydroamination of conjugated enynes
,
Wen Zhang a, Jenny B. Werness b, Weiping Tang a
*
a The School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, United States
b Department of Chemistry, University of Wisconsin, 1101 University Ave, Madison, WI 53706-1322, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular hydroamination of conjugated enyne was developed using commercially available n-
BuLi as a precatalyst. This hydroamination reaction led to products with allene and pyrrolidine functional
groups. One of the enyne hydroamination products was successfully converted to natural products ir-
niine and irnidine in three steps. The scope and mechanism of the enyne hydroamination are also
discussed.
Received 16 August 2008
Received in revised form 13 September
2008
Accepted 15 September 2008
Available online 24 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
alkenes13,14 and 1,2-disubstituted alkenes.15 Hartwig’s group re-
cently reported a rhodium-based catalyst that promoted the
Stereoselective additions to alkenes and alkynes are powerful
methods for the introduction of functionality to organic com-
pounds and have become one of the most influential fields in
modern synthetic organic chemistry. We envision that conjugated
1,3-enyne may represent a new platform for the discovery of novel
stereoselective addition reactions. Three possible additions may
occur for conjugated 1,3-enynes: 1,2-addition to alkene, 3,4-addi-
tion to alkyne, and 1,4-addition across enyne (Scheme 1). While the
regio-, diastereo-, and enantioselectivity for the addition to isolated
alkenes and/or alkynes have been studied extensively, little is
known about the 1,4-addition across conjugated enynes,1 which
may form a stereogenic center and a chiral allene2 in a single step.
We first explored intramolecular hydroamination of conjugated
enynes, which may produce substituted nitrogen heterocycles, an
important class of pharmaceutical agents (Scheme 2). Tethering of
the enyne and amine may simplify the regioselectivity issues il-
lustrated in Scheme 1. However, both allenyl amine 2 and homo-
propargyl amine 3 can potentially be formed.
Impressive progress has been made recently for the transition
metal catalyzed intramolecular additions of amides and sulfon-
amides to alkenes, allenes, and dienes.3 The addition of unprotected
amines to alkenes, arguably the most important donors and ac-
ceptors,4 has been studied in very limited systems (Scheme 3). The
intramolecular addition of unprotected amines to monosubstituted
alkenes has been tested in a number of catalytic systems based on
rare earth metals,5 titanium and zirconium,6,7 zinc,8 alkali metals,9–11
and late transition metals.12 A few catalysts were developed for the
intramolecular addition of unprotected amines to 1,1-disubstituted
intramolecular addition of unprotected amines to a variety of al-
kenes under mild conditions, which represents an important
progress in the field of hydroamination.16 To extend the scope of
olefin substrates for the preparation of nitrogen heterocycles,
highly reactive and sterically less encumbered aminoallenes have
become attractive substrates for hydroamination using catalysts
based on lanthanides,17 group IV transition metals,18 and late
transition metals.19 The conjugated aminodiene is another class of
substrate that has been used to prepare nitrogen heterocycles with
functionalized substituents.20,21 The catalytic intramolecular addi-
tion of unprotected amines to conjugated vinyl arenes was also
realized in several catalytic systems.7,9,22
Despite impressive progress on the hydroamination of carbon–
carbon multiple bonds, the intramolecular hydroamination of
conjugated enynes has never been explored.23 Our group discov-
ered the first intramolecular hydroamination of conjugated enyne
1, which selectively affords allenyl amine 2.24 Herein, we report the
scope, limitation, mechanistic studies, and synthetic applications of
this novel hydroamination reaction.
B
A
1,2-addition
3,4-addition
A
B
4
3
2
A
B
A
B
1
B
B
A
A
1,3-ENYNE
1,4-addition
B
A
* Corresponding author. Tel.: þ1 608 890 1846; fax: þ1 608 262 4888.
E-mail address: wtang@pharmacy.wisc.edu (W. Tang).
Scheme 1. Possible regio-isomers from addition to conjugated enynes.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.045

W. Zhang et al. / Tetrahedron 65 (2009) 3090–3095
3091
R1
or
conditions
HN
1a
N
Ph
N
R2
Ph
R2
catalyst
2
n-Pr
N
H
n-Pr
1b
R1
R1
conditions
conversion
100%
100%
dr
1
(1) 120 mol % n-BuLi;
(2) 20 mol % n-BuLi;
1.8 : 1
1.6 : 1
N
R2
3
Scheme 5. Base-catalyzed enyne hydroamination.
Scheme 2. Intramolecular hydroamination of enynes.
enyne also provided high yield of the hydroamination product
(Table 1, entry 9). Substituted pyrrolidine 2j was obtained as
a mixture of two diastereomers, which yielded only the cis-1,2-
disubstituted pyrrolidine upon hydrogenation (Table 1, entry 10).
Efforts toward the formation of six-membered-ring heterocycles
via hydroamination of enynes were not successful (Table 1, entry
11). It appeared that many olefin isomers were formed under this
condition. In fact, olefin isomerization has been reported as a main
competing pathway in base-catalyzed intramolecular hydro-
amination of monosubstituted alkenes.10 We were surprised that
cis-enyne 1l did not undergo cyclization under our standard con-
ditions (Table 1, entry 12). The gem-dimethyl group30 did not fa-
cilitate the cyclization of enyne 1m (Table 1, entry 13). The less
nucleophilic aniline 1n did not undergo cyclization (Table 1, entry
14). Addition of chelating nitrogen shuts down the hydroamination
of enyne 1o under catalytic condition (Table 1, entry 15). When
120 mol % n-BuLi was used, cyclization of enyne 1o occurred with
a 15% conversion even though the diastereoselectivity was im-
proved significantly (Table 1, entry 16). Changing the chelating
atom to oxygen shuts down the reaction completely (Table 1, entry
17).
Encouraged by the relative high diastereoselectivity for the cy-
clization of aminoenyne 1o, we tried to improve the diaster-
eoselectivity of other enynes by the addition of external
coordinating additives (Table 2). The addition of diisopropylamine
slightly changed the ratio (Table 2, entries 1–7). Diethyl ether and
toluene are not suitable solvents for the hydroamination reaction.
Moderate improvement of the diastereoselectivity could be ach-
ieved by the addition of ethylenediamine (Table 2, entry 14). Ad-
ditives clearly can impact the diastereoselectivity of the enyne
hydroamination reaction. We also tried to quench the reaction with
various proton sources after the treatment of 120 mol % of n-BuLi.
However, no obvious improvement of the diastereoselectivity was
observed.
R1
R2
R2
catalyst
R1
N
H
( )n
( )n
N
(R = H, vinyl, or aryl in most catalytic systems.)
R1
R1
R2
catalyst
( )n
N
H
( )n
N
( n = 1 or 2 )
R2
Scheme 3. Previous work on intramolecular hydroamination of alkenes.
2. Results and discussion
Aminoenyne 1a (Scheme 4) was prepared in three steps in-
volving addition of a terminal alkyne to acrolein, a Johnson–Claisen
rearrangement, and a reductive amination according to the litera-
ture procedures.25 Two strategies can be envisioned for the cata-
lytic hydroamination of conjugated enynes: activation of the enyne
or activation of the amine. Unfortunately, efforts toward activation
of the enyne for nucleophilic attack failed to afford any hydro-
amination product. In most cases, only starting materials were re-
covered in the presence of catalysts based on gold, silver, and
platinum. Interestingly, PtCl2(PPh3)2 catalyst led to isomerization of
enyne (Scheme 4).
PtCl2(PPh3)2
(10 mol%)
Dioxane (0.2M),
120 °C, 21 h
N
1a
n-Pr
Ph
H
E / Z = 1.5 : 1
1a
Scheme 4. Attempts for transition metal catalyzed enyne hydroamination.
We then focused on catalysts that can activate the amino
group. Alkali metals have been used to catalyze the addition of
amines to monosubstituted alkenes,9–11 1,1-disubstituted alkenes,13
1,3-butadienes,21,26 and conjugated vinyl arenes9,27 including
electron-rich vinylarenes28 via deprotonation of the amine fol-
lowed by addition to the double bonds.29 In an effort to develop
a catalyst that is cost-effective and readily accessible, we decided to
explore the potential of alkali metals for the intramolecular
hydroamination of conjugated enynes.
The proposed mechanism for the base-catalyzed hydro-
amination of enynes is shown in Scheme 6.29 The amine N–H was
first deprotonated by n-BuLi to form lithium amide 4, which pre-
sumably served as the catalytic species. A 5-exo-trig cyclization
could generate propargyllithium 5 and/or allenyllithium 6,31 which
could then be protonated by aminoenyne 1 to give allenyl amine 2
and catalyst 4. The fact that no homopropargyl amine 3 was ob-
served suggests that allenyllithium 6 is the predominant species or
the protonation of allenyllithium 6 is much faster than prop-
argyllithium 5. In the case of n-BuLi-catalyzed intramolecular
hydroamination of monosubstituted alkene, it was shown that the
yield of the product dropped from 49% to 12% when n-BuLi was
increased from 30 mol % to 120 mol %.9 This suggests that the
When we first treated aminoenyne 1a with 120 mol % n-BuLi at
ꢀ78 ꢁC in THF, aminoenyne 1a was completely cycloisomerized to
allenyl pyrrolidine 2a with a 1.8:1 diastereomeric ratio after 1 h
(Scheme 5). We then reduced the amount of n-BuLi to 20 mol % and
increased the concentration of the aminoenyne to 0.4 M in THF. A
100% conversion was achieved at ꢀ78 ꢁC with
a 1.6:1 di-
astereomeric ratio after 1 h. No homopropargyl amine product was
observed under these conditions.
generation of
unfavorable step and quenching of basic
b
-aminoalkyl lithium anion from lithium amide is an
-aminoalkyl lithium by
b
We then investigated the scope of the hydroamination of con-
jugated aminoenynes using 20 mol % of n-BuLi as a precatalyst
(Table 1). Aminoenynes with different substituents on the amino
group all worked well under optimal conditions with no significant
changes of the yields and diastereomeric ratios. Surprisingly, in-
creasing the steric bulk of the alkyne improved the diastereomeric
ratio from 2:1 to 5:1 (Table 1, entries 3 and 7). A phenyl substituted
amine is required for the high yield of the final product. In contrast,
the enyne hydroamination reaction worked smoothly with
120 mol % n-BuLi (Scheme 5). This implies that the generation of
propargyllithium 5 or allenyllithium 6 from metal amide 4 is a fa-
vorable step.
To probe the mechanism of the enyne hydroamination, we
quenched the reaction with CD3OD after 1 h (Scheme 7).

3092
W. Zhang et al. / Tetrahedron 65 (2009) 3090–3095
Table 1
Table 1 (continued)
Scope of the base-catalyzed enyne hydroaminationa
Yield (%)
drb
Entry
Enyne
Product
Entry
Enyne
Product
Yield (%)
drb
n-Hex
n-Pr
14
15
No reaction
Ph
N
H
n-Pr
n-Pr
93
1.6:1
n-Pr
1
N
N
N
H
1n
Ph
Ph
1a
No reaction
2a
•
N
H
15d
14:1
n-Pr
Me2N
1o
16c
17c
79
2.1:1
n-Pr
n-Pr
N
2
3
4
5
6
7
8
9
N
H
Me2N
2o
2b
1b
n-Pr
83
2.0:1
No reaction
N
H
n-Pr
i-Pr
N
H
i-Pr
2c
N
MeO
1p
1c
a
b
c
All reactions were performed at ꢀ78 ꢁC with n-BuLi (20 mol %) in THF (0.4 M).
Ratios were determined using NMR in CD3COCD3.
n-BuLi (120 mol %), 0.1 M.
95
1.8:1
n-Hex
n-Hex
N
Conversion estimated by 1H NMR.
d
N
H
2d
1d
Surprisingly, we found that the deuterium content of proton Ha in
product 2d was about 85%, while proton Hb had almost no deute-
rium. This suggests that the allenyllithium 8 is the major lithium
species. The coordination of nitrogen to lithium may shift the
equilibrium from 7 to 8. The inter-conversion of lithium species 7, 8,
9, and 10 and the potential epimerization of each intermediate may
complicate the diastereoselectivity issue of the enyne hydro-
amination reaction.31
Substituted pyrrolidines exist in numerous natural products and
pharmaceutical agents, and display a broad spectrum of biological
activities.32 For example, irniine 16 (Scheme 3) was isolated from
the tubers of Arisarum vulgare, a toxic Amceae responsible for hu-
man and animal poisonings in Morocco.33 Irniine34 displayed sig-
nificant antibacterial and antimycotic activity,35 and a strong
binding affinity for DNA.36 From the same natural source, de-
rivatives of irniine such as irnidine 17 have also been isolated.37
We envisioned that an alkyne-zipper reaction38 could convert
the allene functional group next to the pyrrolidine ring in 2a–j to
a terminal alkyne, which can then be further transformed to a de-
sired functionality. Indeed, treatment of hydroamination product
80
1.8:1
n-Hex
n-Hex
n-Hex
n-Hex
i-Pr
2e
N
N
i-Pr
N
H
1e
70
2.1:1
Bn N
H
Bn
2f
1f
73
5.0:1
t-Bu
t-Bu
t-Bu
i-Pr
N
H
i-Pr
2g
N
1g
72
1.7:1
t-Bu
Bn
N
N
Bn
2h
H
1h
Ph
Ph
78
1.0:1
2d with excess potassium hydride in
a solution of 1,3-
N
N
H
Ph
Ph
1i
2i
Table 2
Hydroamination of enyne 1aa
Me
Me
Entry n-BuLi Amine/equiv
Solvent T (ꢁC)
Time (h) Conversion
dr
88
1.3:1
(equiv)
of 1a to 2a (%)
n-Pr
10
n-Pr
n-Pr
N
N
H
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
1.0
0.5
0.5
1.0
1.0
1.0
1.0
1.0
0.5
i-Pr2NH/8.0
i-Pr2NH/4.0
i-Pr2NH/1.0
i-Pr2NH/1.0
i-Pr2NH/1.0
i-Pr2NH/1.0
i-Pr2NH/4.0
Et3N/1.0
TMEDA/1.0
TMEDA/0.5
TMEDA/1.0
TMP/1.0
H2N(CH2)3NH2/1.0 THF
H2N(CH2)2NH2/1.0 THF
H2N(CH2)2NH2/0.5 THF
H2N(CH2)2NH2/2.0 THF
H2N(CH2)2NH2/0.5 THF
THF
THF
THF
Et2O
Et2O
ꢀ78
ꢀ78
ꢀ78
ꢀ78
1
1
1
1
100
100
100
0
22
33
100
27
56
100
100
100
50
100
100
60
1:1
Ph
1:1.1
1:1.5
d
Ph
2j
1j
( )2
ꢀ78 to 0 1
1:2.2
1:1.1
1:1.1
1:1.4
1:1.7
1:2.2
1:1.8
1:2.3
1:1.5
1:4.5
1:1.9
1:2.8
1:1.4
PhMe ꢀ78
1
1
1
1
1
1
1
1
1
1
1
1
11
12
Complex mixture
No reaction
N
H
THF
THF
THF
THF
THF
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
Ph
1k
9
10
11
12
13
14
15
16
17
i-Pr
HN
t-Bu
1l
Me
Me
100
13
No reaction
t-Bu
a
Reaction concentration was 0.1 M, THF was dry from the column, and quenched
MeOH
TMP¼tetramethylpiperidine.
i-Pr
N
H
by
(0.1 mL)
at
ꢀ78 ꢁC.
TMEDA¼tetramethylethylenediamine,
1m

W. Zhang et al. / Tetrahedron 65 (2009) 3090–3095
Li
3093
cyclization under our standard conditions. The low cost of com-
mercially available n-BuLi precatalyst and the mild conditions make
this hydroamination feasible for large scale production of
substituted pyrrolidines. The deuterium labeling study indicated
that the product could be further deprotonated leading to multiple
lithium species. We also showed that the diastereoselectivity could
be improved by the addition of amine additives. This result en-
courages further development of a catalytic, diastereo-, and enan-
tioselective hydroamination method for conjugated enynes using
chiral additives. The resulting allenyl substituted pyrrolidines could
be further functionalized as demonstrated in the divergent syn-
thesis of the natural products irniine and irnidine. The sequential
enyne hydroamination followed by alkyne-zipper reaction should
be applicable to the synthesis of other pyrrolidines with remote
functional groups, such as the family of broussonetine
iminosugars.32
R1
R1
n-BuLi
1
N
Li
N
5
R2
4
R2
R1
Li
R1
N
N
6
R2
R2
2
4
1
Scheme 6. A proposed mechanism for the base-catalyzed enyne hydroamination.
n-BuLi (1.2 equiv)
n-Hex
THF, -78 °C, 1 h
HN
Me
quench with CD3OD
Hb
d-2d
n-Hex
100% conversion
dr = 1 : 1
N
Me
n-Hex
Ha/D
1d
4. Experimental
n-Hex
n-Hex
4.1. General experimental procedures
CD3OD
Li
N
Li
8
All reactions in non-aqueous media were conducted under
a positive pressure of dry argon within glassware that had been
oven dried prior to use unless otherwise noted. Anhydrous solu-
tions of reaction mixtures were transferred via an oven dried sy-
ringe or cannula. All solvents were dried prior to use. Thin layer
chromatography was performed using precoated silica gel plates
(EMD Chemical Inc. 60, F254). Flash column chromatography was
N
Me
N
Me
D
Me
d-2d
7
Li
Li
n-Hex
n-Hex
performed with silica gel (Sillicycle, 40–63 mm). Infrared spectra
N
N
Me
9
(IR) were obtained as neat oils on a Bruker Equinox 55 Spectro-
10
Me
photometer. 1H and 13C nuclear magnetic resonance spectra (NMR)
Scheme 7. Deuterium labeling of the enyne hydroamination product.
were obtained on
100 MHz, respectively) and are recorded in parts per million (
downfield of TMS (
dicate that final products have >95% purity. High resolution mass
spectra (HRMS) were performed by Analytical Instrument Center at
the School of Pharmacy on an IonSpec ProMALDI Fourier transform
ion cyclotron resonance (FTICR) mass spectrometer.
a Varian Unity-Inova 400 MHz (400 and
d
)
d
¼0) in CDCl3, CD3COCD3. The NMR spectra in-
diaminopropane completely isomerized allene 2d to terminal al-
kyne 11 shown in Scheme 8. Sonogashira cross-coupling39 between
alkyne 11 and iodobenzene 12 or 1-iodo-2-methoxybenzene 13
provided penultimate intermediates 14 and 15. Palladium catalyzed
hydrogenation of alkyne 14 and 15 then cleanly afforded natural
products irniine 16 and its congener irnidine 17.
4.2. Experimental procedures
Pd(PPh3)4 (1.5 mol %)
4.2.1. General procedure for the synthesis of aminoenynes from
corresponding esters
KH (5.0 equiv),
H2N(CH2)3NH2
THF, rt, 30 min,
81%
CuI (2.5 mol %)
Et3N/THF = 4/1
12 or 13 (5 equiv)
(
)
7
2d
Enyne ester (0.19 mmol) was dissolved in 2 mL of toluene and
cooled to ꢀ78 ꢁC, a solution of DIBALH (0.19 mL, 0.19 mmol,1.0 M in
hexane) was added slowly, and then the mixture was stirred at
ꢀ78 ꢁC for 2 h. The reaction was quenched by water, the combined
aqueous phases were extracted with Et2O (3ꢂ5 mL). The combined
organic layers were washed by brine, dried over Na2SO4, filtered,
and concentrated to give the crude aldehydes. To a suspension of
aldehyde and MgSO4 (200 mg) in 2 mL dry toluene was added
amine (0.19 mmol). The reaction mixture was stirred for 12 h at
room temperature. The mixture was then filtered and concentrated
in vacuo to afford the imine. The imine was dissolved in methanol
(3 mL), sodium borohydride was added at 0 ꢁC, and the reaction
mixture was slowly warmed up to room temperature and stirred
for 2 h. The reaction was quenched by water, extracted with ethyl
acetate, the organic phase was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo to afford yellow oil,
which was purified by flash chromatography (EtOAc/MeOH¼10:1,
Rf¼0.2) to obtain the trans-aminoenynes.
N
11
(
)
7
(
)
7
H2, Pd/C (10%)
MeOH, rt, 12 h
N
R
N
R
16: R = H, 75%
17: R = OCH3, 57%
14: R = H, 52%
15: R = OCH3, 55%
12: iodobenzene, 13: 1-iodo-2-methoxybenzene
Scheme 8. Synthesis of irniine and irnidine.
3. Conclusion
In summary, we reported the scope and limitations of a base-
catalyzed intramolecular hydroamination of conjugated enynes.
The reaction was catalyzed by lithium amide to yield allenyl
substituted five-membered pyrrolidines in up to 95% yield. A ster-
eogenic center and an axial chiral allene were generated in this
cycloisomerization reaction and a diastereomeric ratio of up to 5:1
was achieved. Attempts to make six-membered piperidines led to
significant olefin isomerization. cis-Enynes did not undergo
4.2.1.1. Compound
1a. (E)-N-Phenethyldec-4-en-6-yn-1-amine,
37% yield. 1H NMR (400 MHz, CDCl3, TMS):
d
0.98 (t, J¼7.2 Hz, 3H),
1.50–1.59 (m, 4H), 2.09 (t, J¼6.8 Hz, 2H), 2.26 (dt, J¼2.0, 7.2 Hz, 2H),
2.62 (t, J¼7.2 Hz, 2H), 2.78–2.82 (m, 2H), 2.85–2.89 (m, 2H), 5.44

3094
W. Zhang et al. / Tetrahedron 65 (2009) 3090–3095
(dt, J¼16, 2.0 Hz, 1H), 6.02 (dt, J¼15.6, 7.2 Hz, 1H), 7.18–7.31 (m, 5H).
13C NMR (100 MHz, CDCl3):
13.5, 21.3, 22.2, 29.1, 30.7, 36.3, 49.1,
(m, 2H). 13C NMR (100 MHz, CDCl3, TMS):
30.1, 31.7, 32.1, 33.2, 35.5, 37.8, 52.7, 57.1, 72.8, 126.2, 128.6, 128.9,
141.0. IR (film): .
3027, 2952, 2926, 2855, 1454, 1118, 746, 697 cmꢀ1
HRMS (EI) for C19H32N (Mþ1), 274.2530 (calcd), found 274.2538.
d 14.4, 20.9, 22.9, 26.0,
d
51.0, 79.1, 88.8, 110.3, 126.1, 128.4, 128.6, 140.0, 142.4. IR (film):
3025, 2960, 1453, 1126, 954 cmꢀ1. HRMS (MALDI) for C18H26
(Mþ1), 256.20598 (calcd), found 256.20473.
n
n
N
4.2.4. Synthesis of 1-methyl-2-(non-8-ynyl)pyrrolidine 11
4.2.1.2. Compound 1j. (E)-3-Methyl-N-phenethyldec-4-en-6-yn-1-
amine. 1H NMR (400 MHz, CDCl3, TMS):
0.97–1.01 (m, 6H), 1.46–
Potassium hydride (570 mg, 5 mmol, 5.0 equiv, 30% in mineral
oil) was washed with dry ether three times under argon. Then,
1,3-diaminepropane (10 mL) was added at room temperature
and gently heated the flask until the mixture began to foam,
then stirred for 1 h. The allene 2d (215 mg, 1 mmol) was added
slowly to the mixture at 0 ꢁC, the resulting slurry was stirred at
room temperature for 30 min, then quenched reaction with
NH4Cl solution at 0 ꢁC under argon. The reaction mixture was
extracted with EtOAc (3ꢂ10 mL), dried over Na2SO4, filtered,
evaporated, and purified by flash chromatography (EtOAc/MeOH/
Et3N¼5:5:0.1, Rf¼0.2) to give alkyne 7 (174 mg, 81% yield). 1H
d
1.50 (m, 2H), 1.52–1.56 (m, 2H), 2.16–2.21 (m, 1H), 2.26 (dt, J¼2.0,
7.2 Hz, 2H), 2.59 (dt, J¼2.8, 7.6 Hz, 2H), 2.78–2.81 (m, 2H), 2.85–2.89
(m, 2H), 5.36–5.42 (m, 1H), 5.90 (dd, J¼8.0, 16.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3, TMS): d 13.5, 20.2, 21.3, 22.2, 35.3, 36.2, 36.6, 47.6,
51.0, 79.1, 88.8, 108.6, 126.0, 128.4, 128.6, 139.9, 148.0. IR (film):
n
2960, 1453, 1124, 957, 747 cmꢀ1. HRMS (MALDI) for C19H28N (Mþ1),
270.22163 (calcd), found 270.22135.
4.2.2. General procedure for the base-catalyzed intramolecular
hydroamination of conjugated enynes
NMR (400 MHz, CDCl3, TMS):
d 1.17–1.44 (m, 11H), 1.47–1.56 (m,
Enyne 1 was dissolved in dry THF (0.4 M solution), was added
with n-butyllithium (20 mol %, 1.6 M in hexane) at ꢀ78 ꢁC and
stirred at this temperature for 1 h. The reaction was quenched by
methanol and purified by flash chromatography to obtain product 2
as light yellow oil.
2H), 1.63–1.70 (m, 2H), 1.72–1.78 (m, 1H), 1.87–1.96 (m, 2H),
2.05–2.14 (m, 1H), 2.18 (dt, J¼2.8, 7.2 Hz, 2H), 2.30 (s, 3H), 3.05
(dt, J¼2.0, 9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 18.3, 21.7,
26.5, 28.4, 28.6, 29.0, 29.8, 30.7, 33.6, 40.3, 57.2, 66.3, 68.0, 84.6.
IR (film):
n N
2929, 2856, 1121, 987 cmꢀ1. HRMS (EI) for C14H26
(Mþ1), 208.2060 (calcd), found 208.2056.
4.2.2.1. Compound
2a. 2-(Hexa-1,2-dienyl)-1-phenethylpyrroli-
0.87–0.97 (m, 3H), 1.37–
dine. 1H NMR (400 MHz, CDCl3, TMS):
d
4.2.5. Synthesis of compounds 14 and 15
1.42 (m, 2H), 1.62–1.89 (m, 3H), 1.92–2.02 (m, 3H), 2.23–2.30 (m,
1H), 2.33–2.41 (m, 1H), 2.79–2.86 (m, 3H), 3.05–3.15 (m, 1H), 3.17–
3.22 (m, 1H), 4.98–5.04 (m, 1H), 5.09–5.19 (m, 1H), 7.17–7.29 (m,
To a mixture of alkyne (11) (1.8 mmol), Pd(PPh3)4 (30 mg,
0.026 mmol, 1.5 mol %), and CuI (8.4 mg, 0.045 mmol, 2.5 mol %) in
Et3N/THF (4/1, 5 mL) was added iodobenzene (12) or 1-iodo-2-
methoxybenzene (13) (5.0 equiv) at room temperature. After the
mixture was stirred overnight, the reaction was quenched with
NH4Cl solution and then extracted with EtOAc (3ꢂ10 mL). The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, concentrated, and crude product was purified by flash
chromatography (EtOAc/MeOH¼10:1 with 1% Et3N, Rf¼0.2) to ob-
tain product 14 or 15.
5H). 13C NMR (100 MHz, CDCl3):
d 13.6, 22.0, 22.2 (minor), 22.3
(major), 30.8 (minor), 31.0 (major), 31.5 (major), 31.8 (minor), 35.2
(major), 35.3 (minor), 53.2, 55.6 (major), 55.8 (minor), 65.2 (minor),
65.3 (major), 91.2, 93.1, 125.8, 128.2, 128.5 (major), 128.6 (minor),
140.6, 204.3 (minor), 204.6 (major). IR (film):
n 2960, 2360, 2341,
1454, 955, 748, 669 cmꢀ1. HRMS (MALDI) for C18H26N (Mþ1),
256.20598 (calcd), found 256.20486.
4.2.2.2. Compound
2j. 2-(Hexa-1,2-dienyl)-3-methyl-1-phene-
0.86–0.94 (m,
4.2.5.1. Compound 14. 1-Methyl-2-(9-phenylnon-8-ynyl)pyrroli-
thylpyrrolidine. 1H NMR (400 MHz, CDCl3, TMS):
d
dine, 52% yield. 1H NMR (400 MHz, CDCl3, TMS):
d 1.26–1.35 (m,
3H), 1.01 (t, J¼6.4 Hz, 3H), 1.36–1.46 (m, 3H), 1.92–2.00 (m, 3H),
2.04–2.14 (m, 1H), 2.27–2.37 (m, 3H), 2.74–2.85 (m, 2H), 3.07–3.18
(m, 1H), 3.22–3.29 (m, 1H), 4.93–4.96 (m, 1H), 5.12–5.16 (m, 1H). 13C
8H), 1.42–1.48 (m, 2H), 1.50–1.64 (m, 2H), 1.69–1.77 (m, 2H), 1.81–
1.87 (m, 1H), 1.94–2.03 (m, 2H), 2.18–2.22 (m, 1H), 2.27 (dd, J¼9.2,
18.4 Hz, 1H), 2.38–2.41 (m, 4H), 3.25 (dt, J¼2.8, 10.4 Hz, 1H), 7.26–
NMR (100 MHz, CDCl3, TMS):
d
13.86 (minor), 13.88 (major), 18.3
7.28 (m, 3H), 7.38–7.40 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 19.4,
(major), 18.4 (minor), 22.6, 31.0 (major), 31.1 (minor), 31.3 (minor),
31.4 (major), 35.16 (minor), 35.25 (major), 39.7 (major), 39.8 (mi-
nor), 52.48 (minor), 52.51 (major), 56.4 (minor), 56.6 (major), 73.9
(minor), 74.1 (major), 91.3, 92.7 (minor), 92.8 (major), 126.11 (mi-
nor),126.14 (major),128.5, 128.8 (minor),128.9 (major),141.0, 205.7
21.6, 26.7, 28.7, 28.8, 29.1, 29.7, 30.4, 32.6, 39.8, 56.6, 66.8, 80.6, 90.4,
124.0, 127.4, 128.1, 131.5. IR (film):
n 2930, 2854, 2775, 1490, 1457,
1240 cmꢀ1. HRMS (EI) for C20H30N (Mþ1), 284.2373 (calcd), found
284.2363.
(major), 206.0 (minor). IR (film):
n
3027, 2955, 2871, 2790, 1961,
4.2.5.2. Compound
methyl-pyrrolidine, 55% yield. 1H NMR (400 MHz, CDCl3, TMS):
d 1.23–1.34 (m, 7H), 1.43–1.50 (m, 3H), 1.59–1.81 (m, 5H), 1.89–
15. 2-(9-(2-Methoxyphenyl)non-8-ynyl)-1-
1496,1121, 698 cmꢀ1. HRMS (MALDI) for C19H28N (Mþ1), 270.22163
(calcd), found 270.22078.
1.96 (m, 1H), 1.99–2.04 (m, 1H), 2.15 (dd, J¼9.2, 18.0 Hz, 1H), 2.33
(s, 3H), 2.46 (t, J¼7.2 Hz, 2H), 3.11 (dt, J¼2.0, 9.6 Hz, 1H), 3.87 (s,
3H), 6.84–6.89 (m, 2H), 7.21–7.25 (m, 1H), 7.36–7.38 (m, 1H). 13C
4.2.3. Hydrogenation of pyrrolidine 2j
Pyrrolidine 2j (131 mg, 0.49 mmol) was dissolved in methanol
(5 mL), Pd/C (10%) was added and stirred under H2 (1 atm) at room
temperature overnight. The reaction mixture was filtered through
Celite and the solvent was evaporated to yield the crude product,
which was purified by flash chromatography (EtOAc/PE¼1:1,
Rf¼0.3) to obtain 3j (84 mg, 63%).
NMR (100 MHz, CDCl3):
30.6, 33.4, 40.2, 55.7, 57.1, 66.5, 76.6, 94.6, 110.5, 113.1, 120.3,
128.8, 133.6, 159.7. IR (film): 2928, 2855, 2773, 1457, 1260,
1025 cmꢀ1
HRMS (EI) for C21H30
(Mꢀ1), 312.2322 (calcd),
found 312.2324.
d 19.7, 21.7, 26.6, 28.75, 28.80, 29.1, 29.8,
n
.
N
4.2.3.1. Compound 3j. 2-Hexyl-3-methyl-1-phenethylpyrrolidine.
4.2.6. Synthesis of irniine 16 and irnidine 17
1H NMR (400 MHz, CDCl3, TMS):
d
0.88 (t, J¼7.2 Hz, 3H), 0.99 (d,
To a mixture of 14 or 15 in MeOH was added 10% Pd/C and
stirred at room temperature under H2 (1 atm) overnight. The re-
action mixture was filtered and purified by flash chromatography
(EtOAc/MeOH¼10:1 with 1% Et3N, Rf¼0.2) to give natural product
16 or 17.
J¼6.8 Hz, 3H), 1.26–1.42 (m, 10H), 1.53–1.59 (m, 1H), 1.83–1.94 (m,
2H), 1.97–2.06 (m, 2H), 2.29 (ddd, J¼5.6, 7.6, 17.2 Hz, 1H), 2.36 (ddd,
J¼5.6, 7.0, 11.6 Hz, 1H), 2.74–2.84 (m, 2H), 2.99 (ddd, J¼6.4, 7.0,
9.2 Hz, 1H), 3.19 (dt, J¼2.8, 9.6 Hz, 1H), 7.17–7.22 (m, 3H), 7.25–7.30

W. Zhang et al. / Tetrahedron 65 (2009) 3090–3095
3095
4.2.6.1. Compound 16. Irniine,33 75% yield. 1H NMR (400 MHz,
CDCl3, TMS): 1.17–1.30 (m, 13H), 1.38–1.45 (m, 1H), 1.57–1.79 (m,
6. Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.; Scott, P. Chem. Commun.
2004, 894; Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 43,
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Biomol. Chem. 2007, 5, 1975.
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inghouse, T.; Horino, Y. J. Am. Chem. Soc. 2003, 125, 9560; Ryu, J.-S.; Marks, T. J.;
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d
5H),1.88–1.98 (m, 2H), 2.12 (ddd, J¼9.2, 8.4, 9.2 Hz,1H), 2.30 (s, 3H),
2.60 (t, J¼8.4 Hz, 2H), 3.07 (ddd, J¼2.0, 7.6, 7.2 Hz, 1H), 7.15–7.18 (m,
3H), 7.25–7.29 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 21.8, 26.7, 29.3,
29.48, 29.51, 29.6, 30.0, 30.8, 31.5, 33.8, 36.0, 40.4, 57.3, 66.5, 125.5,
128.2, 128.4, 142.9. IR (film): 2925, 2853, 2774, 1454, 745,
697 cmꢀ1
n
.
4.2.6.2. Compound 17. Irnidine,37 57% yield. 1H NMR (400 MHz,
CDCl3, TMS): 1.19–1.31 (m, 13H), 1.42–1.51 (m, 1H), 1.53–1.60 (m,
d
2H), 1.65–1.73 (m, 2H), 1.76–1.82 (m, 1H), 1.90–1.96 (m, 1H), 2.02–
2.06 (m, 1H), 2.17 (dd, J¼9.2, 15.6 Hz, 1H), 2.34 (s, 3H), 2.59 (t,
J¼8.0 Hz, 2H), 3.13 (ddd, J¼2.4,10.0, 9.6 Hz,1H), 3.81 (s, 3H), 6.83 (d,
J¼8.0 Hz, 1H), 6.87 (ddd, J¼1.2, 9.6, 9.6 Hz, 1H), 7.12 (dd, J¼1.6,
7.6 Hz, 1H), 7.16 (ddd, J¼1.6, 8.0, 7.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3):
d 21.7, 26.7, 29.49, 29.54, 29.57, 29.61, 29.8, 30.0, 30.1, 30.6,
33.4, 40.2, 55.2, 57.1, 66.6, 110.2, 120.2, 126.7, 129.7, 131.3, 157.4. IR
(film):
n
2924, 2853, 2771, 1493, 1240, 1032, 749 cmꢀ1
.
Acknowledgements
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23. A Pd catalyzed Intermolecular hydroamination of conjugated enynes yielded
We thank the University of Wisconsin Graduate School and the
School of Pharmacy for generous startup funding, and the School of
Pharmacy Analytical Instrument Center (AIC) for mass spectrome-
try services and NMR support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.045.
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