Synthesis of new quinuclidine derivatives via Pd-mediated cross-coupling and cross-benzannulation reactions

Article abstract of DOI:10.1016/j.tet.2009.05.030

New functionalized quinuclidines were prepared via palladium-catalyzed addition reactions of terminal alkynes (donors) to internal alkynes (acceptors). The enantiopure terminal alkynes were derivatives of quincoridine and quincorine, two semi-natural Cinc

Full text of DOI:10.1016/j.tet.2009.05.030

Tetrahedron 65 (2009) 6226–6235
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new quinuclidine derivatives via Pd-mediated cross-coupling
and cross-benzannulation reactions
,
b
,
b
b
c
Stefania To¨to¨s a , Manfred Fild , Carsten Tho¨ne , Ion Grosu
*
a ‘Raluca-Ripan’ Institute for Research in Chemistry, ‘Babes-Bolyai’ University, 30 Fantanele str., 400294, Cluj-Napoca, Romania
b Institut fu¨r Anorganische und Analytische Chemie der Technischen Universita¨t, Hagenring 30, 38106 Braunschweig, Germany
c Faculty of Chemistry and Chemical Engineering, ‘Babes-Bolyai’ University, 11 Arany Janos str., 400028, Cluj-Napoca, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
New functionalized quinuclidines were prepared via palladium-catalyzed addition reactions of terminal
alkynes (donors) to internal alkynes (acceptors). The enantiopure terminal alkynes were derivatives of
quincoridine and quincorine, two semi-natural Cinchona alkaloids. The processes exhibited high chemo-
selectivity and excellent diastereoselectivity, the E-enynes being obtained as single products in almost all
cases. The synthesis of new tetra and pentasubstituted benzene derivatives in good yields by [2þ2þ2]
benzannulation of the diynes, obtained by the palladium-catalyzed homodimerization of 10,11-didehy-
dro quincoridine and 10,11-didehydro quincorine, with terminal alkynes and in fair yield by [4þ2]
benzannulation of an enyne derivative of 10,11-didehydro quincoridine with 2,4-hexane-diyne are
reported.
Received 16 January 2009
Received in revised form 29 April 2009
Accepted 14 May 2009
Available online 21 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Et
Et
1. Introduction
N
N
N
N
O
O
Carbon–carbon bond-forming reactions are considered the most
important processes in organic chemistry and represent key steps
in the building of more complex molecules from simple precursors.
In the last years, metal-catalyzed cross-coupling reactions have
been extensively employed as ‘direct’ methodologies for carbon–
carbon bond formation between unsaturated species such as vinyl,
aryl and alkynyl moieties.1–4
Cinchona alkaloids and their derivatives, readily available in
both pseudo-enantiomeric forms, are playing an important role as
versatile chiral basic catalysts, ligands, chromatographic selectors
and NMR discriminating agents; all of these applications having
direct connection with asymmetric synthesis and chiral discrimi-
nators.5 The Sharpless asymmetric dihydroxylation of olefins using
various Cinchona alkaloid derivatives as chiral monodentate ligands
for OsO4 is one of the most known application.6 The mechanism of
this reaction was also extensively analyzed by Sharpless et al.6,7 and
Corey and Noe8 and the most efficient ligands for promoting face-
selective dihydroxylation of olefins were found to be derivatives of
bis-cinchona alkaloids such as (DHQD)2PHAL and (DHQD)2PYDZ
(Fig. 1).
H
H
OMe
MeO
N
N
(DHQD)2PHAL
Et
Et
N
N
N
N
O
O
H
H
OMe
MeO
N
N
(DHQD)2PYDZ
Figure 1. (DHQD)2PHAL and (DHQD)2PYDZ, bis-cinchona alkaloids.
asymmetric catalysis. Lemaire et.al.9 have developed a new family
of N,P-ligands derived from quincoridine (QCD) and quincorine
(QCI) with applications in hydroformylation, asymmetric hydro-
silylation and asymmetric Grignard cross-coupling reactions.
A remarkable number of functionalized quinuclidines are valu-
able chiral building blocks for pharmacology and medicinal
chemistry (Fig. 2). They are selective agonists for a variety of re-
ceptors (e.g., neurokinin-1 (NK1) A, 5-HT3 B, 5-HT4 C) and are able
to act as squalene synthase inhibitors D.10–13
Additionally, bidentate N,P-ligands have acquired a growing
importance in the development of coordination chemistry and
* Corresponding author. Tel.: þ40 264 420718; fax: þ40 264 420441.
E-mail address: stefy9@yahoo.com (S. To¨to¨s).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.030

S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
6227
hydroxymethyl-5-vinyl-2-quinuclidine] 2 as terminal (donor) al-
kynes. These alkynes were prepared efficiently in two steps from 1
and 2 through a modified procedure based on the known literature
method (Scheme 2).23,24
O
H
N
HN
OMe
Ph
Ph
N
O
Me
N
N
B
A
i) 1.25 eq. Br2, CHCl3, 0 °C-r.t.
ii) 3.5 eq.NaOH, 0.2 eq. aliquat 336,
t-BuOH, 2h, reflux
iii) 1 eq. 3, 1.3 eq. CH3COCl, THF,
0 °C-r.t.
selective nonpeptide
antagonist for the human
eurokinin NK1 receptor
high affinity 5-HT3 receptor
partial agonist
N
N
RO
HO
3 R = H
5 R = Ac
QCD 1
O
N+
i) 1.25 eq. Br2, CHCl3, 0 °C-r.t.
ii) 3.5 eq.NaOH, 0.2 eq. aliquat 336,
t-BuOH, 2h, reflux
iii) 1 eq. 4, 1.3 eq. CH3COCl, THF,
0 °C-r.t.
EtO
Br-
O
N
Cl
N
OH
O
RO
4 R = H
6 R = Ac
H2N
OMe
HO QCI 2
N
C
D
Scheme 2. The synthesis of terminal alkynes from QCD and QCI.
high affinity 5-HT4 receptor
agonist
squalene synthase inhibitor
inhibition of cholesterol
biosynthesis
2.1. Trisubstituted enynes from 10,11-didehydro QCD
Figure 2. Medicinally relevant quinuclidine compounds.
Coupling reactions between 10,11-didehydro quincoridine
(QCD) derivatives 3 and 5 as donor alkynes with acceptor alkynes,
which exhibit ester and ketone functionalities as electron with-
drawing groups were investigated. When 1 equiv of 3 or 5 was
treated with 1 equiv of acceptor alkyne in the presence of 2 mol % of
Pd(OAc)2 and 2 mol % of TDMPP in THF at room temperature (rt),
the corresponding 1,2,4-trisubstituted enynes 7a–e and 8a,b were
obtained in verygood yields (Table 1). Except entries 4 and 5 (Table 1)
all reactions proceeded smoothly and gave a single geometric
isomer (assigned E on the basis of 1H NMR spectra and the
reaction mechanism).25,26 The vinylic hydrogen atom in 7a–c
Addition and cycloaddition reactions wherein the product is the
simple sum of the reactants constitute an economical way to build
more complex structures from simple building blocks.2 Transition-
metal-catalyzed cyclo-trimerization of alkynes is a useful method
for the construction of substituted benzene derivatives and many
transition-metal complexes have been employed as catalysts.14–19
Yamamoto et al. have developed a procedure for the intermolecular
palladium-catalyzed formal [2þ2þ2] trimerization of alkynes to
give multisubstituted benzene derivatives. Homodimerization of
terminal alkynes and subsequent [4þ2] benzannulation with
diynes allowed the formation of tetrasubstituted benzenes as
a single reaction product in fair to good yields (Scheme 1).20
and 8a,b exhibits a low-field shift (Table 2) being at
a-position
referred to the anisotropic group (ester or ketone). Moreover,
since in compounds 7b,c and 8a the vinylic hydrogen atom is
R1
R1
R1
[Pd]
[Pd]
2R1
Table 1
R2
R2
Palladium-catalyzed addition of 3 and 5 to internal alkynes
R1
R2
Scheme 1. Cyclo-trimerization of alkynes with diynes.
R2
R'
3
4
R''
R''
2
5'
4'
2 mol % Pd(OAc)2
2 mol % TDMPP
5
6'
Herein, we considered it of interest to investigate the preparation
of new 1,2,4-trisubstituted enyne, 1,2,3,5-tetra and 1,2,3,4,5-penta-
substituted benzene functionalized quinuclidines, via palladium-
catalyzed cross-coupling and cross-benzannulation reactions. These
derivatives are obtained starting from enantiopure 10,11-didehydro
QCD and 10,11-didehydro QCI and they are important candidates as
ligands for chiral catalysts or chiral discriminating agents.
H
+
N
3'
9'
8'
RO
R'
THF, r.t.
N
RO
3 R = H
5 R = Ac
7'
2' 1'
7a-e R = H
8a-b R = 1C0'O21C1'H3
Entry
Donor alkyne R
Acceptor alkyne
Product
Yield [%]
2. Results and discussion
R0
R00
1
2
3
H
H
H
H
H
Ac
Ac
CH3
CO2C2H5
CO2C2H5
CO2CH3
COCH3
COCH3
CO2CH3
COCH3
7a
7b
7c
7d, 7f
7e
94
73
84
67
80
81
53
C6H5
C6H5
C6H5
C2H5
C6H5
C2H5
Conjugated enynes are important units for a large variety of
natural products and they are found in many man-made de-
rivatives. Synthetic enynes are mainly obtained by palladium-cat-
alyzed cross-coupling reactions between alkynes and vinyl halides
or sulfonates.21 Trost et al.22 demonstrated that 1,2,4-trisubstituted
enynes can be efficiently prepared via selective ‘syn’-addition of
a terminal alkyne (donor alkyne) to an internal alkyne (acceptor
alkyne) in the presence of catalytic amounts of palladium acetate
and of an electron rich, sterically encumbered, ligand as tris(2,6-
dimethoxyphenyl) phosphine (TDMPP).
4a
5b
6
8a
8b
7
a
A mixture of E/Z isomers was obtained.
Reaction performed 24 h at rt and 3 h at reflux, the transposition product 7f was
b
obtained.
Table 2
1H NMR data (
d, CDCl3) for the vinylic H atom in 7a–c and 8a,b
In order to explore the applications of this addition reaction in the
series of semi-natural Cinchona alkaloids we used 10,11-didehydro
derivatives 3, 4, 5 and 6 of quincoridine (QCD) [(2R,4S,5R)-2-hydroxy-
methyl-5-vinyl-2-quinuclidine] 1 and quincorine (QCI) [(2S,4S,5R)-2-
Compound
7a
7b
7c
8a
8b
d
(ppm)
5.92
6.27
6.13
6.18
6.29

6228
S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
4''
5''
6''
3''
2''
5
1''
1
2
H3COC
4
6
H
3
COCH3
2 mol % Pd(OAc)2
2 mol % TDMPP
THF, r.t.
5'
4'
H
COCH3
HO
6'
3
+
3'
8'
+
9'
N
Ph
HO
N
2'
1' 7'
7f
7d
63%, major product
Scheme 3. Cross-coupling of 3 with 4-phenyl-3-butyn-2-one.
37%, minor product
not affected by the anisotropy of the phenyl group, it is trans to
this anisotropic unit.
prove this a pure sample of 8b was heated to reflux in THF for 5 h.
The equilibrium mixture contained >99% of compound 8c (from 1H
NMR), this being more stable than its conjugated isomer 8b. The
configurations of olefins 7e and 8c were assigned through NOE
experiments. Upon irradiation of the ketone methyl group, large
NOE’s were recorded for the vinylic hydrogen atom (Scheme 4,
arrow I) and the protons of the methylene group (Scheme 4, arrow
II), suggesting their closed position. These observations confirmed
the Z configurations of the olefins. The isomerization processes
proceeded stereo-selectively, only the Z-isomers being obtained.
The vinyl methyl unit in 7a is also deshielded (
d
¼2.20 ppm) by
the ester group and that means it adopts the cis-position to this
anisotropic substituent. When 4-phenyl-3-butyn-2-one was
employed as acceptor (Table 1, entry 4), using 1:1 ratio of reactants
under the standard conditions, the reaction lead to a mixture of E
and Z isomers, which couldn’t be separated by column chroma-
tography on silica gel (Scheme 3). The E/Z ratio was found to be
63:37 from 1H NMR spectrum, which showed two singlets for the
vinylic hydrogen atoms at 6.78 ppm (minor product) and 6.46 ppm
(major product), respectively. These data are consistent with the
proposed geometry, because in the Z-isomer the vinylic hydrogen is
more deshielded due to the influence of both anisotropic groups
(ketone and phenyl) than in the E-isomer, which is affected only by
the anisotropy of the ketone.
2.2. Trisubstituted enynes from 10,11-didehydro QCI
Changing the donor alkynes from 3 and 5 to 4 and 6 the cross-
coupling reactions with acceptor alkynes furnished the desired
enynes in moderate yields (Table 3). In the case of alkyne 4 O-
protection of the 1,2-aminoalcohol was necessary. Low conversions
were recorded (Table 3, entries 1 and 2) even at high temperatures
or by increasing the ratio of catalyst. The diminished yields are
mainly due to the influence of the free OH group. This consideration
is supported by the much better yields of the addition reactions
(Table 3, entries 3–7) carried out with the O-acylated derivative 6.
Except entry 2 all reactions afforded a single geometric isomer E
illustrating the high chemoselectivity and diastereoselectivity of
the process. In 1H NMR spectra of 9a and 10a–e the vinylic hy-
drogen atom is deshielded by the ester or ketone group (Table 4).
For entry 2 the ratio E/Z was 85:15 (from 1H NMR spectrum) and the
low diastereoselectivity is perhaps due to high temperature re-
quired for the conversion of reactants. The conjugated enyne 10d
Using 4-ethyl-3-butyn-2-one as acceptor (Table 1, entry 5) un-
der the standard conditions, the reaction was not completed after
24 h. Raising the temperature to 60 ꢀC to enforce full conversion
with 1:1 ratio of the reactants, the isomerization of the product was
observed and the isolated mixture contained 3% of 7g and 97% of
7e, respectively (from 1H NMR spectra) (Scheme 4). It is known that
unsaturated aldehydes, ketones, carboxylic acids, carboxylic acid
esters, carboxylic acid amides and nitriles isomerize using triethyl
amine, sodium hydroxide or sodium methoxide as catalysts, in
an equilibrium that normally lies on the side of the conjugated
isomer.27 In our case we assumed that the isomerization is due to
the strong basicity of the bridgehead nitrogen atom. In order to
8
7
Table 3
2
H31COC
4
Palladium-catalyzed addition of 4 and 6 to internal alkynes
3
5
5'
4'
R'
3
6
H
6'
3'
COCH3
R''
9'
8'
2
5
2 mol % Pd(OAc)2
2 mol % TDMPP
THF, r.t.
4
N
1'
5'
4'
RO
+
7'
H
2 mol % Pd(OAc)2
2 mol % TDMPP
2'
N
R''
RO
6'
Et
8'
3'
7g R = H
8b R = Ac
+
N
3 R = H
5 R = Ac
N
2'
THF, r.t.
R'
7'
1'
9'
RO
RO
4 R = H
6 R = Ac
Δ
base
9a-b R = H
11'
10'
10a-e R = CO2CH3
I
6
H
CH3
5
4
Entry
Donor alkyne R
Acceptor alkyne
Product
Yield [%]
2
1
11'
H3COC
3
R0
R00
10'
5'
4'
1
2a
3
4
5
6
7
H
H
CH3
C6H5
CH3
C6H5
C6H5
C2H5
C6H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2CH3
COCH3
9a
26
31
70
67
68
59
61
6'
II
3'
9b, 9c
10a
10b
10c
10d
10e
8'
9'
N
Ac
Ac
Ac
Ac
Ac
RO
7'
11'
1'
2'
7e R = H
8c R = 1C0'OCH3
COCH3
a
A mixture of E and Z isomers was obtained.
Scheme 4. Cross-coupling reactions of 3 and 5 with 4-ethyl-3-butyn-2-one.

S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
6229
Table 4
1H NMR data (
d, CDCl3) for the vinylic H atom in 9a and 10a–e
Compound
9a
10a
10b
10c
10d
10e
d
(ppm)
5.93
5.94
6.18
6.18
6.28
6.39
could be again smoothly transformed in its more stable isomer 10f
by self-base-catalyzed isomerization due to the strong basicity of
the bridgehead nitrogen atom by heating a pure sample of 10d to
reflux in THF for 5 h (Scheme 5). The ratio 10d/10f was 5:95 from
the 1H NMR spectrum. The NOE experiment confirmed the Z con-
figuration of the olefin 10f. Large NOE effects were recorded for the
vinylic hydrogen atom (Scheme 5, arrow I) and for the methylene
group (Scheme 5, arrow II) upon irradiation of the ketone methyl
group.
Figure 3. The molecular structure of 11 (H-atoms are omitted for clarity; ellipsoids at
50% probability level).
I
6
H
5
4
CH3
8
7
2
H31COC
3
13'
2
1
4
H3COC
12'
6
3
5
5'
4'
5'
4'
H
6'
II
6'
Δ
8'
3'
3'
8'
N
O
2'
N
base
7'
2'
1'
O
7'
1'
H31C1'
O
11'
9'
10f
9'
10'
10'
H3C
O
10d
Scheme 5. The base-catalyzed isomerization of the enyne 10d.
2.3. Synthesis of dimers
To examine the application of [2þ2þ2] cyclo-trimerization of
alkynes to Cinchona alkaloid derivatives we used the dimers 11 and
12 as diynes. These dimers were reported for the first time by
Hoffmann and co-workers and were obtained using a self-coupling
reaction in the presence of PdCl2(PPh3)2, CuI, I2 (0.5 equiv) and
Et3N.28 Eglinton reaction29 for the homocoupling of the enantio-
pure 10,11-didehydro quincoridine (QCD) 3 and 10,11-didehydro
quincorine (QCI) 4 afforded the desired diynes 11 and 12 in very
good yields and without the formation of by-products (Scheme 6).
Figure 4. Hydrogen-bonded chains in the lattice of 11.
molecule and vice versa in order to give dimer units by hydrogen
bonds. On the other hands these dimeric units form a helix through
hydrogen bonds, which involve the nitrogen atoms and the protons
of the non participating (to the formation of the dimer) –OH groups
of the dimers (Fig. 4).
In 12 the diyne fragment is also slightly bent, which is pointed
out from the angles C(2)–C(1)–C(14) 179.6(2), C(1)–C(2)–C(3)
178.6(2), C(2)–C(3)–C(4) 177.9(2), C(3)–C(4)–C(24) 174.3(2) (Fig. 5).
In the lattice, the molecules of 12 are linked into infinite chains
through hydrogen bonds (Fig. 6).
OH
5
9'
2'
1'N
10
8
4
11
11'
2 eq. Cu(OCOCH3)2,
3'
6'
Py: MeOH=1:1, reflux, 5 h
7
2
7'
6
N
3
N
85%
4'
10'
1
HO
8'
5'
9
11
2
3
HO
8
5
HO
4
7
2'
2 eq. Cu(OCOCH3)2,
Py: MeOH=1:1, reflux, 5 h
11
11'
9'
10
6
N1
3'
1' N
3
2
6'
N
4
9
2
7'
71%
10'
4'
5'
12
OH
8'
HO
Scheme 6. Homocoupling reactions of 10,11-didehydro QCD 3 and 10,11-didehydro
QCI 4.
Figure 5. The molecular structure of 12 (H-atoms are omitted for clarity; ellipsoids at
Colourless crystals suitable for X-ray analysis (Figs. 3 and 5)
were obtained through slow diffusion of n-hexane into a concen-
trated CH2Cl2 solution of 11 and 12. The molecular structure of 11
reveals the slightly bent behaviour of the diyne fragment, which is
obvious from the angles C(2)–C(1)–C(14) 176.05(19), C(1)–C(2)–
C(3) 179.0(2), C(2)–C(3)–C(4) 179.0(2) and C(3)–C(4)–C(24)
177.9(2) (Fig. 3).
50% probability level).
In the lattice of 11 the hydrogen atom of one –OH group of
a molecule is directed towards the oxygen atom of another
Figure 6. View of the lattice of 12.

6230
S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
R
R
HO
N
HO
N
5 mol % Pd(PPh3)4
2 R
+
N
THF, reflux
N
HO
OH
13 R = -Ph
14 R = -CH2OCH3
15 R = -Ph (57%)
16 R = -CH2OCH3 (60%)
11
R
R
HO
5 mol % Pd(PPh3)4
THF, reflux
2 R
+
N
N
N
HO
13 R = -Ph
N
OH
14 R = -CH2OCH3
12
HO
17 R = -Ph (72 %)
18 R = -CH2OCH3 (54 %)
Scheme 7. The synthesis of tetrasubstituted benzene derivatives.
2.4. Synthesis of tetrasubstituted benzene derivatives
Reactions of terminal alkynes 13 and 14 with diynes 11 and 12 in
the presence of 5 mol % of Pd(PPh3)4 in THF at reflux furnished the
tetrasubstituted benzenes in good yields (Scheme 7). These de-
rivatives were obtained as single reaction products and the 1H NMR
and mass spectra were in full agreement with the proposed
structures.
2.5. Synthesis of pentasubstituted benzene derivative
The cross-benzannulation reaction of the mixture of E/Z enynes
7d/7f with 2,4-hexadiyne 19 gave the pentasubstituted benzene 20
in fair yield (Scheme 8). The moderate yield of this reaction can be
reasonably explained based on literature data.20 The benzannula-
tion process requires the migration of a hydrogen atom from the E-
position of an enyne moiety and the E-isomer 7d must be converted
into Z-isomer 7f. While, the inversion proceeds thermally, thereby
explaining the high temperature required (100 ꢀC) and therefore
the lower yield.
Figure 7. The molecular structure of 20 (H-atoms are omitted for clarity; ellipsoids at
50% probability level).
exhibited high regio- and diastereoselectivity, the E-enynes being
obtained as single products in almost all cases. 10,11-Didehydro
quincorine 4 has failed as donor, but its O-acylated analogue 6 gave
very good results in the cross-coupling reactions. The formal
[2þ2þ2] intermolecular trimerization of alkynes via palladium-
catalyzed cross-benzannulation reactions affords tetra- and penta-
substituted benzene derivatives, which are not easily available us-
ing conventional methods. The presented highly functionalized
quinuclidines will find an application particularly in pharmaceutical
industry and medicinal chemistry. The pharmaceutical importance
of the Cinchona alkaloids through the centuries and the various
receptor qualities of well known quinuclidines are focused in the
new enantiopure quinuclidine building blocks.
Ph
H3COC
H3C
H3COC
CH3
5 mol % Pd(PPh3)4
THF, 100 °C, 23 %
H
+
N
HO
H3C
HO
H3C
N
19
7d/7f
20
Scheme 8. The synthesis of pentasubstituted benzene derivative 20.
Slow diffusion of diethyl ether into a concentrated CH2Cl2
solution of 20 produced colourless crystals and the single crystal X-
ray analysis provided the molecular structure of the target penta-
substituted benzene derivative (Fig. 7). The torsion angle of the
aromatic rings of the biphenyl unit is 42.2(5).
4. Experimental section
4.1. General
3. Conclusions
All reactions were performed under a dry nitrogen atmosphere
using standard Schlenk techniques. Tetrahydrofuran (THF) was
freshly distilled under nitrogen from sodium/benzophenone.
Pd(OAc)2 and tris-(2,6-dimethoxyphenyl) phosphine (TDMPP)
In summary, the addition reactions of terminal alkynes to in-
ternal alkynes allowed the formation, under mild conditions, of
new quinuclidine derivatives in very good yields. The process

S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
6231
were purchased from Fluka and Aldrich, respectively. Pd(PPh3)4
was prepared using the literature procedure.30 Quincorine (QCI)
and quincoridine (QCD) were donated from Buchler GmbH. Pre-
parative column chromatography was performed on Fluka silica gel
136.85 (C-100), 138.41 (C-3), 165.35 (CO). MS (EI) m/z (%): 339 (100)
[Mþ], 310 (94) [MꢁC2H5]þ, 308 (54) [MꢁCH2OH]þ, 266 (32)
[MꢁC2H5CO2]þ. Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N 4.13.
Found: C, 74.23; H, 7.32; N, 4.18.
(particle size 30–60 mm). Analytical TLC was carried out on Poly-
gram Sil G/UV254 plates (0.2 mm silica gel).
4.2.3. 5-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-phenyl-(E)-2-penten-4-ynoic acid methyl
ester (7c)
NMR spectra were recorded with a Bruker DRX-400 spectrom-
eter in CDCl3 using the residual solvent signal at
(
d
¼7.26 (1H) or 77.0
13C) ppm as the internal standard. Mass spectra were recorded
Prepared according to general procedure from 0.6 g (3.63 mmol)
of 3, 0.69 g (4.31 mmol) of methyl-phenylpropiolate, 16.32 mg
(2 mol %) of Pd(OAc)2 and 32.17 mg (2 mol %) of TDMPP. The residue
was purified by column chromatography with t-Bu-Me-ether/ace-
tonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 0.99 g of 7c (84%) as
using a Finnigan MAT 90 spectrometer operating in EI or FAB mode.
Melting points were determined on a Bu¨chi 510 Melting Point ap-
paratus and are uncorrected.
4.2. General procedure for the cross-couplings of terminal
alkynes with internal alkynes
a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC)
d 1.29–1.35 (m, 1H, H-
30),1.45–1.64 (m, 3H, 2H-80, H-30),1.90–1.91 (m,1H, H-40), 2.61–2.65
(m, 1H, H-50), 2.76–3.01 (m, 5H, 2H-60, 2H-70, H-20), 3.14 (br s, 1H,
–OH), 3.40 (dd, J¼11.4, 4.9 Hz, 1H, H-90), 3.47–3.53 (m, 1H, H-90),
3.54 (s, 3H, –OCH3), 6.17 (s, 1H, H-2), 7.25–7.34 (m, 5H, HPh); 13C
A mixture of Pd(OAc)2 (0.02 equiv) and TDMPP (0.02 equiv) in
50 ml of absolute THF was stirred at rt for 15 min and then the
acceptor alkyne (1.2 equiv) was added. After 5 min the donor
alkyne (1 equiv) was added and stirring was continued until TLC
analysis indicated complete consumption of the reactants. The re-
action mixture was then concentrated in vacuo and the resulting
crude product was purified by column chromatography to give the
pure product.
NMR (100 MHz, CDCl3, 25 ꢀC): 24.25 (C-30), 25.26 (C-80), 27.23 (C-
d
40), 29.19 (C-50), 47.51 (C-60), 48.36 (C-70), 51.38 (–OCH3), 57.24 (C-
20), 61.94 (C-90), 82.99 (C-4), 99.23 (C-5), 123.58 (C-2), 127.81 (C-200,
C-600), 128.27 (C-300, C-500), 128.86 (C-400), 136.66 (C-100), 138.82 (C-3),
165.72 (CO). MS (EI) m/z (%): 325 (12) [Mþ], 310 (6) [MꢁCH3]þ, 294
(10) [MꢁCH2OH]þ. Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N,
4.30. Found: C, 73.91; H, 7.03; N, 4.27.
4.2.1. 5-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-methyl-(E)-2-penten-4-ynoic acid ethyl
ester (7a)
4.2.4. 6-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-4-phenyl-(E)-3-hexen-5-yn-2-one (7d)
Prepared according to general procedure from 0.6 g
(3.63 mmol) of 3, 0.40 g (4.35 mmol) of ethyl-2-butynoate,
16.32 mg (2 mol %) of Pd(OAc)2 and 32.17 mg (2 mol %) of TDMPP.
The residue was purified by column chromatography with t-Bu-
Me-ether/acetonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 1 g of 7a
Prepared according to general procedure from 0.4 g (2.42 mmol)
of 3, 0.45 g (3.12 mmol) of 4-phenyl-3-butyn-2-one, 10.86 mg
(2 mol %) of Pd(OAc)2 and 21.41 mg (2 mol %) of TDMPP. The residue
was purified by column chromatography with t-Bu-Me-ether/ace-
tonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 0.50 g of E/Z (63:37)
1
(94%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
1.20
mixture (67%) as a yellow oil. H NMR (400 MHz, CDCl3, 25 ꢀC):
(t, J¼7.1 Hz, 3H, CH3CH2–), 1.29–1.36 (m, 1H, H-30), 1.44–1.64 (m,
3H, H-30, 2H-80), 1.86–1.89 (m, 1H, H-40), 2.20 (d, J¼1.4 Hz, –CH3),
2.57–2.61 (m, 1H, H-50), 2.75–3.00 (m, 6H, 2H-60, 2H-70, –OH, H-20),
3.41 (dd, J¼11.3, 4.9 Hz, 1H, H-90), 3.50–3.55 (m, 1H, H-90), 4.09 (q,
J¼7.1 Hz, 2H, CH3CH2–), 5.92 (d, J¼1.4 Hz, 1H, H-2); 13C NMR
d
1.34–1.41 (m, 1H, H-30), 1.50–1.72 (m, 3H, 2H-80, H-30), 1.97 (s, 3H,
–CH3), 1.91–1.98 (m, 1H, H-40), 2.67–2.71 (m, 1H, H-50), 2.81–3.07
(m, 5H, 2H-60, 2H-70, H-20), 3.39–3.70 (m, 3H, 2H-90, –OH), 6.46 (s,
1H, H-3), 7.38 (s, 5H, HPh); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 24.31
(C-30), 25.32 (C-80), 27.22 (C-40), 29.29 (C-50), 30.41 (C-1), 47.56 (C-
60), 48.33 (C-70), 57.04 (C-20), 62.01 (C-90), 69.16 (C-5), 100.32 (C-6),
128.20 (C-200, C-600), 128.40 (C-300, C-500), 129.11 (C-400), 133.41 (C-3),
136.08 (C-100), 137.01 (C-4), 199.22 (C-2). MS (EI) m/z (%): 309 (80)
[Mþ], 292 (8) [MꢁOH]þ, 278 (100) [MꢁCH2OH]þ, 266 (17)
[MꢁCH3CO]þ. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.51; H, 7.56; N, 4.57.
(100 MHz, CDCl3, 25 ꢀC):
d 14.23 (CH3CH2–), 20.13 (CH3–), 24.26 (C-
30), 25.42 (C-80), 27.27 (C-40), 29.09 (C-50), 47.64 (C-60), 48.41 (C-70),
57.14 (C-20), 59.90 (CH3CH2–), 62.03 (C-90), 84.02 (C-4), 97.37 (C-5),
123.63 (C-2), 138.15 (C-3), 166.09 (CO). MS (EI) m/z (%): 277 (100)
[M]þ, 260 (6) [MꢁOH]þ, 248 (89) [MꢁC2H5]þ, 246 (66)
[MꢁCH2OH]þ, 232 (24) [MꢁC2H5O]þ, 204 (31) [MꢁC2H5CO2]þ.
Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C,
69.12; H, 8.42; N, 5.10.
4.2.5. 6-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-4-phenyl-(Z)-3-hexen-5-yn-2-one (7f)
4.2.2. 5-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-phenyl-(E)-2-penten-4-ynoic acid ethyl
ester (7b)
Prepared according to general procedure from 0.4 g (2.42 mmol)
of 3, 0.45 g (3.12 mmol) of 4-phenyl-3-butyn-2-one, 10.86 mg
(2 mol %) of Pd(OAc)2 and 21.41 mg (2 mol %) of TDMPP. The residue
was purified by column chromatography with t-Bu-Me-ether/ace-
tonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 0.50 g of E/Z (63:37)
Prepared according to general procedure from 0.6 g (3.63 mmol)
of 3, 0.85 g (4.88 mmol) of ethyl-phenylpropiolate, 16.32 mg
(2 mol %) of Pd(OAc)2 and 32.17 mg (2 mol %) of TDMPP. The residue
was purified by column chromatography with t-Bu-Me-ether/ace-
tonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 0.9 g of 7b (73%) as
1
mixture (67%) as a yellow oil. H NMR (400 MHz, CDCl3, 25 ꢀC):
d
1.50–1.72 (m, 4H, 2H-80, 2H-30), 2.10–2.12 (m, 1H, H-40), 2.50 (s,
3H, –CH3), 2.50–2.53 (m, 1H, H-50), 2.81–3.07 (m, 5H, 2H-60, 2H-70,
H-20), 3.39–3.70 (m, 3H, 2H-90, –OH), 6.78 (s,1H, H-3), 7.40–7.42 (m,
3H, H-300, H-400, H-500), 7.68–7.70 (m, 2H, H-200, H-600); 13C NMR
a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC)
d
1.16 (t, J¼7.1 Hz, 3H,
–CH2CH3), 1.38–1.44 (m, 1H, H-30), 1.54–1.73 (m, 3H, 2H-80, H-30),
2.00–1.99 (m, 1H, H-40), 2.69–2.74 (m, 1H, H-50), 2.85–3.09 (m, 6H,
2H-60, 2 H-70, H-20, –OH), 3.49 (dd, J¼11.4, 4.9 Hz, 1H, H-90), 3.57–
3.63 (m, 1H, H-90), 4.10 (q, J¼7.1 Hz, 2H, –CH2CH3), 6.27 (s, 1H, H-2),
7.35–7.39 (m, 3H, H-300, H-400, H-500), 7.41–7.44 (m, 2H, H-200, H-600);
(100 MHz, CDCl3, 25 ꢀC):
d
24.41 (C-30), 25.43 (C-80), 27.30 (C-40),
28.06 (C-50), 30.70 (C-1), 47.36 (C-60), 48.40 (C-70), 57.17 (C-20),
62.06 (C-90), 69.16 (C-5), 106.97 (C-6), 127.07 (C-200, C-600), 128.49 (C-
300, C-500), 129.78 (C-400), 131.28 (C-3), 134.20 (C-100), 137.75 (C-4),
197.14 (C-2). MS (EI) m/z (%): 309 (80) [Mþ], 292 (8) [MꢁOH]þ, 278
(100) [MꢁCH2OH]þ, 266 (17) [MꢁCH3CO]þ. Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.51; H, 7.56; N,
4.57.
13C NMR (100 MHz, CDCl3, 25 ꢀC):
d
13.90 (–CH2CH3), 24.30 (C-30),
25.36 (C-80), 27.25 (C-40), 29.24 (C-50), 47.56 (C-60), 48.39 (C-70),
57.11 (C-20), 60.26 (–CH2CH3), 62.00 (C-90), 82.89 (C-4), 99.30 (C-5),
124.19 (C-2), 127.76 (C-300, C-500), 128.27 (C-200, C-600), 128.72 (C-400),

6232
S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
4.2.6. 4-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-ylethynyl)-(Z)-4-hexen-2-one (7f)
Prepared according to general procedure from 0.6 g (3.63 mmol)
of 3, 0.42 g (4.36 mmol) of 3-hexyn-2-one, 16.32 mg (2 mol %) of
Pd(OAc)2 and 32.17 mg (2 mol %) of TDMPP. The residue was puri-
fied by column chromatography with t-Bu-Me-ether/acetonitrile/
25 ꢀC):
d
1.39–1.59 (m, 4H, 2H-80, 2H-30), 1.80 (d, J¼6.8 Hz, 3H, H-6),
1.85–1.88 (m, 1H, H-40), 2.02 (s, 3H, H-110), 2.12 (s, 3H, H-1), 2.58–
2.62 (m,1H, H-50), 2.78–2.94 (m, 3H, H-60, 2 H-70), 3.06–3.01 (m, 2H,
H-20, H-60), 3.08 (s, 2H, H-3), 4.00 (dd, J¼11.9, 5.0 Hz, 1H, H-90), 4.09
(dd, J¼11.9, 9.4 Hz, 1H, H-90), 7.75 (q, J¼6.8 Hz, 1H, H-5); 13C NMR
(100 MHz, CDCl3, 25 ꢀC):
d
16.34 (C-6), 21.03 (C-110), 24.49 (C-30),
NH3 (25%)¼1:1:0.1 as eluent to give 0.76 g of 7e (80%) as a yellow
25.11 (C-80), 27.47 (C-40), 28.98 (C-50), 29.08 (C-1), 48.51 (C-70),
48.77 (C-60), 52.08 (C-3), 54.46 (C-20), 64.17 (C-90), 79.22 (C-130),
97.85 (C-120), 116.99 (C-4), 135.51 (C-5), 171.23 (C-100), 206.24 (C-2).
MS (EI) m/z (%): 303 (17) [Mþ], 260 (12) [MꢁCH3CO]þ, 230 (16)
[MꢁCH3CO2CH2]þ. Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N,
4.62. Found: C, 71.19; H, 8.47; N, 4.55.
1
oil. H NMR (400 MHz, CDCl3, 25 ꢀC):
d
1.42–1.50 (m, 1H, H-30),
1.54–1.74 (m, 3H, 2H-80, H-30), 1.88 (d, J¼6.7 Hz, 3H, H-6), 1.94–1.98
(m, 1H, H-40), 2.21 (s, 3H, H-1), 2.67–2.72 (m, 1H, H-50), 2.86–3.09
(m, 5H, 2H-60, 2H-70, H-20), 3.17 (s, 2H, H-3), 3.23 (br s, 1H, –OH),
3.51 (dd, J¼11.3, 5 Hz, 1H, H-90), 3.60–3.65 (m, 1H, H-90), 5.84 (q,
J¼6.7 Hz, 1H, H-5); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 16.33 (C-6),
24.21 (C-30), 25.47 (C-80), 27.44 (C-40), 29.08 (C-50, C-1), 48.12 (C-60),
48.42 (C-70), 52.14 (C-3), 57.20 (C-20), 62.04 (C-90), 79.12 (C-110),
97.92 (C-100), 117.03 (C-4), 135.50 (C-5), 206.30 (CO). MS (EI) m/z
(%): 261 (100) [Mþ], 230 (84) [MꢁCH2OH]þ, 218 (41) [MꢁCH3CO]þ,
188 (13) [MꢁCH3CO2CH2]þ. Anal. Calcd for C16H23NO2: C, 73.53; H,
8.87; N, 5.36. Found: C, 75.44; H, 8.96; N, 5.40.
4.2.10. 5-((10S,20S,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-methyl-(E)-2-penten-4-ynoic acid ethyl
ester (9a)
Prepared according to general procedure from 0.3 g (1.81 mmol)
of 4, 0.24 g (2.17 mmol) of ethyl-2-butynoate, 8.16 mg (2 mol %) of
Pd(OAc)2 and 16.00 mg (2 mol %) of TDMPP. The residue was purified
by column chromatography with t-Bu-Me-ether/acetonitrile/NH3
(25%)¼1:1:0.1 as eluent to give 0.13 g of 9a (26%) as a yellow oil. 1H
4.2.7. 5-((10S,20R,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-phenyl-(E)-2-penten-4-ynoic acid methyl
ester (8a)
NMR (400 MHz, CDCl3, 25 ꢀC):
d
0.75–0.81 (m, 1H, H-30), 1.20 (t,
J¼7.1 Hz, 3H, –CH2CH3), 1.34–1.49 (m, 2H, 2H-80), 1.86–1.90 (m, 1H,
2H-40), 1.93–2.00 (m, 1H, H-30), 2.20 (d, J¼1.4 Hz, 3H, –CH3), 2.49–
2.56 (m,1H, H-70), 2.61–2.65 (m,1H, H-50), 2.80–2.93 (m, 2H, H-60, H-
70), 2.98–3.08 (m, 2H, H-20, –OH), 3.22 (dd, J¼13.3,10.0 Hz,1H, H-60),
Prepared according to general procedure from 0.6 g (2.90 mmol)
of 5, 0.55 g (3.47 mmol) of methyl-phenylpropiolate, 13.00 mg
(2 mol %) of Pd(OAc)2 and 25.00 mg (2 mol %) of TDMPP. The resi-
due was purified by column chromatography with t-Bu-Me-ether/
acetonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 0.86 g of 8a (81%)
3.39–3.45 (m, 2H, 2H-90), 4.08 (q, J¼7.1 Hz, 2H, –CH2CH3), 5.93 (d,
13
J¼1.4 Hz, 1H, H-2); C NMR (100 MHz, CDCl3, 25 ꢀC):
d 14.16
as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
1.41–1.60 (m, 4H,
(–CH2CH3), 20.08 (–CH3), 24.90 (C-30), 26.11 (C-80), 26.54 (C-40), 28.68
(C-50), 39.51 (C-70), 56.76 (C-60), 56.91 (C-20), 59.81 (–CH2CH3), 62.57
(C-90), 83.32 (C-4), 98.19 (C-5), 123.49 (C-2), 138.23 (C-3), 166.04
(CO). MS (EI) m/z (%): 277 (73) [Mþ], 248 (83) [MꢁC2H5]þ, 246 (65)
[MꢁCH2OH]þ, 232 (26) [MꢁC2H5O]þ. Anal. Calcd for C16H23NO3: C,
69.29; H, 8.36; N, 5.05. Found: C, 69.37; H, 8.29; N, 4.95.
2H-80, 2H-30), 1.92–1.93 (m, 1H, H-40), 2.00 (s, 3H, H-110), 2.61–2.65
(m, 1H, H-50), 2.77–3.09 (m, 5H, H-20, 2H-60, 2H-70), 3.53 (s, 3H,
CH3OCO–), 3.99 (dd, J¼11.9, 4.8 Hz, 1H, H-90), 4.07 (dd, J¼11.9,
9.2 Hz, 1H, H-90), 6.18 (s, 1H, H-2), 7.25–7.30 (m, 3H, H-200, H-600, H-
400), 7.31–7.36 (m, 2H, H-300, H-500); 13C NMR (100 MHz, CDCl3,
25 ꢀC):
d
21.03 (C-110), 24.52 (C-30), 24.94 (C-80), 27.32 (C-40), 29.11
(C-50), 48.29 (C-60), 48.51 (C-70), 51.36 (CH3OCO–), 54.46 (C-20),
64.11 (C-90), 82.99 (C-4), 99.27 (C-5), 123.62 (C-2), 127.81 (C-200, C-
600), 128.28 (C-300, C-500), 128.83 (C-400), 136.65 (C-100), 138.82 (C-3),
165.70 (CH3OCO–), 171.18 (C-100). MS (EI) m/z (%): 367 (1) [Mþ], 352
(1) [MꢁCH3]þ. Anal. Calcd for C22H25NO4: C, 71.91; H, 6.86; N, 3.81.
Found: C, 71.83; H, 6.96; N, 3.72.
4.2.11. 5-((10S,20S,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-phenyl-(E/Z)-2-penten-4-ynoic acid ethyl
ester (9b/9c)
Prepared according to general procedure from 0.6 g (3.63 mmol)
of 4, 0.75 g (4.31 mmol) of ethyl-phenylpropiolate, 40.80 mg
(5 mol %) of Pd(OAc)2 and 80.43 mg (5 mol %) of TDMPP. The resi-
due was purified by column chromatography with t-Bu-Me-ether/
acetonitrile/NH3 (25%)¼1:1:0.1 as eluent to give 0.38 g of E/Z
(85:15) mixture (30%) as a yellow oil. 1H NMR (400 MHz, CDCl3,
4.2.8. 6-((10S,20R,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-4-ethyl-(E)-3-hexen-5-yn-2-one (8b)
Prepared according to general procedure from 0.44 g (2.12 mmol)
of 5, 0.25 g (2.60 mmol) of 3-hexyn-2-one, 10.00 mg (2 mol %) of
Pd(OAc)2 and 18.80 mg (2 mol %) of TDMPP. The residue was purified
by column chromatography with t-Bu-Me-ether/acetonitrile/NH3
(25%)¼1:2:0.25 as eluent to give 0.34 g of 8b (53%) as a yellow oil. 1H
25 ꢀC):
d
0.73–0.82 (m, 1H, H-30), 1.05 (t, J¼7.1 Hz, 3H, –CH2CH3),
1.32–1.48 (m, 2H, 2H-80), 1.88–1.97 (m, 2H, H-30, H-40), 2.47–2.57
(m, 1H, H-70), 2.63–2.68 (m, 1H, H-50), 2.81–2.93 (m, 2H, H-60, H-70),
2.97–3.05 (m, 1H, H-20), 3.21 (br s, 1H, –OH), 3.21 (dd, J¼13.2,
–10.0 Hz, 1H, H-60), 3.35–3.43 (m, 2H, 2H-90), 3.95–4.01/4.10–4.15
(q, J¼7.1 Hz, 2H, –CH2CH3), 6.17/7.04 (s, 1H, H-2), 7.21–7.27 (m, 3H,
H-300, H-400, H-500), 7.31–7.36 (m, 2H, H-200, H-600); 13C NMR
NMR (400 MHz, CDCl3, 25 ꢀC):
d
1.04 (t, J¼7.5 Hz, 3H, H-8), 1.42–1.61
(m, 4H, 2H-80, 2H-30),1.89–1.94 (m,1H, H-40), 2.02 (s, 3H, H-110), 2.13
(s, 3H, H-1), 2.59–2.65 (m, 3H, H-50, H-7), 2.78–2.94 (m, 3H, H-60, 2 H-
70), 3.0–3.10 (m, 2H, H-60, H-20), 4.01 (dd, J¼11.9, 4.8 Hz, 1H, H-90),
4.10 (dd, J¼11.9, 9.3 Hz, 1H, H-90), 6.29 (s, 1H, H-3); 13C NMR
(100 MHz, CDCl3, 25 ꢀC):
d
13.71/13.83 (–CH2CH3), 24.91 (C-30),
26.03 (C-80), 26.54 (C-40), 28.69/28.79 (C-50), 39.48 (C-70), 56.64 (C-
60), 56.72/56.91 (C-20), 60.16/61.38 (–CH2CH3), 62.52 (C-90), 82.20
(C-4), 95.75/99.99 (C-5), 124.08 (C-2), 127.68/128.11 (C-300, C-500),
128.21/128.50 (C-200, C-600), 128.64/128.76 (C-400), 134.64/136.79 (þC-
100), 138.45/142.45 (C-3), 165.29 (CO). MS (EI) m/z (%): 339 (15) [M ],
310 (13) [MꢁC2H5]þ, 277 (29) [MꢁC2H5OꢁOH]þ, 262 (13)
[MꢁC6H5]þ. Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13.
Found: C, 74.39; H, 7.35; N, 4.20.
(100 MHz, CDCl3, 25 ꢀC):
d
12.85 (C-8), 21.04 (C-110), 24.61 (C-30),
25.05 (C-80), 25.96 (C-7), 27.42 (C-40), 29.14 (C-50), 31.79 (C-1), 48.43
(C-60), 48.51 (C-70), 54.42 (C-20), 64.21 (C-90), 83.14 (C-5), 98.61 (C-6),
129.77 (C-3),143.18 (C-4),171.24 (C-100),197.68 (C-2). MS (EI) m/z (%):
303 (83) [Mþ], 260 (26) [MꢁCH3CO]þ, 244 (36) [MꢁCH3CO2]þ, 230
(100) [MꢁCH3CO2CH2]þ. Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31;
N, 4.62. Found: C, 71.33; H, 8.26; N, 4.58.
4.2.12. 5-((10S,20S,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-methyl-(E)-2-penten-4-ynoic acid ethyl
ester (10a)
4.2.9. 4-((10S,20R,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-ylethynyl)-(Z)-4-hexen-2-one (8c)
Enyne 8b (0.15 g, 0.5 mmol) isomerized upon refluxing in THF
Prepared according to general procedure from 0.6 g (2.90 mmol)
of 6, 0.39 g (3.48 mmol) of ethyl-2-butynoate, 13.01 mg (2 mol %) of
for 5 h furnishing the enyne 8c (99%). 1H NMR (400 MHz, CDCl3,

S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
6233
Pd(OAc)2 and 25.64 mg (2 mol %) of TDMPP. The residue was puri-
4.2.15. 6-((10S,20S,40S,50S)-20-Acetoxymethyl-10-azabicyclo
fied by column chromatography with t-Bu-Me-ether/acetonitrile/
NH3 (25%)¼10:1:0.25 as eluent to give 0.64 g of 10a (70%) as a yel-
[2.2.2]oct-50-yl)-4-ethyl-(E)-3-hexen-5-yn-2-one (10d)
Prepared according to general procedure from 0.88 g
(4.25 mmol) of 6, 0.49 g (5.09 mmol) of 3-hexyn-3-one, 19.08 mg
(2 mol %) of Pd(OAc)2 and 37.60 mg (2 mol %) of TDMPP. The residue
was purified by column chromatography with t-Bu-Me-ether/ace-
tonitrile/NH3 (25%)¼10:2:0.25 as eluent to give 0.75 g of 10d (59%)
low oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC): 0.88–0.93 (m, 1H, H-30),
d
1.20 (t, J¼7.1 Hz, 3H, –CH2CH3), 1.36–1.51 (m, 1H, 2H-80), 1.90 (br s,
1H, H-40), 2.02 (s, 3H, H-110), 1.98–2.07 (m, 1H, H-30), 2.21 (d,
J¼1.4 Hz, 3H, –CH3), 2.57–2.65 (m, 2H, H-70, H-50), 2.83–2.97 (m, 2H,
H-70, H-60), 3.11–3.19 (m, 1H, H-20), 3.26 (dd, J¼13.4, 10.0 Hz, 1H, H-
60), 3.96 (dd, J¼11.8, 5.2 Hz,1H, H-90), 4.02 (dd, J¼11.8, 9.2 Hz,1H, H-
90), 4.08 (q, J¼7.1 Hz, 2H, –CH2CH3), 5.94 (d, J¼1.4 Hz, 1H, H-2). 13C
as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d 0.89–0.95 (m,1H,
H-30),1.05 (t, J¼7.5 Hz, 3H, –CH2CH3),1.36–1.51 (m, 2H, 2H-80),1.86–
1.96 (m,1H, H-40), 2.02 (s, 3H, H-110),1.99–2.06 (m,1H, H-30), 2.12 (s,
3H, -CH3), 2.58–2.66 (m, 4H, H-70, H-50, –CH2CH3), 2.83–2.98 (m, 2H,
H-70, H-60), 3.12–3.20 (m, 1H, H-20), 3.28 (dd, J¼13.5, 10.0 Hz, 1H, H-
60), 3.97 (dd, J¼11.7, 5.5 Hz, 1H, H-90), 4.02 (dd, J¼11.7, 9.3 Hz, 1H, H-
NMR (100 MHz, CDCl3, 25 ꢀC):
d 14.15 (–CH2CH3), 20.07 (–CH3),
20.97 (C-110), 25.15 (C-30), 25.94 (C-80), 26.64 (C-40), 28.28 (C-50),
40.21 (C-70), 54.12 (C-20), 56.79 (C-60), 59.79 (–CH2CH3), 64.58 (C-
90), 83.33 (C-4), 98.10 (C-5), 123.50 (C-2), 138.20 (C-3), 166.00 (CO),
171.19 (C-100). MS (EI) m/z (%): 319 (59) [Mþ], 290 (41) [MꢁC2H5]þ,
274 (14) [MꢁC2H5O]þ, 260 (11) [MꢁCH3CO2]þ, 246 (100)
[MꢁC2H5CO2]þ. Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.54; H, 7.96; N, 4.43.
90), 6.28 (s,1H, H-3); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 12.81 (C-8),
20.99 (C-110), 25.25 (C-30), 25.96 (C-80, C-7), 26.74 (C-40), 28.46 (C-
50), 31.74 (C-1), 40.24 (C-70), 54.20 (C-20), 56.89 (C-60), 64.61 (C-90),
82.46 (C-5), 99.44 (C-6), 129.63 (C-3), 143.31 (C-4), 171.21 (C-100),
197.61 (C-2). MS (EI) m/z (%): 303 (95) [Mþ], 260 (47) [MꢁCH3CO]þ,
244 (27) [MꢁCH3CO2]þ, 230 (100) [MꢁCH3CO2CH2]þ. Anal. Calcd for
C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found: C, 71.33; H, 8.29; N,
4.56.
4.2.13. 5-((10S,20S,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-phenyl-(E)-2-penten-4-ynoic acid ethyl
ester (10b)
Prepared according to general procedure from 0.5 g (2.41 mmol)
of 6, 0.50 g (2.87 mmol) of ethyl-phenylpropiolate, 10.08 mg
(2 mol %) of Pd(OAc)2 and 21.37 mg (2 mol %) of TDMPP. The residue
was purified by column chromatography with t-Bu-Me-ether/ace-
tonitrile/NH3 (25%)¼10:1:0.25 as eluent to give 0.62 g of 10b (67%)
4.2.16. 6-((10S,20S,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-4-phenyl-(E)-3-hexen-5-yn-2-one (10e)
Prepared according to general procedure from 0.43 g
(2.07 mmol) of 6, 0.36 g (2.49 mmol) of 4-phenyl-3-butyn-2-one,
9.30 mg (2 mol %) of Pd(OAc)2 and 18.37 mg (2 mol %) of TDMPP.
The residue was purified by column chromatography with t-Bu-
Me-ether/acetonitrile/NH3 (25%)¼10:2:0.25 as eluent to give 0.44 g
as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d 0.87–0.92 (m,1H,
H-30),1.05 (t, J¼7.1 Hz, 3H, –CH2CH3),1.34–1.48 (m, 2H, 2H-80),1.91–
1.92 (m, 1H, H-40), 1.96–2.00 (m, 1H, H-30), 2.02 (s, 3H, H-110), 2.56–
2.66 (m, 2H, H-50, H-70), 2.85–2.96 (m, 2H, H-70, H-60), 3.10–3.18 (m,
1H, H-20), 3.25 (dd, J¼13.4,10.0 Hz,1H, H-60), 3.95 (dd, J¼11.9, 5.2 Hz,
1H, H-90), 3.98 (q, J¼7.1 Hz, 2H, –CH2CH3), 4.00 (dd, J¼11.9, 9.4 Hz,
1H, H-90), 6.18 (s,1H, H-2), 7.24–7.28 (m, 3H, H-300, H-400, H-500), 7.30–
1
of 10e (61%) as a yellow oil. H NMR (400 MHz, CDCl3, 25 ꢀC):
d
0.90–0.95 (m, 1H, H-30), 1.37–1.55 (m, 2H, 2H-80), 1.89 (s, 3H,
–CH3), 1.94–1.95 (m, 1H, H-40), 2.03 (s, 3H, H-110), 1.97–2.05 (m, 1H,
H-30), 2.60–2.70 (m, 2H, H-50, H-70), 2.87–2.99 (m, 2H, H-60, H-70),
3.13–3.21 (m, 1H, H-20), 3.28 (dd, J¼13.4, 10.1 Hz, 1H, H-60), 3.95–
4.05 (m, 2H, 2H-90), 6.39 (s, 1H, H-2), 7.30 (s, 5H, HPh); 13C NMR
7.35 (m, 2H, H-200, H-600); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 13.88
(–CH2CH3), 21.01 (C-110), 25.26 (C-30), 25.95 (C-80), 26.69 (C-40),
28.48 (C-50), 40.27 (C-70), 54.20 (C-20), 56.75 (C-60), 60.21 (–CH2CH3),
64.63 (C-90), 82.26 (C-4), 99.97 (C-5), 124.15 (C-2), 127.72 (C-300, C-
500), 128.27 (C-200, C-600), 128.69 (C-400), 136.84 (C-100), 138.45 (C-3),
165.33 (CO), 171.22 (C-100). MS (EI) m/z (%): 381 (73) [Mþ], 352 (60)
[MꢁC2H5]þ, 308 (100) [MꢁC2H5CO2]þ. Anal. Calcd for C23H27NO4: C,
72.42; H, 7.13; N, 3.67. Found: C, 72.33; H, 7.19; N, 3.75.
(100 MHz, CDCl3, 25 ꢀC): 21.05 (C-110), 25.20 (C-30), 25.84 (C-80),
d
26.71 (C-40), 28.52 (C-50), 30.50 (-CH3), 40.29 (C-70), 54.30 (C-20),
56.66 (C-60), 64.49 (C-90), 77.20 (C-4), 82.45 (C-5), 128.32 (C-200, C-
600), 128.50 (C-300, C-500), 129.22 (C-400), 133.63 (C-2), 136.10 (C-100),
137.04 (C-3), 171.25 (C-100), 199.35 (CO). MS (EI) m/z (%): 351 (100)
[Mþ], 308 (26) [MꢁCH3CO]þ, 292 (28) [MꢁCH3CO2]þ, 278 (73)
[MꢁCH3CO2CH2]þ. Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N,
3.99. Found: C, 75.26; H, 7.13; N, 3.82.
4.2.14. 5-((10S,20S,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-phenyl-(E)-2-penten-4-ynoic acid methyl
ester (10c)
4.2.17. 4-((10S,20S,40S,50S)-20-Acetoxymethyl-10-azabicyclo
[2.2.2]oct-50-ylethynyl)-(Z)-4-hexen-2-one (10f)
Prepared according to general procedure from 0.40 g
(1.93 mmol) of 6, 0.37 g (2.31 mmol) of methyl-phenylpropiolate,
8.67 mg (2 mol %) of Pd(OAc)2 and 17.10 mg (2 mol %) of TDMPP. The
residue was purified by column chromatography with t-Bu-Me-
ether/acetonitrile/NH3 (25%)¼10:2:0.25 as eluent to give 0.48 g of
Enyne 10d (0.2 g, 0.6 mmol) isomerized upon refluxing in THF
for 5 h furnishing the enyne 10f (95%). 1H NMR (400 MHz, CDCl3,
25 ꢀC):
d
0.87–0.93 (m, 1H, H-30), 1.35–1.50 (m, 2H, 2H-80), 1.80 (d,
J¼6.8 Hz, 3H, H-6), 1.86–1.91 (m, 1H, H-40), 2.02–2.08 (m, 1H, H-30),
2.02 (s, 3H, H-110), 2.12 (s, 3H, H-1), 2.57–2.64 (m, 2H, H-50, H-70),
2.83–2.97 (m, 2H, H-70, H-60), 3.08 (s, 2H, H-3), 3.13–3.20 (m, 1H, H-
20), 3.26 (dd, J¼13.4, 10.0 Hz, 1H, H-60), 3.96 (dd, J¼11.8, 5.2 Hz, 1H,
H-90), 4.01 (dd, J¼11.8, 9.3 Hz, 1H, H-90), 5.75 (q, J¼6.8 Hz, 1H, H-5);
10c (68%) as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d 0.87–
0.92 (m, 1H, H-30), 1.37–1.47 (m, 2H, 2H-80), 1.91 (br s, 1H, H-40),
1.95–1.99 (m, 1H, H-30), 2.01 (s, 3H, H-110), 2.55–2.65 (m, 2H, H-50,
H-70), 2.84–2.95 (m, 2H, H-70, H-60), 3.09–3.17 (m, 1H, H-20), 3.24
(dd, J¼13.4, 10.1 Hz, 1H, H-60), 3.53 (s, 3H, –CH3), 3.94 (dd, J¼11.7,
5.1 Hz, 1H, H-90), 4.00 (dd, J¼11.7, 9.3 Hz, 1H, H-90), 6.18 (s, 1H, H-2),
7.24–7.28 (m, 3H, H-300, H-500, H-400), 7.30–7.35 (m, 2H, H-200, H-600);
13C NMR (100 MHz, CDCl3, 25 ꢀC): 16.26 (C-6), 20.98 (C-110), 25.18
d
(C-30), 26.02 (C-80), 26.77 (C-40), 28.30 (C-50), 29.03 (C-1), 40.25 (C-
70), 52.07 (C-3), 54.13 (C-20), 57.23 (C-60), 64.63 (C-90), 78.52 (C-130),
98.56 (C-120), 117.04 (C-4), 135.35 (C-5), 171.21 (C-100), 206.22 (C-2).
MS (EI) m/z (%): 303 (8) [Mþ], 260 (27) [MꢁCH3CO]þ, 230 (12)
[MꢁCH3COCH2]þ. Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N,
4.62. Found: C, 71.18; H, 8.38; N, 4.69.
13C NMR (100 MHz, CDCl3, 25 ꢀC): 20.91 (C-110), 25.17 (C-30), 25.84
d
(C-80), 26.60 (C-40), 28.39 (C-50), 40.16 (C-70), 51.22 (–CH3), 54.09 (C-
20), 56.60 (C-60), 64.53 (C-90), 82.20 (C-4), 100.07 (C-5), 123.37 (C-2),
127.67 (C-300, C-500), 128.19 (C-200, C-600), 128.70 (C-400), 136.58 (C-100),
138.82 (C-3), 165.60 (CO), 171.09 (C-100). MS (EI) m/z (%): 367 (100)
[Mþ], 352 (43) [MꢁCH3]þ, 308 (98) [MꢁCH3CO2]þ, 294 (63)
[MꢁCH3CO2CH2]þ. Anal. Calcd for C22H25NO4: C, 71.91; H, 6.86; N,
3.81. Found: C, 72.05; H, 6.93; N, 3.70.
4.3. General procedure for the Eglinton reaction
To a solution of finely powdered cupric acetate monohydrate
(1.5 equiv) in pyridine/methanol (1:1) (2 ml/1.5 mmol alkyne) was

6234
S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
added terminal alkyne (1 equiv) 3 or 4. The deep blue suspension
becomes green when heated under reflux. After 3–5 h of heating,
the solution was cooled and the solvent removed in vacuo. The
residue was treated with an aqueous solution of NH3 (25%) and
extracted with CH2Cl2. The organic layer was dried over Na2SO4 and
the solvent removed in vacuo. The resulting crude product was
purified by column chromatography (t-Bu-Me-ether/MeOH/NH3
(25%)¼10:3:0.25) to afford the desired dimeric alkynes 11 and 12.
The spectral data for these are in agreement with that already
reported in literature.28
(72%) as white a solid. Mp¼110–112 ꢀC. 1H NMR (400 MHz, CDCl3,
25 ꢀC)
d 0.54–0.59 (m, 1H), 0.70–0.74 (m, 1H), 1.27–1.44 (m, 2H),
1.54–1.79 (m, 5H), 2.00 (br s, 1H), 2.42–2.49 (m, 1H), 2.58–2.60 (m,
1H), 2.65–2.85 (m, 4H), 3.05–3.58 (m, 10H), 3.60–3.66 (m, 1H),
7.26–7.39 (m, 7H), 7.44 (s, 1H), 7.46 (s, 1H), 7.52 (s, 1H), 7.54 (s, 2H);
13C NMR (100 MHz, CDCl3, 25 ꢀC)
d 24.29, 24.82, 26.21, 26.61, 27.39,
28.58, 29.01, 39.54, 39.72, 40.42, 55.16, 56.56, 56.77, 57.69, 62.53,
63.13, 78.82, 101.59, 121.65, 123.15, 126.04, 127.08 (2C), 127.28,
127.64, 127.74 (2C), 128.88 (2C), 129.27 (2C), 139.88, 140.51, 141.55,
145.88, 146.43. MS (EI) m/z (%): 532 (100) [Mþ], 501 (26)
[MꢁCH3O]þ. Anal. Calcd for C36H40N2O2: C, 81.17; H, 7.52; N, 5.26.
Found: C, 81.24; H, 7.47; N, 5.19.
4.4. General procedure for the synthesis of tetrasubstituted
benzene derivatives 15–18
4.4.4. 1,5-Dimethoxymethyl-2-((10S,20S,40S,50S)-20-hydroxymethyl-
10-azabicyclo[2.2.2]oct-50-ylethynyl)-3-((100S,200S,400S,500S)-200-
hydroxymethyl-100-azabicyclo[2.2.2] oct-500-yl)-benzene (18)
A mixture of alkyne 13 or 14 (2 equiv), diyne 11 or 12 (1 equiv)
and Pd(PPh3)4 (0.05 equiv) in absolute THF (10 ml) was stirred
under reflux until TLC analysis indicated complete consumption of
the reactants. The reaction mixture was concentrated in vacuo and
the crude product was purified by column chromatography.
Prepared according to general procedure from 0.3 g (0.91 mmol)
of 12, 0.13 g (1.89 mmol) of 14, 52.00 mg (5 mol %) of Pd(PPh3)4. The
residue was purified by column chromatography with t-Bu-Me-
ether/MeOH/NH3 (25%)¼1:1:0.1 as eluent to give 0.26 g of 18 (54%)
as a white solid. Mp¼173–175 ꢀC. 1H NMR (400 MHz, CDCl3, 25 ꢀC)
4.4.1. 1,5-Diphenyl-2-((10S,20S,40S,50S)-20-hydroxymethyl-10-
azabicyclo[2.2.2]oct-50-ylethynyl)-3-((100S,200S,400S,500S)-200-
d
0.64–0.69 (m, 1H), 0.82–0.88 (m, 1H), 1.35–1.64 (m, 5H), 1.91–1.92
hydroxymethyl-100-azabicyclo[2.2.2]oct-500-yl)-benzene (15)
Prepared according to general procedure from 0.3 g (0.91 mmol)
of 11, 0.20 g (1.96 mmol) of 13, 52.00 mg (5 mol %) of Pd(PPh3)4. The
residue was purified by column chromatography with t-Bu-Me-
ether/MeOH/NH3 (25%)¼10:3:0.25 as eluent to give 0.30 g of 15
(57%) as a white solid. Mp¼212–213 ꢀC. 1H NMR (400 MHz, CDCl3,
(m, 1H), 1.97 (br s, 1H), 2.04–2.09 (m, 1H), 2.53–2.60 (m, 1H), 2.67–
2.75 (m, 1H), 2.80–2.89 (m, 1H), 2.90–2.95 (m, 2H), 3.32 (s, 3H), 3.37
(s, 3H), 3.05–3.55 (m, 19H), 4.40 (s, 2H), 4.51 (s, 2H), 7.22 (s, 1H),
7.24 (s, 1H); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 24.03, 25.22, 26.30,
26.97, 27.34, 28.34, 29.10, 39.30, 36.62, 40.43, 54.73, 57.08, 57.27,
57.54, 58.18, 58.65, 62.65, 62.98, 73.21, 74.47, 102.71, 121.65, 123.65,
124.21, 137.57, 140.92, 145.49. MS (EI) m/z (%): 468 (100) [Mþ], 453
(85) [MꢁCH3]þ, 423 (46) [MꢁCH3COCH2]þ. Anal. Calcd for
C28H40N2O4: C, 71.76; H, 8.60; N, 5.98. Found: C, 71.70; H, 8.63; N,
6.05.
25 ꢀC)
d 0.98–1.03 (m, 1H), 1.21–1.32 (m, 2H), 1.40–1.55 (m, 3H),
1.66–1.73 (m, 3H), 2.04–2.05 (m, 1H), 2.54–2.58 (m, 1H), 2.62–2.80
(m, 4H), 2.83 (dd, J¼13.8, 10.3 Hz, 1H), 2.88–2.97 (m, 1H), 3.10 (dd,
J¼13.9, 10.2 Hz, 1H), 3.16–3.25 (m, 3H), 3.45–3.49 (m, 2H), 3.61 (t,
J¼10.7 Hz, 1H), 7.26–7.39 (m, 7H), 7.42–7.45 (m, 3H), 7.51 (s, 1H),
7.53 (s, 1H); 13C NMR (100 MHz, CDCl3, 25 ꢀC)
d
23.63, 24.27, 25.55,
4.5. General procedure for the synthesis of pentasubstituted
benzene derivative 20
27.33, 27.80, 28.06, 29.52, 39.59, 45.45, 47.40, 48.41, 48.84, 57.31,
58.19, 62.03, 62.40, 79.49, 101.03, 121.72, 123.22, 126.10, 127.03 (2C),
127.30, 127.66, 127.80, 128.92 (2C), 129.30 (2C), 139.78, 140.55,
141.48, 145.48, 146.04. MS (EI) m/z (%): 532 (100) [Mþ], 503 (64)
[MꢁCHO]þ. Anal. Calcd for C36H40N2O2: C, 81.17; H, 7.57; N, 5.26.
Found: C, 81.09; H, 7.61; N, 5.30.
A mixture of enyne (7d/7f) (0.35 g, 1.13 mmol) and diyne 19
(0.1 g, 1.28 mmol) and 65.00 mg (5 mol %) Pd(PPh3)4 in absolute
THF (10 ml) was stirred at 100 ꢀC until TLC analysis indicated
complete consumption of the reactants. The solution was concen-
trated in vacuo and the residue was purified by column chroma-
tography with t-Bu-Me-ether/MeOH/NH3 (25%)¼10:3:0.25 as
eluent to give 0.1 g (23%) of 20 as a white solid.
4.4.2. 1,5-Dimethoxymethyl-2-((10S,20R,40S,50S)-20-hydroxymethyl-
10-azabicyclo[2.2.2]oct-50-ylethynyl)-3-((100S,200R,400S,500S)-200-
hydroxymethyl-100-azabicyclo[2.2.2] oct-500-yl)-benzene (16)
Prepared according to general procedure from 0.3 g (0.91 mmol)
of 11, 0.126 g (1.80 mmol) of 14, 52.00 mg (5 mol %) of Pd(PPh3)4.
The residue was purified by column chromatography with t-Bu-
Me-ether/MeOH/NH3 (25%)¼1:1:0.1 as eluent to give 0.25 g of 16
4.5.1. [5-((10S,20R,40S,50S)-20-Hydroxymethyl-10-azabicyclo
[2.2.2]oct-50-yl)-3-methyl-4-prop-1-ynyl-biphenyl-2-yl]-
methylketone (20)
Mp¼183–185 ꢀC. 1H NMR (400 MHz, CDCl3, 25 ꢀC)
d 1.12–1.18 (m,
(60%) as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 ꢀC)
d
1.10–1.13
1H), 1.39–1.45 (m, 1H), 1.69–1.82 (m, 2H), 1.86 (s, 3H), 2.02–2.04 (m,
1H), 2.11 (s, 3H), 2.31 (s, 3H), 2.93–3.03 (m, 4H), 3.08–3.18 (m, 2H),
(m, 1H), 1.34–1.69 (m, 7H), 1.96 (br s, 2H), 2.74–2.96 (m, 8H), 3.01–
3.13 (m, 3H), 3.31 (s, 3H), 3.36 (s, 3H), 3.28–3.36 (m, 3H), 3.37–3.59
(m, 4H), 4.38 (s, 2H), 4.50 (s, 2H), 7.13 (s, 1H), 7.20 (s, 1H); 13C NMR
3.42–3.48 (m, 2H), 3.50–3.56 (m, 1H), 7.02 (s, 1H), 7.22–7.25 (m, 2H),
13
7.28–7.36 (m, 3H); C NMR (100 MHz, CDCl3, 25 ꢀC)
d 4.70, 18.26,
(100 MHz, CDCl3, 25 ꢀC)
d
23.44, 25.52, 27.57, 27.74, 27.84, 29.51,
23.42, 27.33, 27.84, 32.25, 39.17, 45.12, 48.68, 57.73, 62.05, 77.20,
96.42,124.48,124.75,127.94,128.75 (2C),128.85 (2C),136.59,136.63,
139.73, 140.17, 144.63, 207.45. MS (EI) m/z (%): 387 (100) [Mþ], 372
(57) [MꢁCH3]þ, 356 (63) [MꢁCH3O]þ. Anal. Calcd for C26H29NO2: C,
80.59; H, 7.54; N, 3.61. Found: C, 80.65; H, 7.48; N, 3.65.
39.04, 45.40, 47.97, 48.40, 48.69, 57.10, 57.42, 58.15, 58.58, 62.16,
62.19, 73.14, 74.43, 77.50, 102.07, 121.63, 123.58, 124.24, 137.41,
141.05, 144.61. MS (FAB) m/z (%): 469 [MþH]þ. Anal. Calcd for
C28H40N2O4: C, 71.76; H, 8.60; N, 5.98. Found: C, 71.68; H, 8.65; N,
6.01.
4.6. Crystal structure analyses
4.4.3. 1,5-Diphenyl-2-((10S,20S,40S,50S)-20-hydroxymethyl-10-
azabicyclo[2.2.2]oct-50-ylethynyl)-3-((100S,200S,400S,500S)-200-
The crystal structure data for 11, 12 and 20 were collected on
hydroxymethyl-100-azabicyclo[2.2.2]oct-500-yl)-benzene (17)
Prepared according to general procedure from 0.2 g (0.60 mmol)
of 12, 0.13 g (1.27 mmol) of 13, 34.00 mg (5 mol %) of Pd(PPh3)4. The
residue was purified by column chromatography with t-Bu-Me-
ether/MeOH/NH3 (25%)¼10:3:0.25 as eluent to give 0.23 g of 17
a Bruker SMART 1000CCD area detector (graphite-monochromated
Mo K
a
radiation,
l
¼71.073 pm) at ꢁ140 ꢀC in the
u- and 4-scan
mode. Empirical absorption corrections were applied using the
program SADABS. The structures were solved by direct methods
using SHELXS-86/97,31 and subjected to full-matrix least-squares

S. To¨to¨s et al. / Tetrahedron 65 (2009) 6226–6235
6235
refinement on F2 using SHELXL-93/97,32 with anisotropic dis-
placement parameters for non-H atoms.
13. Brown, G. R.; Foubister, A. J.; Freeman, S.; McTaggart, F.; Mirrlees, D. J.; Reid, A.
C.; Smith, G. D.; Taylor, M. J.; Thomason, D. A.; Whittamore, P. R. O. Bioorg. Med.
Chem. Lett. 1997, 7, 597.
14. Grotjahn, D. B. Transition Metal alkyne Complexes: Transition Metal-Catalyzed
Cyclotrimerization. In Comprehensive Organometallic Chemistry II; Wilkinson,
Stone, Abel, Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 741–770.
15. Agenet, N.; Gandon, V.; Peter, K.; Vollhardt, C.; Malacria, M.; Aubert, C. J. Am.
Chem. Soc. 2007, 129, 8860.
CCDC-710575 (12), CCDC-710576 (11) and CCDC-710577 (20)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223/336
033; e-mail: deposit@ccdc.cam.ac.uk].
16. Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697.
17. Ruba, E.; Schmid, R.; Kirchner, K.; Calhorda, M. J. J. Organomet. Chem. 2003, 682,
204.
18. (a) Varela, J. A.; Castedo, L.; Saa´, C. J. Am. Chem. Soc. 1998, 120, 12147; (b) Varela,
J. A.; Saa´, C. J. Organomet. Chem. 2009, 694, 143.
19. (a) Yoshida, K.; Morimoto, I.; Mitsudo, K.; Tanaka, H. Chem. Lett. 2007, 36, 998;
(b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901; (c) Li, J.; Jiang, H.; Chen,
M. J. Org. Chem. 2001, 66, 3627; (d) Fu¨ rstner, A.; Rumbo, A. J. Org. Chem. 2000,
65, 2608.
Acknowledgements
We thank the Buchler GmbH Braunschweig for financial support
of a part of this research and for the gifts of quincorine and
quincoridine.
20. Grevorgian, V.; Radhakrishnan, U.; Takeda, A.; Rubina, M.; Rubin, M.; Yama-
moto, Y. J. Org. Chem. 2001, 66, 2835.
21. For the synthesis of substituted enynes see also: (a) Hoshi, M.; Kawamura, N.;
Shirakawa, K. Synthesis 2006, 1961; (b) Thadani, A. N.; Rawal, V. H. Org. Lett.
2002, 4, 4321; (c) Bates, C. G.; Saejueng, P.; Venkataraman, D. Org. Lett. 2004, 6,
1441; (d) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844; (e) Ranu, B. C.; Chatto-
padhyay, K. Org. Lett. 2007, 9, 2409; (f) Suginome, M.; Shirakura, M.; Yamamoto,
A. J. Am. Chem. Soc. 2006, 128, 14438.
22. (a) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruther, G. J. Am. Chem. Soc.
1997, 119, 698; (b) Trost, B. M.; Harms, A. E. Tetrahedron Lett. 1996, 37, 3971.
23. (a) Schrake, O.; Braje, W.; Hoffmann, H. M. R.; Wartchow, R. Tetrahedron:
Asymmetry 1998, 9, 3717; (b) Hoffmann, H. M. R.; Schrake, O. Tetrahedron:
Asymmetry 1998, 9, 1051.
24. Fild, M.; Tho¨ne, C.; To¨to¨s, S. Eur. J. Inorg. Chem. 2004, 749.
25. Trost, B. M.; McIntosh, M. C. J. Am. Chem. Soc. 1995, 117, 7255.
26. Trost, B. M.; Chan, C.; Ruther, G. J. Am. Chem. Soc. 1987, 109, 3486.
27. Hubert, A. J.; Reimlinger, H. Synthesis 1969, 97.
28. Frackenpohl, J.; Braje, W. M.; Hoffmann, H. M. R. J. Chem. Soc., Perkin Trans. 1
2001, 47.
References and notes
1. Tsuji, T. Palladium Reagents and Catalysts; Wiley & Sons: Chichester, UK, 1995.
2. de Meijere, A.; Diederich, F. Metal Catalyzed Cross-coupling Reactions, 2nd,
Completely Revised and Enlarged Edition; Wiley & Sons: Weinheim, 2004.
3. Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
4. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
5. Kacprzak, K.; Gawron´ ski, J. Synthesis 2001, 961.
6. Norrby, P. O.; Kolb, H. C.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 8470.
7. Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.;
Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069.
8. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
9. Salluzo, C.; Breuzard, J.; Pellet-Rostaing, S.; Vallet, M.; Le Guyader, F.; Lemaire,
M. J. Organomet. Chem. 2002, 98.
10. Seward, E. M.; Swain, C. J.; Merchant, K. J.; Owen, S. N.; Sabin, V.; Cascieri, M. A.;
Sadowski, S.; Strader, C.; Baker, R. Bioorg. Med. Chem. Lett. 1993, 3, 1361.
11. Clark, R. D.; Muchowski, J. M.; Weinhardt, K. K.; Dillon, M. P.; Lee, C. H.; Bley, K.
R.; Bonhaus, D. W.; Wong, E. H. J.; Eglen, R. M. Bioorg. Med. Chem. Lett. 1995, 5,
1853.
29. Campbell, I. D.; Eglinton, G. Org. Synth. 1965, 45, 39.
30. Hartley, F. R. Organomet. Chem. Rev. Sect. A 1970, 6, 119.
31. Sheldrix, G. M. SHELXS-86/97, A Program for Solving Crystal Structures; University
of Go¨ttingen: Go¨ttingen, Germany, 1997.
32. Sheldrix, G. M. SHELXS-93/97, A Program for Refining Crystal Structures; Uni-
versity of Go¨ttingen: Go¨ttingen, Germany, 1997.
12. Yang, D.; Soulier, J. L.; Sicsic, S.; Mathe´-Allainmat, M.; Bre´mont, B.; Croci, T.;
Cardamone, R.; Aureggi, G.; Langlois, M. J. Med. Chem. 1997, 40, 608.