Immobilized DMAP derivatives rivaling homogeneous DMAP

Article abstract of DOI:10.1002/ejoc.201001507

The copper-catalyzed Huisgen reaction between azides and alkynes was utilized to covalently attach derivatives of 4-(dimethylamino)pyridine (DMAP) to a polystyrene resin (PS) support. The catalytic potential of these constructs as determined in acylation and aza-Morita-Baylis-Hillman reactions far exceeds that of commercially available DMAP-PS resins and is fully competitive with DMAP in homogeneous solution. Immobilization of 3,4-diaminopyridine catalysts on polystyrene by using the copper-catalyzed Huisgen reaction allowed the preparation of new supported catalysts ofunprecedented catalytic activity in acylation and aza-Morita-Baylis-Hillman reactions. Copyright

Full text of DOI:10.1002/ejoc.201001507

FULL PAPER
DOI: 10.1002/ejoc.201001507
Immobilized DMAP Derivatives Rivaling Homogeneous DMAP
Valerio D’Elia,[a] Yinghao Liu,[a] and Hendrik Zipse*[a]
Keywords: Acylation / Homogeneous catalysis / Immobilization / Supported catalysis / Organocatalysis
The copper-catalyzed Huisgen reaction between azides and
alkynes was utilized to covalently attach derivatives of 4-(di-
methylamino)pyridine (DMAP) to a polystyrene resin (PS)
mined in acylation and aza-Morita–Baylis–Hillman reactions
far exceeds that of commercially available DMAP-PS resins
and is fully competitive with DMAP in homogeneous solu-
support. The catalytic potential of these constructs as deter- tion.
Introduction
For decades 4-(dimethylamino)pyridine (DMAP; 1) and
its derivatives,[1] such as 4-pyrrolidinopyridine (PPY; 2),
have belonged to the synthetic chemist’s toolbox as versatile
and efficient nucleophilic catalysts for fundamental chemi-
cal transformations, including acylation,[1,2] synthesis of es-
ters[3] and sulfonamides,[4] silylation,[5] Morita–Baylis–Hill-
Figure 1. Selected nucleophilic catalysts based on the DMAP motif.
man reaction,[6] CO2 fixation,[7] and kinetic resolutions.[8]
Moreover, such reagents have been widely used in reactor
chemistry.[9] With the advent of the “green chemistry” con- Results and Discussion
cept[10] and the rising call for better sustainability, factors
The catalytically active pyridine units were attached to
such as catalyst recoverability[11] and recyclability are be-
coming increasingly important. Efforts have therefore been
undertaken to support DMAP on cross-linked polystyrene
beads.[12] Although these catalysts showed a good degree
of recoverability and can apparently be reused without any
dramatic loss of activity, the catalytic performance of these
heterogeneous catalysts is often significantly lower than
those of their homogeneous equivalents. In the last few
years, new, elegant immobilization strategies have been ex-
plored, including the immobilization of DMAP on mesopo-
rous silica nanospheres,[6h] on silica-coated magnetic par-
ticles,[13] or the microencapsulation of linear DMAP poly-
mers.[14] In spite of these remarkable advances, a hetero-
geneous system able to approach or even surpass the per-
formance of the homogeneous catalysts has not yet been
reported. Tricyclic DMAP derivatives 3 and 4 (Figure 1)
have recently been shown to exhibit excellent activity in
acylation reactions in homogeneous solution.[2b,3d] We now
report that immobilization of catalyst 4 on a polystyrene
support leads to catalysts of unprecedented catalytic ac-
tivity, while preserving the benefits of facile recoverability
and recyclability.
the polystyrene support by using the copper-catalyzed Hu-
isgen reaction between azides and alkynes. A number of
alkyne-substituted derivatives of 3,4-diaminopyridine cata-
lyst 4 were therefore synthesized in racemic form and at-
tached to an azide-modified Merrifield resin as shown in
Scheme 1. In order to characterize the influence of the
linker structure on the catalytic activity in acylation reac-
tions, soluble catalysts with variable side chains were also
synthesized according to the synthetic protocol shown in
Scheme 1. This included soluble catalyst 7a, with a simple
n-hexyl side chain, as well as catalysts 8b and 8c, with tria-
zolyl-substituted side chains of variable length. The cata-
lytic potential of the immobilized catalysts and their soluble
counterparts were first explored in the acetylation of terti-
ary alcohol 10 (Table 1). All reactions eventually proceeded
to full conversion, and the rate of reaction could thus be
characterized by the reaction half-life t1/2 using the ap-
proach described previously.[2c] For the sake of comparison,
we also include kinetic data for the commercially available
DMAP (1) and its immobilized version DMAP-PS (12). Pe-
rusal of the kinetic data for the soluble 3,4-diaminopyridine
catalysts shows that variation of the side chain attached to
the nitrogen substituent at the C-3 position of the pyridine
ring had no major influence on the catalytic activity. All of
these systems react significantly faster than with DMAP (1)
itself. This is not the case for immobilized catalyst 9b, the
kinetics of which are comparable to those of homogeneous
[a] Department of Chemistry, LMU München,
Butenandtstrasse 5-13, 81377 München, Germany
Fax: +49-89-218077738
E-mail: zipse@cup.uni-muenchen.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001507.
Eur. J. Org. Chem. 2011, 1527–1533
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H. Zipse et al.
FULL PAPER
Scheme 1. Synthesis of immobilized catalysts and their soluble counterparts: [a] See Held et al.[2b] [b] The TMS protecting group was
removed in K2CO3/MeOH before performing the “click reaction”, see Exp. Sect. [c] 1% crosslinked polystyrene. [d] Catalyst loading
expressed as mmol of catalyst per g of polymer.
DMAP and more than ten times slower than its soluble resin 9c was more than eight times more effective than the
analogue 8c. Loss of activity represents a common draw- commercially available DMAP-PS resin under otherwise
back of catalyst immobilization and is attributed to changes identical reaction conditions by using the same molar
in the micro-environment of the catalyst and to the in- amount of catalyst. This difference closely parallels that of
creased difficulty for the reactants to diffuse to the catalyti- the soluble counterparts DMAP and 8c and thus indicates
cally active core. It has been shown[12d,15] that extending the that resin support and linker structure lead to only minor
distance between the pyridine moiety and the bulky poly- perturbations in the intrinsic catalytic potential of these cat-
styrene beads has beneficial effects on the activity of the alysts.
catalyst.
Whether the immobilized catalysts synthesized here
could be used repeatedly after separation from the reaction
mixture by filtration, was explored with repeated runs of
the reaction shown in Table 1 with catalyst 9c. These experi-
ments were conducted such that the catalyst was filtered off
from the reaction mixture after 12 h, washed thoroughly
with dichloromethane and methanol, dried in vacuo for
12 h and then reused without any further modification
(Table 2). This procedure was accompanied by only mini-
mal loss of catalyst (approx. 1–2%) per cycle. Analogous
results were obtained for catalyst 9b within ten catalytic cy-
cles in 24 h (see the Supporting Information).
Table 1. Catalytic activity of immobilized and soluble pyridine cat-
alysts.[a]
Entry
Catalyst
t1/2 [min]
Soluble catalysts
1
2
3
4
5
6
DMAP (1)
151Ϯ2[b]
67Ϯ0.1[b]
18Ϯ0.1[b]
21Ϯ0.1
16Ϯ0.1
18Ϯ0.1
PPY (2)
Table 2. Yields for the benchmark reaction shown in Table 1 for
the repeated use of catalyst 9c by keeping a constant reaction time
of 12 h.
4
7a
8b
8c
Run
Yield [%][a]
Run
Yield [%][a]
Immobilized catalysts
1
2
3
4
5
100 (95)[b]
6
7
92
93
95
100
99
98
7
8
9
DMAP-PS (12)
504Ϯ8
166Ϯ3
58Ϯ2
8
9b
9c
9[c]
96 (91)[b]
92
93
10[c]
[a] Reagents and conditions: 10 (0.2 m), Ac2O (2.0 equiv.), NEt3
(3.0 equiv.), catalyst (0.1 equiv.), CDCl3, room temp. [b] Data from
Held et al.[2c]
[a] Determined by 1H NMR spectroscopy. [b] Isolated yield after
column chromatography. [c] In 24 h.
In our case, after inclusion of a longer linker unit (cata-
The application of supported catalyst 9c was extended to
lyst 9c), the catalytic performance of the immobilized cata- the reaction between secondary alcohols and anhydrides,
lyst approached that of its soluble counterparts. Catalyst because these play a significant role in protecting-group
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Immobilized DMAP Derivatives
chemistry and in the kinetic resolution of chiral alcohols. more active under otherwise identical conditions, providing
1-(1-Naphthyl)ethanol (13) and cyclohexanol (14) were cho- essentially complete conversion after 10 h. The shortest re-
sen as model substrates and were acylated with acetic or action half-life (51 min) was determined for catalyst 8c. Ex-
isobutyric anhydride (Table 3). The catalytic performance periments with supported catalysts (10 mol-%) revealed an
of 9c was again compared with that of the commercially equally large influence of the catalyst structure: whereas
available DMAP-PS. Due to the much higher intrinsic reac- only slow turnover was observed for the DMAP-PS resin,
tivity of secondary alcohols compared to their tertiary fast reactions and synthetically useful yields were obtained
counterparts,[16] the amount of catalyst employed could be with resin 9c. Measured t1/2 values for both systems indicate
reduced significantly, with 9c requiring just 0.1–0.5 mol-% an intrinsic activity difference of 10 for the selected sub-
to efficiently promote the isobutyrylation of the alcohol strate pair. After filtration, washing with chloroform, and
substrates within a synthetically useful time. A further re- drying in vacuo for 12 h, catalyst 9c could be successfully
duction of catalytic load, down to just 0.05 mol-% of cata- reused for five more runs, although a slight loss of activity
lyst 9c, was possible for the acetylation reaction; however, was noticed in the last of these cycles (Table 4, Entries 9–
this reaction shows a significant background rate[16] and 13), or for the synthesis of other aza-MBH products (En-
smaller differences in catalytic performance between 9c and tries 14–16). The t1/2 values assembled in Table 4 also al-
DMAP-PS were therefore measured.
lowed the effect of the resin and linker structure on the
catalyst activity to be quantified. By assuming a linear de-
pendence of the reaction rate on the catalyst concentration,
the reaction half-lives of 110 min measured for 9c and of
57 min for catalyst 4, imply that immobilization reduces the
catalyst activity by a factor of 4.
Table 3. Results of the acylation of secondary alcohols promoted
by catalyst 9c and DMAP-PS (12).[a]
Table 4. Catalytic activity of immobilized and soluble pyridine cat-
alysts in the aza-MBH reaction.
Catalyst
(mol-%)
Entry Product
t1/2 [min] Time [min] Yield [%][b]
1
2
3
4
5
6
7
8
9
15a
15a
15a
15b
15b
15c
15c
15d
15d
9c (0.1)
9c (0.5)
12 (0.5)
9c (0.5)
12 (0.5)
9c (0.05)
12 (0.1)
9c (0.1)
12 (0.1)
40Ϯ1
ca. 15[d]
123Ϯ2
60Ϯ1
270Ϯ9
135Ϯ5
101Ϯ2
96Ϯ3
330
120
625
100 (93)[c]
98
Entry
Catalyst
Product
t1/2 [min]
Time [h] Yield [%][a]
94
95 (90)[c]
90
Soluble catalysts (5 mol-% catalyst)[b]
340
1120
1020
1045
780
97 (93)[c]
99
1
2
3
4
5
6
DMAP (1)
PPY (2)
17a
17a
17a
17a
17a
17a
745Ϯ4
355Ϯ2
57Ϯ1
67Ϯ1
60Ϯ1
51Ϯ1
60
20
10
10
10
10
93
84
99
97
98
98
97 (88)[c]
92
4
7a
8b
8c
219Ϯ4
1045
[a] Reagents and conditions: alcohol (0.2 m), Ac2O (2.0 equiv.),
NEt3 (3.0 equiv.), CDCl3, room temp. [b] Determined by 1H NMR
spectroscopy. [c] Isolated yield after column chromatography. [d] A
conversion of 60% was measured after just 20 min of reaction time,
but an accurate kinetic study was not possible under the selected
conditions (see the Supporting Information).
Immobilized catalysts (10 mol-% catalyst)
7
12
9c
9c
9c
9c
9c
9c
9c
9c
9c
17a
17a
17a
17a
17a
17a
17a
17b
17c
17d
1125Ϯ100
110Ϯ7
21
12
12
12
12
20
25
16
16
16
54
93 (87)[d]
92
8
9[c]
–
–
–
–
–
–
–
–
10[c]
11[c]
12[c]
13[c]
14[e]
15[e]
16[e]
90
92
95
90
Given the excellent performance of resin 9c in acylation
reactions, we next turned our attention to the aza-Morita–
Baylis–Hillman (aza-MBH) reaction as a synthetically ver-
satile and atom-economic C–C bond-forming reaction.[6k]
The use of DMAP-PS resin catalysts for this reaction has
been tested previously by Shi et al.[6c] In this case, moderate
yields were obtained after up to 72 h of reaction time by
employing as much as 20 mol-% of catalyst.
We selected here the reaction of tosyl imines 16a–d with
methyl vinyl ketone (MVK) as benchmark, again in combi-
nation with selected homogeneous or supported pyridine
catalysts (Table 4). Using 5 mol-% of DMAP as a reference
(homogeneous) catalyst, we found that the reaction pro-
ceeds slowly with a reaction half-life of 745 min. The diami-
94 (81)[d]
90 (78)[d]
89 (63)[d,f]
1
[a] Determined by H NMR spectroscopy. [b] 16 (0.125 m), MVK
(1.2 equiv.), CDCl3. [c] Catalyst is recycled from the previous entry.
[d] Isolated yield after column chromatography. [e] The catalyst had
been already employed for the reactions in Entries 7–12. [f] 20% of
benzaldehyde (from hydrolysis of 16d) was also recovered.
Conclusions
The immobilization of 3,4-diaminopyridines on polystyr-
nopyridine catalysts 4, 7a, 8b, and 8c were significantly ene support with aid of the copper-catalyzed Huisgen reac-
Eur. J. Org. Chem. 2011, 1527–1533
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1529

H. Zipse et al.
FULL PAPER
to a solution of tosylimine 16a–d (3.75 mmol), methyl vinyl ketone
(4.5 mmol, 315 mg), and 1,3,5-trimethoxybenzene (1.0 mmol,
168 mg, internal standard) in CDCl3 (30 mL). The reaction vessel
was shaken at room temperature (480 rpm). Periodically, the agita-
tion was interrupted for about 1 min until all the resin floated on
top of the solution, thus allowing the removal of 100 μL of a solid-
free sample from the bottom of the reaction mixture by using a
syringe. The sample was diluted with CDCl3 (0.6 mL) and sub-
sequently submitted to NMR spectroscopy to determine the kinetic
information. At the end of the reaction, the heterogeneous mixture
was filtered under reduced pressure through a Büchner funnel cov-
ered by a disc of filter paper. The catalyst was washed with CHCl3
(3ϫ50 mL), collected in a dry 50 mL flask and dried under high
vacuum at 60 °C overnight. The filtrate was concentrated under
reduced pressure, and the crude material was purified by column
chromatography on silica gel (hexanes/EtOAc, 4:1) to afford the
desired MBH product, together with 2–20% of aromatic aldehyde
derived from the partial hydrolysis of the tosylimine substrates 16a–
d.
tion leads to new catalysts of high activity that can be easily
recovered. The measured reaction half-lives depend signifi-
cantly on both the nature of the pyridine catalyst and on
the length of the linker unit. In acylation reactions, the most
active combination was found to exceed the catalytic ac-
tivity of commercially available polystyrene-DMAP eight-
fold, whereas a tenfold difference was found for the aza-
MBH reaction.
Experimental Section
General: Methods and the treatment of kinetic data are described
in detail in the Supporting Information. Commercial PS-DMAP
polymer (base loading ca. 3.0 mmol/g DMAP, polystyrene
crosslinked with 2% DVB) and Merrifield’s resin (mesh: 100–200,
loading: 2.0–3.0 mmol/g Cl–, polystyrene crosslinked with 1%
DVB) were purchased from Sigma–Aldrich and dried under vac-
uum at 60 °C overnight before use.
Synthesis of Homogeneous Catalysts
Acylation (Homogeneous Catalysts): The experimental procedure
and the kinetic data treatment were carried out as described pre-
viously.[2c]
(5-Ethyl-5,5a,6,7,8,9,9a,10-octahydropyrido[3,4-b]quinoxalin-2-
ium-2-yl) Trihydroborate (6): Racemic building block 5[2b] (0.41 g,
1.90 mmol, 1.0 equiv.) was dissolved in anhydrous THF (10 mL),
and the temperature of the solution was set to –10 °C by using an
ice/NaCl bath. To this solution, a solution of BH3SMe2 (2 m in
THF, 0.95 mL, 1.9 mmol, 1.0 equiv.) was added dropwise through
a rubber septum by using a syringe within 10 min. After the ad-
dition was complete, the ice/NaCl bath was removed, and the reac-
tion mixture was warmed to room temperature for 5 min. TLC
analysis (EtOAc/NEt3/MeOH, 10:1:1; Rf = 0.90) showed complete
conversion of the starting material. The reaction solvent was re-
moved under reduced pressure, and the residual oil was purified by
filtration through a silica gel plug (EtOAc/NEt3/MeOH, 10:1:1) to
afford 6 (0.42 g, 1.82 mmol, 95 %) as a white solid; m.p. 190–
193 °C. 1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J = 6.4 Hz, 1
H, 3-H), 7.50 (s, 1 H, 1-H), 6.28 (d, J = 6.4 Hz, 1 H, 4-H), 3.61
(br. s, 1 H, N-H), 3.46–3.28 (m, 4 H, NCH2CH3, 5a-H, 9a-H),
2.90–2.00 (br. s, 3 H, BH3), 1.93 (m, 1 H), 1.81–1.68 (m, 3 H),
1.61–1.37 (m, 3 H), 1.32 (m, 1 H), 1.19 (t, J = 7.1 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 140.3, 138.9, 130.5, 129.4,
103.4, 59.1, 47.6, 43.7, 30.7, 27.3, 24.9, 19.1, 12.0 ppm. IR (solid):
Acylation (Heterogeneous Catalysts) and Catalyst Recovery: Two
stock solutions (in anhydrous CDCl3) were prepared in dry, cal-
ibrated 10 mL flasks: stock solution A: anhydride (1.2 m); stock
solution B: alcohol (0.6 m) and Et3N (1.8 m). Under N2, the two
solutions were mixed in a dry 50 mL flask, and anhydrous CDCl3
(10 mL) was added to adjust the concentration of the reagents to
the same values used in the case of the homogeneous catalysts. The
appropriate amount of resin was subsequently added, and the flask
was closed with a rubber septum. The reaction vessel was shaken
at room temperature at 480 rpm. Periodically, the agitation was in-
terrupted for about 1 min until all the resin floated on top of the
solution, thus allowing removal of 100 μL of a solid-free sample
from the bottom of the reaction mixture by using a syringe. The
sample was placed in a vial; 80 μL of this solution was removed by
using a calibrated pipette, placed in a dry NMR tube and diluted
with anhydrous CDCl3 (0.8 mL). The sample was subsequently
submitted to NMR spectroscopy to obtain the kinetic data, which
were treated as described previously.[2c] At the end of the reaction,
the heterogeneous mixture was filtered under reduced pressure
through a Büchner funnel covered by a disc of filter paper. The
catalyst was washed with CH2Cl2 (50 mL), CH2Cl2/MeOH (1:1;
50 mL), and finally with CH2Cl2 (100 mL). It was collected in a
dry 50 mL flask and dried under high vacuum at 60 °C overnight.
The filtrate was placed in an extraction funnel and washed with
saturated aqueous NH4Cl (30 mL) and with saturated NaHCO3
(30 mL). The organic phase was dried with MgSO4, filtered, and
concentrated under reduced pressure. The crude material was fil-
tered through a plug of silica gel (hexanes/EtOAc, 10:1) to afford
the desired ester with high yields and purity.
ν = 3228, 2935, 2294, 1686, 1611, 1532, 1173, 1096 cm–1. HRMS
˜
(ESI–): calcd. for [C13H22BN3 + HCOO]– 276.1889; found
276.1893.
5-Ethyl-10-hexyl-5,5a,6,7,8,9,9a,10-octahydropyrido[3,4-b]quin-
oxaline (7a): Compound 6 (0.82 g, 3.55 mmol, 1.0 equiv.) was dis-
solved in anhydrous THF (15 mL). Butyllithium (2.5 m in hexanes,
1.7 mL, 4.25 mmol, 1.2 equiv.) was added dropwise to this solution
through a rubber septum at –78 °C. After 15 min, hexyl bromide
(0.75 mL, 5.32 mmol, 1.5 equiv.) was added, and the reaction mix-
ture was warmed to room temperature overnight. The reaction was
quenched by adding EtOH (1 mL), and the solvent was sub-
sequently removed under reduced pressure. The raw material was
taken up in MeOH (10 mL), and concentrated HCl (0.32 mL,
1.1 equiv.) was added dropwise at 0 °C. The reaction mixture was
stirred at this temperature for 5 min, then the solvent was removed
under reduced pressure, and the crude material was taken up in
CH2Cl2 (20 mL) and saturated aqueous K2CO3 (10 mL). The aque-
ous layer was washed with CH2Cl2 (5 mL), and the combined or-
ganic layers were dried with Na2SO4, filtered, and concentrated
under reduced pressure to yield an oil, which was purified by col-
umn chromatography on silica gel (EtOAc/NEt3/MeOH, 20:2:1) to
Morita–Baylis–Hillman Reaction (Homogeneous Catalysts): Two
stock solutions were prepared in dry calibrated 5 mL flasks: stock
solution A: tosylimine (0.15 m), methyl vinyl ketone (0.18 m) and
1,3,5-trimethoxybenzene (0.1 m) (internal standard) in CDCl3;
stock solution B: catalyst (0.0375 m) in CDCl3. Under N2, stock
solution A (0.5 mL) and stock solution B (0.1 mL) were injected
into an NMR tube, which was sealed by melting its opening with
a flame. The sample was periodically submitted to NMR analysis
to collect the kinetic information.
Morita–Baylis–Hillman Reaction (Heterogeneous Catalysts) and
Catalyst Recovery: Supported catalyst 9c (0.375 mmol) was added
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Immobilized DMAP Derivatives
afford 7a (0.64 g, 2.12 mmol, 60%) as a pale-yellow oil together
with unprotected starting material 6 (0.30 g, 1.38 mmol, 39%). H
NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 5.5 Hz, 1 H, 3-H), 7.70
4.58 mmol, 50%) as a pale-yellow oil together with unprotected
starting material 6 (0.90 g, 3.89 mmol, 43%). 1H NMR (300 MHz,
CDCl3): δ = 7.78 (d, J = 5.5 Hz, 1 H, 3-H), 7.72 (s, 1 H, 1-H), 6.38
1
(s, 1 H, 1-H), 6.37 (d, J = 5.5 Hz, 1 H, 4-H), 3.54–3.29 (m, 3 H, (d, J = 5.5 Hz, 1 H, 4-H), 3.48 (m, 3 H, NCH2CH3, 5a-H), 3.25
NCH2CH3, 5a-H), 3.22 [m, 2 H, NCH2(C5H11)], 3.04 (m, 1 H, 9a- (m, 3 H, NCH2CH2CH2CϵCSiMe3, 9a-H), 2.30 (t, J = 6.8 Hz, 2
H), 1.86 (m, 2 H), 1.59 (m, 6 H), 1.33 (m, 8 H), 1.16 (t, J = 7.1 Hz,
H, NCH2CH2CH2CϵCSiMe3), 1.82 (m, 4 H), 1.59 (app. d, 4 H),
3 H, NCH2CH3), 0.90 [m, 3 H, N(C5H10)CH3] ppm. 13C NMR 1.40 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H, CH3), 0.18 [s, 9 H, Si-
(75 MHz, CDCl3): δ = 140.5, 140.1, 132.0, 130.9, 104.5, 55.4, 54.5,
(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 140.7, 140.3, 131.9,
47.2, 41.1, 31.7, 28.0, 27.0, 26.9, 25.5, 22.7, 22.3, 22.2, 14.0,
130.6, 106.4, 104.6, 85.4, 55.2, 54.9, 45.9, 41.1, 28.0, 26.8, 24.2,
11.5 ppm. IR (film): ν = 2928, 2855, 1580, 1514, 1354, 1266,
22.3, 22.2, 17.4, 11.5, 0.14 ppm. IR (film): ν = 2935, 2857, 2173,
˜
˜
1074 cm–1. HRMS (ESI+): calcd. for [C19H31N3 + H]+ 302.2591; 1580, 1515, 1355, 1248 cm–1. HRMS (ESI+): calcd. for [C21H33N3Si
found 302.2590.
+ H]+ 356.2517; found 356.2514.
5-Ethyl-10-(prop-2-ynyl)-5,5a,6,7,8,9,9a,10-octahydropyrido[3,4-b]-
quinoxaline (7b): Compound 6 (1.76 g, 7.61 mmol, 1.0 equiv.) was
dissolved in anhydrous THF (40 mL), and butyllithium (2.5 m in
hexanes, 3.35 mL, 8.37 mmol, 1.1 equiv.) was added dropwise to
this solution through a rubber septum at –78 °C. After 15 min, pro-
pargyl bromide (80 wt.-% in toluene, 1.0 mL, 9.13 mmol,
1.2 equiv.) was added, and the reaction mixture was warmed to
room temperature overnight. The reaction was quenched by adding
EtOH (3 mL), and the solvent was subsequently removed under
reduced pressure. The raw material was taken up in MeOH
(20 mL), and concentrated HCl (0.70 mL, 1.1 equiv.) was added
dropwise to this solution at 0 °C. The reaction mixture was stirred
at this temperature for 5 min, then the solvent was removed under
reduced pressure and the crude material was taken up in CH2Cl2
(40 mL) and saturated K2CO3 (20 mL). The aqueous layer was
washed with CH2Cl2 (10 mL), and the combined organic layers
were dried with Na2SO4, filtered, and concentrated under reduced
pressure to yield an oil, which was purified by column chromatog-
raphy on silica gel (EtOAc/NEt3/MeOH, 20:2:1) to afford 7b
(1.58 g, 6.19 mmol, 80%) as a pale-yellow solid; m.p. 162–164 °C.
1H NMR (300 MHz, CDCl3): δ = 7.85 (m, 2 H, 1-H, 3-H), 6.36
(d, J = 5.5 Hz, 1 H, 4-H), 4.17 (dd, J = 18.3, 2.3 Hz, 1 H,
NCH2CϵCH), 3.92 (dd, J = 18.3, 2.3 Hz, 1 H, NCH2CϵCH),
3.52–3.13 (m, 4 H, NCH2CH3, 5a-H, 9a-H), 2.20 (s, 1 H,
NCH2CϵCH), 2.01 (m, 1 H), 1.85–1.57 (m, 4 H), 1.54–1.23 (m, 3
H), 1.17 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 142.0, 141.0, 133.0, 129.5, 104.0, 78.5, 72.4, 57.6, 52.6,
5-Ethyl-10-(pent-4-ynyl)-5,5a,6,7,8,9,9a,10-octahydropyrido[3,4-b]-
quinoxaline (7c): Compound 7cЈ (1.50 g, 4.22 mmol, 1.0 equiv.) was
dissolved in MeOH (15 mL), and K2CO3 (0.87 g, 6.33 mmol,
1.5 equiv.) was added. The reaction mixture was stirred at room
temperature overnight, then the solvent was removed under re-
duced pressure, and the crude material was partitioned between
water (100 mL) and CH2Cl2 (200 mL). The aqueous layer was
washed with CH2Cl2 (50 mL), and the combined organic layers
were dried with Na2SO4, filtered, and concentrated under reduced
pressure to afford the title compound as a greenish oil (1.15 g,
1
4.06 mmol, 96%). H NMR (300 MHz, CDCl3): δ = 7.73 (app. d,
2 H, 3-H, 1-H), 6.37 (d, J = 5.4 Hz, 1 H, 4-H), 3.47 (m, 3 H,
NCH2CH3, 5a-H), 3.22 (m, 3 H, NCH2CH2CH2CϵCH, 9a-H),
2.24 (t, J = 10.9 Hz, 2 H, NCH2CH2CH2CϵCH), 2.00 (s, 1 H,
NCH2CH2CH2CϵCH), 1.83 (m, 4 H), 1.58 (m, 4 H), 1.39 (m, 2 H),
1.15 (t, J = 7.1Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 140.8, 140.3, 131.9, 130.6, 104.6, 83.6, 69.0, 55.2, 54.9, 46.3, 40.9,
28.0, 26.7, 24.4, 22.4, 22.0, 16.0, 11.4 ppm. IR (film): ν = 3289,
˜
2932, 2856, 2116, 1579, 1514, 1355, 1266, 1065 cm–1. HRMS
(ESI+): calcd. for [C18H25N3 + H]+ 284.2121; found 284.2121.
10-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-ethyl-5,5a,6,7,
8,9,9a,10-octahydropyrido[3,4-b]quinoxaline (8b): Compound 7b
(0.26 g, 1.0 mmol, 1.0 equiv.) was dissolved in anhydrous THF
(10 mL), and the solution was degassed by purging with N2 for
5 min. Benzyl azide (0.16 g, 1.2 mmol, 1.2 equiv.) was added, fol-
lowed by a catalytic amount of CuBr and N,N-diisopropylethylam-
ine (DIPEA; 0.34 mL, 2.0 mmol, 2.0 equiv.). The reaction mixture
was stirred at room temperature for 2 h, then the solution was par-
titioned between CH2Cl2 (20 mL) and saturated K2CO3 (10 mL).
The aqueous layer was washed with CH2Cl2 (10 mL), and the com-
bined organic layers were dried with Na2SO4, filtered, and concen-
trated under reduced pressure to yield an oil that was purified by
column chromatography on silica gel (EtOAc/NEt3/MeOH, 20:2:1)
42.1, 35.2, 28.0, 27.2, 23.5, 20.9, 11.7 ppm. IR (solid): ν = 3096,
˜
2932, 2095, 1587, 1524, 1440, 1274, 1240, 1184, 1076 cm–1. HRMS
(ESI+): calcd. for [C16H21N3 + H]+ 256.1808; found 256.1806.
5-Ethyl-10-[5-(trimethylsilyl)pent-4-ynyl]-5,5a,6,7,8,9,9a,10-octa-
hydropyrido[3,4-b]quinoxaline (7cЈ, Precursor of 7c): Compound 6
(2.10 g, 9.1 mmol, 1.0 equiv.) was dissolved in anhydrous THF
(40 mL), and butyllithium (2.5 m in hexanes, 4.40 mL, 10.92 mmol,
1.2 equiv.) was added dropwise to this solution through a rubber
septum at –78 °C. The reaction mixture was stirred at –78 °C for
15 min and then warmed to 0 °C in an ice bath. After 15 min, (5-
iodo-1-pentynyl)trimethylsilane (11.4 mmol, 1.25 equiv.) was added
dropwise, and the reaction mixture was warmed to room tempera-
ture overnight. The reaction was quenched by adding EtOH
(5 mL), and the solvent was subsequently removed under reduced
pressure. The raw material was taken up in MeOH (20 mL), and
concentrated HCl (0.85 mL, 1.1 equiv.) was added dropwise to this
solution at 0 °C. The reaction mixture was stirred at this tempera-
ture for 5 min, then the solvent was removed under reduced pres-
sure, and the crude material was taken up in CH2Cl2 (50 mL) and
saturated K2CO3 (20 mL). The aqueous layer was washed with
CH2Cl2 (10 mL), and the combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure to yield
an oil, which was purified by column chromatography on silica
1
to afford 8b (350 mg, 0.90 mmol, 90%) as a white foam. H NMR
(400 MHz, CDCl3): δ = 7.73 (s, 2 H, 3-H, 1-H), 7.34 (s, 1 H, tri-
azole-H), 7.33–7.22 (m, 2 H), 7.24–7.07 (m, 3 H), 6.32 (d, J =
5.5 Hz, 1 H, 4-H), 5.43 (d, J = 7.5 Hz, 1 H, CH2Ph), 5.39 (d, J =
7.5 Hz, 1 H, CH2Ph), 4.65 (d, J = 16.7 Hz, 1 H, NCH2-triazole),
4.43 (d, J = 16.7 Hz, 1 H, NCH2-triazole), 3.44–3.09 (m, 4 H,
NCH2CH3, 5a-H, 9a-H), 2.08 (s, 1 H), 1.77 (m, 1 H), 1.65–1.41
(m, 4 H), 1.40–1.27 (m, 2 H), 1.11 (t, J = 6.9 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 144.6, 141.1, 140.4, 134.8, 131.7,
130.6, 129.0, 128.6, 127.8, 122.2, 104.3, 56.3, 54.0, 53.7, 42.3, 41.7,
27.7, 27.2, 22.9, 21.4, 11.6 ppm. IR (solid): ν = 2931, 2856, 1361,
˜
1267, 1200, 1047 cm–1. HRMS (ESI+): calcd. for [C23H28N6 + H]+
389.2448; found 389.2442.
10-[3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propyl]-5-ethyl-5,5a,6,7,
8,9,9a,10-octahydropyrido[3,4-b]quinoxaline (8c): Compound 7c
(0.38 g, 1.3 mmol, 1.0 equiv.) was dissolved in anhydrous THF
gel (EtOAc/NEt3/MeOH, 20:2:1; Rf = 0.90) to afford 7cЈ (0.90 g, (15 mL), and the solution was degassed by purging with N2 for
Eur. J. Org. Chem. 2011, 1527–1533
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1531

H. Zipse et al.
FULL PAPER
5 min. Benzyl azide (0.34 g, 2.6 mmol, 2.0 equiv.) was added, fol-
lowed by a catalytic amount of CuBr and DIPEA (0.44 mL,
2.6 mmol, 2.0 equiv.). The reaction mixture was stirred at room
temperature for 2 h, then the solution was partitioned between
CH2Cl2 (25 mL) and saturated K2CO3 (10 mL); the aqueous layer
was washed with CH2Cl2 (10 mL), and the combined organic layers
were dried with Na2SO4, filtered, and concentrated under reduced
pressure to yield an oil that was purified by column chromatog-
raphy on silica gel (EtOAc/NEt3/MeOH, 20:2:1) to afford 8c as a
pale-yellow foam (0.35 g, 0.85 mmol, 65%). 1H NMR (300 MHz,
CDCl3): δ = 7.75 (d, J = 5.4 Hz, 1 H, 3-H), 7.63 (s, 1 H, 1-H), 7.36
(m, 3 H), 7.26 (m, 3 H), 6.37 (d, J = 5.4 Hz, 1 H, 4-H), 5.49 (s, 2
H, CH2Ph), 3.53–3.34 (m, 3 H, NCH2CH3, 5a-H), 3.29–3.17 (m, 2
H, 9-NCH2R), 3.17–3.04 (m, 1 H, 9a-H), 2.74 (t, J = 7.7 Hz, 2 H,
NCH2CH2CH2-triazole), 1.95 (m, 3 H), 1.73 (m, 1 H), 1.55 (app.
s, 4 H), 1.36 (app. s, 2 H), 1.14 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 147.9, 140.8, 140.1, 134.9, 131.7,
130.7, 129.1, 128.6, 128.0, 120.7, 104.6, 55.1, 54.8, 54.0, 46.6, 41.0,
loading of 1.30 mmol/g catalyst and an efficiency of 87% for the
“click reaction”.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, kinetic data and graphics, NMR and IR
1
frequencies, copies of H and 13C NMR spectra, supporting refer-
ences.
Acknowledgments
Financial support for this project by the Deutsche Forschungs-
gemeinschaft through the focus program SPP 1179 “organocata-
lysis” is gratefully acknowledged.
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˜
2854, 1579, 1514, 1455, 1354, 1266, 1214, 1048 cm–1. HRMS
(ESI+): calcd. for [C25H32N6 + H]+ 417.2761; found 417.2760.
Synthesis of Polystyrene-Supported Catalysts
Supported Catalyst 9b: Polystyrene-azide (PS-N3; 0.80 g, 2.1 mmol
–
N3 , 1.0 equiv.) was suspended in an anhydrous THF/DMF mix-
ture (1:1; 20 mL), and the suspension was degassed by purging with
N2 for 5 min. Compound 7b (0.70 g, 2.7 mmol, 1.3 equiv.) was
added, followed by a catalytic amount (10 mol-%) of CuBr-
(PPh3)3 (0.19 g, 0.2 mmol, 0.1 equiv.) and DIPEA (0.72 mL,
4.2 mmol, 2.0 equiv.). With the mixture still under N2, the reaction
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water/DMF (1:1; 80 mL), water (80 mL), water/MeOH (1:1;
80 mL), MeOH (80 mL), THF/MeOH (1:1; 80 mL), and finally
THF (150 mL). It was dried under vacuum at 60 °C for 24 h to
give a dark-red resin (9b; 1.30 g, 96%). The FTIR spectrum of
the solid showed the disappearance of the azide stretching band at
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2093 cm–1 and the presence of new absorption bands at ν = 1532,
˜
1264, 1197, 1183 cm–1, belonging to the backbone of the supported
catalyst. Elemental analysis: found C 78.24, H 7.53, N 12.26. On
the basis of the nitrogen content it was possible to calculate a load-
ing of 1.46 mmol/g catalyst and an efficiency of 93% for the “click
reaction”.
Supported Catalyst 9c: Polystyrene-azide (PS-N3; 0.65 g, 1.7 mmol
–
N3 , 1.0 equiv.) was suspended in an anhydrous mixture of THF/
DMF (1:1, 12 mL), and the suspension was degassed by purging
with N2 for 5 min. Compound 7c (0.72 g, 2.5 mmol, 1.5 equiv.) was
added, followed by a catalytic amount (10 mol-%) of CuBr(PPh3)3
(0.16 g, 0.17 mmol, 0.1 equiv.) and DIPEA (0.73 mL, 4.25 mmol,
2.5 equiv.). With the mixture still under N2, the reaction vessel was
rotated in a water bath at 50 °C for 2 d, during which time the
color of the reaction mixture turned to brown and then black. The
resin was filtered and washed with DMF (80 mL), water/DMF (1:1;
80 mL), water (80 mL), water/MeOH (1:1; 80 mL), MeOH
(80 mL), THF/MeOH (1:1; 80 mL), and finally THF (150 mL). It
was dried under vacuum at 60 °C for 24 h to give a brown resin
(9c; 1100 g, 97%). The FTIR spectrum of the solid showed the
disappearance of the azide stretching band at ν = 2093 cm–1 and
˜
the presence of new absorption bands at ν = 1668, 1580, 1513,
˜
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basis of the elemental analysis it was possible to calculate a catalyst
1532
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1527–1533

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Received: November 10, 2010
Published Online: January 27, 2011
Eur. J. Org. Chem. 2011, 1527–1533
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1533