Polymer-supported hantzsch 1,4-dihydropyridine ester: An efficient biomimetic hydrogen source

Article abstract of DOI:10.1002/adsc.200700344

An efficient synthesis of a polymer-supported Hantzsch 1,4-dihydropyridine ester has been developed and its use in a variety of reduction reactions was studied using α,β-unsaturated aldehydes, imines and an activated benzoquinone as substrates. Reductive amination using the polymer-supported Hantzsch 1,4-dihydropyridine ester and a catalytic amount of 1.5 M HCl was found to proceed rapidly and with good yields.

Full text of DOI:10.1002/adsc.200700344

COMMUNICATIONS
DOI: 10.1002/adsc.200700344
Polymer-Supported Hantzsch1,4-Dihydropyridine Ester: An
Efficient Biomimetic Hydrogen Source
Rongjun He,a Patrick H. Toy,b,* and Yulin Lama,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Fax : (+65)-6779-1691; e-mail: chmlamyl@nus.edu.sg
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, Peopleꢀs Republic of China
b
Fax : (+852)-2857-1586; e-mail: phtoy@hku.hk
Received: July 13, 2007; Revised: October 22, 2007; Published online: December 14, 2007
Supporting information for thisarticle isavailable on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient synthesis of a polymer-sup-
ported Hantzsch 1,4-dihydropyridine ester has been
developed and itsuse in a variety of reduction reac-
tions was studied using a,b-unsaturated aldehydes,
iminesand an activated benzoquinone assubstrates.
Reductive amination using the polymer-supported
Hantzsch 1,4-dihydropyridine ester and a catalytic
amount of 1.5M HCl wasfound to proceed rapidly
and with good yields.
portant transformations both in biological organisms
and industrial processes. Whilst chemical hydrogena-
tion reactionshave generally relied on metal cata-
lysts[3] or metal hydrides, recent studies have shown
that metal-free transfer hydrogenation reactions can
be accomplished in what can be considered a biomim-
etic strategy using the combination of an organocata-
lyst and a dihydropyridine (Hantzsch) ester.[4,5] In
Keywords: biomimetic hydrogen source; 1,4-dihy-
dropyridine; Hantzsch ester; polymer-supported re-
ducing agent; reduction; reductive amination
Advances in the use of polymers in organic synthe-
sis[1] have led to the development of improved tech- such metal-free reactions, the Hantzsch ester can
nologiesfor the preparation of chemical librarie.s In
serve as a surrogate for NADH or FADH2 and the re-
particular, the use of polymer-supported reagents[2] in actionsare attractive compared to metal-based reduc-
what is commonly referred to as polymer-assisted or- tionsbecaues complete removal of metal impurities
ganic synthesis is an attractive technique that com- from reaction products is often difficult but necessary,
bines the advantages of solid-phase chemistry with especially in the production of pharmaceutical inter-
[6]
those of solution-phase synthesis. In this technique, a mediatesdue to toxicity isues.
polymer-bound reagent is added to a substrate in so-
In order to facilitate reduction processes, several
lution to effect a chemical transformation. In addition polymer-supported reducing agents have been devel-
to the reagent, undesired reagent by-products formed oped, many of which are immobilized on an insoluble
are bound to the polymeric-support, thus allowing the polymeric matrix.[7] The primary advantage of using
product to be purified by simple filtration. Further- such polymer supports in this context lies in the insol-
more, since both the substrate and product are in so- ubility of such supported reagents, which simplifies
lution during the reaction, conventional solution- separation of the product from the spent reagent.
phase analytical techniques, such as thin-layer chro- However, the heterogeneousnature of such reactions
matography, can be employed for reaction monitor- also imposes various limitations,[8] and in recent years
ing. The versatility of this methodology facilitates the soluble polymer supports[8,9] have been increasing ex-
process of library synthesis and has been the main ploited in an effort to combine the useful features of
stimulus for the recent growth of interest in polymer- both heterogeneous and homogeneous reaction sys-
supported reagents and catalysts.
Hydrogenationsof double-bond containing com-
poundssuch ascarbonyl,s alkenesand iminesare im-
tems. To date various soluble polymer-supported re-
[10]
agentsincluding phopshine,s
Swern oxidants,[11]
a
borane complex,[7a,12] and nitroxyl radicals,[13] among
54
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 54 – 60

Polymer-Supported Hantzsch 1,4-Dihydropyridine Ester
COMMUNICATIONS
others, have been developed. However to our knowl- key intermediate 5 in 52% yield. It isworth noting
edge, no report of any type of polymer-supported that prolonged reaction heating resulted in lower
Hantzsch ester has appeared in the literature. To ad- yield of 5 due to the formation of by-products.
dress the need for a metal- and purification-free (mix,
With compound 5 in hand, we carried out a con-
filter and evaporate) reduction process, we herein densation of it with formaldehyde and methyl 3-
present the synthesis of soluble polymer-supported amino-2-butenoate which afforded 6 in 63% yield.
Hanztsch 1,4-dihydropyridine ester 1 (Scheme 1) and Subsequent polymerization of 6 with styrene using
its use in the reduction of various substrate types.
The synthesis of 1 began with the conversion of 4- odsafforded polymer 1. However, analysis of 1 pro-
vinylbenzyl chloride (2) into 4-vinylbenzyl alcohol duced by thismethod uisng
1H NMR showed that
standard AIBN-initiated radical polymerization meth-
(3). Previously this has been accomplished by reaction 40% of the dihydropyridine groupshad been convert-
of 2 with acetate ion followed by saponification.[14] ed to pyridine moieties[n :n2 wasderived by either
1
However, in thisproject we osught a new and direct
procedure for the conversion of 2 into 3, and exam- CO2CH3 of dihydropyridine (d=3.65 ppm) with the
ined varioushydrolyisreaction condition.s Unlike CH3 in CO2CH3 of pyridine (d=3.87 ppm) or by com-
comparing the integration ratio of the CH3 in
the hydrolysis of benzyl chloride, which proceeded paring the integration ratiosof H (d=3.35 ppm) and
1
very efficiently under basic conditions, the hydrolysis H2 (d=8.80 ppm) (Scheme 1], which do not have re-
of 2 wasmore complicated and readily afforded the
by-product di(4-vinylbenzyl) ether (4). Hence, various peared to be heat-sensitive and a long reaction time
reaction conditionswere studied (Table 1) and it was at elevated temperature isgenerally required for radi-
ducing ability. Since the dihydropyridine unit of 6 ap-
found that 3 could be obtained in 98% yield when 2 cal polymerization, we decided to copolymerize 5
wastreated with NaOH (0.1 equiv.) in H 2O and with styrene to obtain polymer-supported keto ester
Bu4NBr (1 equiv.) as phase-transfer catalyst (Table 1, 7. Polymer 7 wasamenable to KBr FTIR (i.e., the ap-
entry 8). Alcohol 3 wasthen reacted with methyl ace-
toacetate in the presence of DBU for 2 h to afford and H NMR analysis. Using such techniques, the sty-
pearance of C=O signals at 1744 cmÀ1 and 1719 cmÀ1)
1
Scheme 1. Synthesis of polymeric reagent 1.
Adv. Synth. Catal. 2008, 350, 54 – 60
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
55

Rongjun He et al.
COMMUNICATIONS
Table 1. Synthesis of 3.
[a]
Entry Reagentsand Solvent
Reaction Conditions
Result
1
2
NaOH (1 equiv.), Bu4NBr (1 equiv.), H2O
NaOH (1 equiv.), Bu4NBr (1 equiv.), H2O
r.t., 3 h
3: trace amount
3: 24-40%; 4: major product
958C, 1108C or 1308C, 10 min
to 1 h
3
4
NaOH (2 equivs.), Bu4NI (1 equiv.), KI
(0.1 equiv.), H2O
NaOH (2 equivs.), Bu4NI (1 equiv.), KI
(0.1 equiv.), H2O
r.t., 2 h
3: trace amount
658C, 5 h
3: trace amount; 4: major
product
5
6
7
8
NaOH (2 equivs.), H2O, EtOH
H2O
NaOH (0.1 equiv.), Bu4NBr (1 equiv.), H2O
NaOH (0.1 equiv.), Bu4NBr (1 equiv.), H2O
r.t., 24 h
3: 19%, 4: 81%
3: 70%
3: 58%; 4: trace amount
3: 98%; 4: trace amount
reflux under N2, 3 h
1258C, 10 min
1258C, 20 min
[a]
Yield of purified product.
rene/5 (m/n) ratio of 7 wasdetermined to be approxi-
Reduction of a,b-unsaturated aldehydes: List and
mately 5:1, which corresponds to a loading level of co-workers[5a] recently reported the reduction of a,b-
approximately 1.6 mmolgÀ1. Attempts to synthesize unsaturated aldehydes using a Hantzsch ester with di-
polymer 1 by refluxing 7 with formaldehyde and benzylammonium trifluoroacetate (8) asa catalyts.
methyl 3-amino-2-butenoate resulted again in pre- Therefore, with polymer 1 in hand, we proceeded to
dominantly the pyridine formation. We considered examine it in such reactions using trans-4-nitrocinnam-
the mechanism proposed for the reduction of dihydro- aldehyde (9a) in THF (Scheme 2). Using GC to moni-
pyridines[15] and figured that the presence of water
might possibly prevent pyridine formation. Further-
more, in order to shorten the reaction time, we turned
to microwave irradiation. To our delight, after much
experimentation (Table 2), we found that condensa-
tion with 20% H2O in THF asthe oslvent afforded
significantly better results with the amount of pyri-
dine by-product formed wasdramatically reduced
(Entry 5, Table 2). Further addition of H2O resulted
in the precipitation of polymer 7 from the reaction
Scheme 2. Reduction of trans-4-nitrocinnamaldehyde (9a)
with polymer 1.
mixture and the reaction ceased under such condi-
tions.
tor the reaction, it wasfound that the conversion to 3-
(4-nitrophenyl)propionaldehyde (10a) (90%) was
comparable to the reported yield obtained via solu-
tion-phase reduction (94%),[5a] but with 1 allowed for
Table 2. Synthesis of polymer 1.
much easier product isolation. However it should be
Entry Solvent
Condition
Result
noted that with 1, the reaction required 24 h to reach
completion versus 5–6 h for the solution-phase reduc-
tion. Thus, in order to optimize the reaction using 1,
we screened various solvents and found it to be de-
pendent on both solvent and concentration (Table 3).
Amongst the solvents screened, CH2Cl2 wasthe bets
solvent as the reaction was completed within 12 h.
Furthermore, when the concentration of 1 wasin-
creased to 0.2M (Entry 8, Table 3), the reaction was
completed within 4 h.
We next explored the use of 1 in the reduction of a
variety of a,b-unsaturated aldehydes (Table 4). Five
substrates were tested and the results obtained
showed that, in general, both aromatic and aliphatic
substrates could be reduced to the corresponding sa-
turated products in good yields. These results together
1
2
3
4
5
6
7
8
THF
mw, 1008C, n /
20 min
mw, 1008C, n1/
20 min
C
THF/H2O (1
drop)
THF:H2O=1:0.05 mw, 1008C, n1/
20 min
THF:H2O=1:0.1 mw, 1008C, n1/
20 min
THF:H2O=1:0.2 mw, 1008C, n1/
20 min
THF:H2O=1:0.2 mw, 1008C, n1/
10 min
THF:H2O=1:0.2 mw, 1208C, n1/
5 min tracesof 7
THF:H2O=1:0.25 mw, 1008C, No reaction. Pre-
20 min cipitation of 7
tracesof 7
56
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 54 – 60

Polymer-Supported Hantzsch 1,4-Dihydropyridine Ester
COMMUNICATIONS
reported catalysts,[17] we decided to search for a more
efficient procedure for thisreaction. Incidentally, we
discovered that reductive amination of benzaldehyde
with aniline in the presence of a catalytic amount of
1.5M HCl and 1 (1.5 equivs.) was complete within
5 min and 11a wasobtained in 90% yield. Encour-
aged by thisresult, we examined reductive amination
of variouscombinationsof aryl aldehydesand anilines
using the same reaction conditions and obtained ex-
cellent yield in all cases (Table 5).
Table 3. Solvent screening for reduction of a,b-unsaturated
aldehydes.
Entry Solvent Concentration of Time % Conversion[b]
polymer 1[a]
1
2
3
4
5
6
7
8
THF
THF
CH2Cl2 0.05M
CHCl3
DMF
Toluene 0.05M
CH2Cl2 0.1M
CH2Cl2 0.2M
0.05M
0.05M
24 h 90%
12 h 52%
12 h 100%
12 h 81%
12 h 14%
12 h 82%
0.05M
0.05M
Benzoquinone aromatization: In order to identify
additional applicationsof 1, we examined itsues in
7 h
4 h
100%
100%
[a]
Ratio of trans-4-nitrocinnamaldehyde to polymer 1 is
1:1.5.
Determined by GC (Agilent 6890 series GC system).
Table 5. Reductive amination of aldehydes.
[b]
Entry Aldehyde
Amine
Product
Yield[a]
99%
Table 4. Reduction of a,b-unsaturated aldehydes using 1.
1
Entry Substrate
Product
Yield[a]
1
90%
2
3
87%
90%
2
87%
85%
3
4
82%
(24 h)[b]
4
5
6
91%
99%
97%
63% (4 h);
93% (20 h)
5
[a]
Yield of purified product.
[b]
Yield determined by GC (Shimadzu GC-14A gaschro-
matograph) because of difficulty of product isolation.
Decane was used as the internal standard.
with the product purification by filtration work-up
makespolymer 1 an attractive reagent for the reduc-
tion of a,b-unsaturated aldehydes.
7
8
99%
96%
Reductive amination of aldehydes: Reductive ami-
nation reactions with Hantzsch esters has been previ-
ously studied[15] and various catalyst, such as Bronsted
2+ [16c]
acids,[16a–b] Lewisacids[Mg
,
SiO2,[16d] Al2O3,[16d]
Sc
(OTf)3[16e–f]], and thiourea[16g] have been used in this
A
reaction. Generally, in the presence of a catalyst,
these reactions require a few hours to a few days to
go to completion. To examine the utility of 1 in reduc-
tive amination reactions, we treated benzaldehyde
and aniline with 1 (1.5 equivs.) and catalyst 8 (5
mol%) at room temperature for 3 h and obtained
benzylphenylamine (11a) in 27% yield. Since this
yield waslower than what wasobtained uisng other
9
88%
[a]
Yield of purified product.
Adv. Synth. Catal. 2008, 350, 54 – 60
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
57

Rongjun He et al.
COMMUNICATIONS
(EtOAc:hexane=1:5) to give 3 asa colorlessoil; yield:
1.310 g (98%). 1H NMR (CDCl3): d=7.28–7.15 (m, ArH,
4H), 6.65–6.56 (m, CH=CH2, 1H), 5.67–5.61 (d, J=17.4 Hz,
CH=CH2, 1H), 5.16–5.12 (d, J=10.8 Hz, CH=CH2, 1H),
4.48 (s, CH2, 2H), 2.47 (s, OH, 1H); 13C NMR (CDCl3): d=
140.4, 136.8, 136.4, 127.1, 126.2, 113.7, 64.7; MS (EI): m/z=
133.9 (M+); exact mass: calcd. for C9H10O: m/z=134.0732;
found: 134.0732.
the aromatization of 2,3-dichloro-5,6-dicyano-p-ben-
zoquinone (DDQ, 12).[18] Gratifyingly we found that
the reaction wascomplete within 5 min at room tem-
perature. No catalyst was required and product 13
was obtained in essentially quantitative yield [Eq.
(1)].
Synthesis of 4-Vinylbenzyl Acetoacetate (5)
To methyl acetoacetate (1.1 mL, 10.188 mmol) and DBU
(0.385 mL, 2.547 mmol) in toluene (30 mL) wasadded
(1.1393 g, 8.49 mmol) and the mixture wasrefluxed at
3
1258C for 1 h. Thereafter another portion of methyl aceto-
acetate (1.1 mL, 10.188 mmol) wasadded, and the mixture
In conclusion, we have developed a new and direct wasfurther refluxed for 1 h and then concentrated and puri-
fied by column chromatography (EtOAc:hexane=1:5) to
give 5 asa colorlessoil; yield: 0.963 g (52%).
synthesis of alcohol 3 and used it to prepare the first
polymer-supported Hanztsch 1,4-dihydropyridine
ester, 1. The utility of 1 wasdemonstrated by itseffec-
tiveness in the reduction of a,b-unsaturated alde-
hydes, imines and an activated-benzoquinone, with
high yieldsand ismple work-up. Effortsare currently
underway to prepare analogousreagentsthat contain
catalytic moitiesin addition to the 1,4-dihydropyri-
dine ester groups.
1H NMR
(CDCl3): d=7.42–7.30 (m, ArH, 4H), 6.75–6.66 (m, CH=
CH2, 1H), 5.79–5.73 (d, J=17.4 Hz, CH=CH2, 1H), 5.28–
5.25 (d, J=10.8 Hz, CH=CH2, 1H), 5.16 (s, ArCH2, 2H),
3.49 (s, COCH2CO, 2H), 2.24 (s, CH3, 3H); 13C NMR
(CDCl3): d=200.2, 166.8, 137.8, 136.2, 134.7, 128.6, 126.4,
114.4, 66.8, 50.0, 30.0; MS (EI): m/z=218.0 (M+); exact
mass: calcd. for C13H14O3: m/z=218.0943; found: 218.0946.
Synthesis of Monomer 6
Experimental Section
To compound 5 (0.8548 g, 3.917 mmol) in THF (20 mL) was
added methyl 3-aminocrotonate (0.4548 g, 3.917 mmol) and
HCHO (37% solution, 0.108 mL, 3.917 mmol). The mixture
wasrefluxed for 3 h then concentrated and purified by
column chromatography (EtOAc:hexane=1:3) to give 6 as
All chemical reagentswere obtained from Aldrich, Merck,
Lancaster or Fluka and used without further purification.
Analytical TLC wascarried out on pre-coated plates
(Merck silica gel 60, F254) and visualized with UV light or
stained with ninhydrin. Column chromatography was per-
formed with silica (Merck, 70–230 mesh). 1H NMR and
13C NMR spectra were measured at 298 K on a Bruker DPX
300 or DPX 500 Fourier Transform spectrometer. Chemical
shifts were reported in d (ppm), relative to the internal stan-
dard of TMS. The signals observed were described as: s, d, t,
q, m. The number of protons(n) for a given resonance was
indicated asnH. All IR psectra were recorded on a Bio-
Rad FTS 165 spectrometer. Mass spectra were performed
on VG Micromass 7035 spectrometer under EI, Finnigan/
MAT LCQ under ESI (Normal), and Finnigan/MAT 95XL-
T under ESI (accurate). GC analysis were performed on
Agilent 6890 series GC system using a DB-1 column (30 m”
250 mm”0.25 mm) (oven: 508C, injector: 2308C, detector:
2508C) or Shimadzu GC-14 A gaschromatograph uisng a
PEG-HT column (25 m”250 mm”0.15 mm) (oven: 508C, in-
jector: 1008C, detector: 1208C).
1
a yellow solid; yield: 0.807 g (63%). H NMR (CDCl3): d=
7.40–7.30 (m, ArH, 4H), 6.74–6.65 (m, CH=CH2, 1H), 5.76–
5.70 (d, J=17.8 Hz, CH=CH2, 1H), 5.25–5.21 (d, J=
10.8 Hz, CH=CH2, 1H), 5.14 (s, ArCH2, 2H), 3.68 (s,
CO2CH3, 3H), 3.30 (s, CH2, 2H), 2.17 (s, CH3, 6H);
13C NMR (CDCl3): d=168.4, 167.6, 145.7, 145.2, 141.0,
137.1, 136.4, 128.0, 126.2, 113.9, 99.2, 98.9, 65.1, 50.9, 24.8,
19.1, 18.9; MS (EI): m/z=327.3 (M+); exact mass: calcd. for
C19H21NO4: m/z=327.1471; found: 327.1470.
Synthesis of Polymer 7
To monomer 5 (0.3337 g, 1.53 mmol) and s tyrene (1.05 mL,
9.13 mmol) in toluene (8.7 mL) wasadded AIBN (0.0175 g,
0.1066 mmol). The mixture waspurged with N at room
2
temperature for 0.5 h and then heated at 858C for 24 h
under N2. Thereafter the solution was concentrated and the
resulting residue was dissolved in THF (5 mL) and added
slowly into vigorously stirred cold MeOH (08C, 50 mL).
The resulting suspension was filtered by suction filtration
to afford polymer 7; yield: 62%. Loading calculated by
Synthesis of 4-Vinylbenzyl Alcohol (3)
To NaOH (0.04 g, 1 mmol) and Bu4NBr (3.224 g, 10 mmol)
in H2O (50 mL) wasadded 4-vinylbenzyl chloride
(1.409 mL, 10 mmol). The mixture washeated at 125 8C for
20 min and subsequently cooled in an ice/water bath. Upon
cooling, the mixture wasextracted with EtOAc (50 mL”3)
1H NMR: 1.562 mmolgÀ1 1H NMR (CDCl3): d=7.05–6.48
.
(m, ArH, 26H), 5.09 (s, ArCH2, 2H), 3.47 (s , COCH2CO,
2H), 2.21 (s, CH3, 3H), 1.96–0.89 (m, 18H): IR (KBr):
n=3448.8, 3059.7, 3026.0, 2923.5, 2849.8, 1744.2, 1719.7,
1601.4, 1493.2, 1452.7, 1150.1, 1028.8, 759.2, 699.6,
and the combined organic layer wasdried with MgSO , fil-
tered, concentrated and purified by column chromatography
4
540.5 cmÀ1
.
58
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 54 – 60

Polymer-Supported Hantzsch 1,4-Dihydropyridine Ester
COMMUNICATIONS
0.3 mmol). The mixture wasallowed to stir at room temper-
ature for 5 min. Thereafter the mixture waspoured into cold
MeOH (20 mL), filtered and concentrated to afford 13 asa
yellow solid; yield: 0.0455 g (99%). 13C NMR (CDCl3): d=
150.8, 129.2, 113.7, 101.7; MS (EI): m/z=227.8 (M+); exact
mass: calcd. for C8H2Cl2N2O2: m/z=227.9493; found
227.9491.
Synthesis of Polymer 1
From monomer 6: To monomer 6 (0.5 g, 1.53 mmol) and sty-
rene (1.05 mL, 9.13 mmol) in toluene (8.7 mL) wasadded
AIBN (0.0175 g, 0.1066 mmol). The homogeneousmixture
waspurged with N at room temperature for 0.5 h and then
2
heated at 858C for 24 h under N2. Thereafter the solution
wasconcentrated and the crude polymer product which pre-
cipitated was dissolved in THF (5 mL). The polymer prod-
uct was purified by adding the THF solution slowly to vigo-
rously stirred cold MeOH (08C, 50 mL). The resulting sus-
pension was filtered by suction filtration to afford polymer
1; yield: 0.80 g (55%). Loading calculated by 1H NMR:
0.780 mmolgÀ1.
Acknowledgements
We thank the National University of Singapore and the Re-
search Grants Council of the Hong Kong Special Administra-
tive Region, P. R. of China (Project No. HKU 7045/06P) for
financial support of this research.
From polymer 7: To polymer 7 (1.042 g, 1.6272 mmol) in
THF (20 mL) and H2O (4 mL) were added methyl 3-amino-
crotonate (0.1873 g, 1.6272 mmol) and formaldehyde (37%
solution, 0.122 mL, 1.6272 mmol). The homogeneous mix-
ture washeated under microwave irradiation at 100 8C for
20 min and then the product polymer wasprecipitated by
adding the solution slowly to vigorously stirred cold MeOH
(08C, 200 mL). The resulting suspension was filtered to
afford polymer 1 asa white powder; yield: 1.17 g (96%).
References
[1] a) M. Delgado, K. D. Janda, Curr. Org. Chem. 2002, 6,
1031; b) H. Graden, N. Kann, Curr. Org. Chem. 2005, 9,
733.
1
Loading calculated by H NMR only: 0.925 mmolgÀ1, load-
ing calculated based on a combination of %N content (ob-
[2] a) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jack-
son, A. G. Leach, D. A. Longbottom, M. Nesi, J. S.
Scott, R. I. Storer, S. J. J. Taylor, J. Chem. Soc., Perkin
Trans. 1 2000, 3815; b) A. Kirschning, H. Monenschein,
R. Wittenberg, Angew. Chem. Int. Ed. 2001, 40, 650.
[3] a) Y. Moritani, D. H. Appella, V. Jurkauskas, S. L.
Buchwald, J. Am. Chem. Soc. 2000, 122, 6797; b) W. S.
Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998; c) V.
Jurkauskas, J. P. Sadighi, S. L. Buchwald, Org. Lett.
2003, 5, 2417; d) B. H. Lipshutz, J. M. Servesko, T. B
Petersen, P. P. Papa, A. A. Lover, Org. Lett. 2004, 6,
1273.
1
tained via elemental analysis) and H NMR: 0.908 mmolgÀ1.
1H NMR (CDCl3): d=8.80 [s, CH (pyridine), 1H], 7.07–6.49
(m, ArH, 420H), 5.27 [s, ArCH2 (pyridine], 9H), 5.10 [s,
ArCH2 (dihydropyridine), 25H], 3.87 [s, CO2CH3 (pyridine],
4H), 3.65 (s, CO2CH3 (dihydropyridine), 29H), 3.35 [s, CH2
(dihydropyridine), 15H], 2.94 [s, CH3 (pyridine), 7H], 2.19
[s, CH3 (dihydropyridine), 69H], 1.82–0.94 (m, 318H). IR
(KBr): n=3468.9, 3409.6, 3082.3, 3059.2, 3025.5, 2922.8,
2849.6, 1736.02, 1716.55, 1601.8, 1493.2, 1452.4, 1271.2,
1184.2, 1114.0, 759.9, 699.3, 540.4 cmÀ1.
[4] a) A. Hantzsch, Justus Liebigs Ann. Chem. 1882, 215, 1;
b) S.-L. You, Chem. Asian J. 2007, 2, 820.
General Procedure for the Reduction of a,b-
Unsaturated Aldehydes
[5] a) J. W. Yang, M. T. Hechavarria Fonseca, B. List,
Angew. Chem. Int. Ed. 2004, 43, 6660; b) S. G. Ouellet,
J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem. Soc.
2005, 127, 32; c) J. W. Yang, M. T. Hechavarria Fonseca,
N. Vignola, B. List, Angew. Chem. Int. Ed. 2005, 44,
108; d) S. Mayer, B. List, Angew. Chem. Int. Ed. 2006,
45, 4193; e) J. B. Tuttle, S. G. Ouellet, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2006, 128, 12662; f) G. Li, Y.
Liang, J. C. Antilla, J. Am. Chem. Soc. 2007, 129, 5830.
[6] C. E. Garrett, K. Prasad, Adv. Synth. Catal. 2004, 346,
889.
To the respective a,b-unsaturated aldehyde 9 (0.2 mmol) in
CH2Cl2 (1.5 mL) wasadded polymer 1 (0.324 g, 0.3 mmol)
and catalyst 8 (5 mol%). Thismixture wasallowed to stir at
room temperature for 4 h. After which, the mixture wasfil-
tered through silica gel and the latter was washed with a
small volume of EtOAc:hexane (1:3) mixture. The com-
bined filtrate and washing was then concentrated to afford
10.
General Procedure for Reductive Amination
[7] a) F. M. Menger, H. Shinozaki, H.-C. Lee, J. Org.
Chem. 1980, 45, 2724; b) S. Zehani, G. Gelbard, React.
Polym. 1987, 6, 81; c) B. Tamami, N. Goudarzian, J.
Chem. Soc., Chem. Commun. 1994, 1079; d) D. H.
Drewry, D. M. Coe, S. Poon, Med. Res. Rev. 1999, 19,
97; e) A. Kirschning, J. Prakt. Chem. 2000, 342, 508.
[8] a) B. Yan, J. Fell, G. Kumaravel, J. Org. Chem. 1996,
61, 7467; b) D. J. Gravert, K. D. Janda, Chem. Rev.
1997, 97, 489; c) B. Yan, Acc. Chem. Res. 1998, 31, 621;
d) P. Wentworth Jr. , K. D. Janda, Chem. Commun.
1999, 1917; e) P. H. Toy, K. D. Janda, Acc. Chem. Res.
2000, 33, 546.
To the respective aldehyde (0.2 mmol), amine (0.2 mmol)
and polymer 1 (0.324 g, 0.3 mmol) in THF (3 mL) was
added one drop of 1.5M HCl. The mixture wasallowed to
stir at room temperature for 5 min. After which, the mixture
wasfiltered through islica gel and the latter waswahsed
with a small volume of EtOAc:hexane (1:5) mixture. The
combined filtrate and washing was then concentrated to
afford 11.
Procedure for the Aromatization of 12
To 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 12 (0.0454 g,
0.2 mmol) in THF (2 mL) wasadded polymer 1 (0.324 g,
[9] P. L. Osburn, D. E. Bergbreiter, Prog. Polym. Sci. 2001,
26, 2015.
Adv. Synth. Catal. 2008, 350, 54 – 60
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
59

Rongjun He et al.
COMMUNICATIONS
[10] a) C. R. Harrison, P. Hodge, B. J. Hunt, E. Khoshdel,
G. Richardson, J. Org. Chem. 1983, 48, 3721; b) D. E.
Bergbreiter, J. R. Blanton, J. Chem. Soc., Chem.
Commun. 1985, 337; c) T. Holletz, D. Cech, Synthesis
1994, 789; d) P. Wentworth Jr. , A. M. Vandersteen,
K. D. Janda, J. Chem. Soc., Chem. Commun. 1997, 759;
e) A. B. Charette, A. A. Boezio, M. K. Janes, Org. Lett.
2000, 2, 3777; f) M. K. W. Choi, H. S. He, P. H. Toy, J.
Org. Chem. 2003, 68, 9831; g) C. K.-W. Kwong, R.
Huang, M. Zhang, M. Shi, P. H. Toy, Chem. Eur. J.
2007, 13, 2369; h) M. Guino, K. K. Hii, Chem. Soc.,
Rev. 2007, 36, 608.
[11] a) J. M. Harris, Y. Liu, S. Chai, M. D. Andrews, J. C.
Vederas, J. Org. Chem. 1998, 63, 2407; b) M. K. W.
Choi, P. H. Toy, Tetrahedron 2003, 59, 7171.
[12] M. L. Hallensleben, J. Polym. Sci., Polym. Symp. 1974,
47, 1.
[15] T. J. van Bergen, T. Mulder, R. A. van der Veen, R. M.
Kellogg, Tetrahedron 1978, 34, 2377.
[16] a) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem.
Int. Ed. 2005, 44, 7424; b) M. Rueping, E. Sugiono, C.
Azap, T. Theissmann, M. Bolte, Org. Lett. 2005, 7,
3781; c) J. B. Steevens, U. K. Pandit, Tetrahedron 1983,
39, 1395; d) M. Fujii, T. Aida, M. Yoshihara, A. Ohno,
Bull. Chem. Soc. Jpn. 1989, 62, 3845; e) T. Itoh, K.
Nagata, A. Kurihara, M. Miyazaki, A. Ohsawa, A. Tet-
rahedron Lett. 2002, 43, 3105; f) T. Itoh, K. Nagata, M.
Miyazaki, H. Ishikawa, A. Kurihara, A. Ohsawa, Tetra-
hedron 2004, 60, 6649; g) D. Menche, J. Hassfeld, J. Li,
G. Menche, A. Ritter, S. Rudolph, Org. Lett. 2006, 8,
741.
[17] a) T. Godfraind, R. Miller, M. Wibo, Pharmacol. Rev.
1986, 38, 321; b) R. A. Coburn, M. Wierzba, M. J. Suto,
A. J. Solo, A. M. Triggle, D. J. Triggle, J. Med. Chem.
1988, 31, 2103; c) A. Sausins, G. Duburs, Heterocycles
1988, 27, 269; d) M. F. Gordeev, D. V. Patel, E. M.
Gordon, J. Org. Chem. 1996, 61, 924.
[13] a) G. Pozzi, M. Cavazzini, S. Quici, M. Benaglia, G.
DellꢀAnna, Org. Lett. 2004, 6, 441; b) C. W. Y. Chung,
P. H. Toy, J. Comb. Chem. 2007, 9, 115.
[18] J. J. Vanden Eynde, F. Delfosse, A. Mayence, Y. Van
[14] C. H. Bamford, H. Lindsay, Polymer 1973, 14, 330.
Haverbeke, Tetrahedron 1995, 51, 6511.
60
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 54 – 60