Polystyrene-anchored Cinchona ammonium salts: Easily recoverable phase-transfer catalysts for the asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1002/adsc.200404093

Cinchonidine, epicinchonidine, cinchonine or quinine have been N-anchored to cross-linked polystyrene (Merrifield resin) or grafted polystyrene (Syn-Phase Lanterns) affording polymer-supported chiral ammonium salts which are employed as phase-transfer cat

Full text of DOI:10.1002/adsc.200404093

FULL PAPERS
Polystyrene-Anchored Cinchona Ammonium Salts: Easily
Recoverable Phase-Transfer Catalysts for the Asymmetric
Synthesis of a-Amino Acids
´
´
Rafael Chinchilla, Patricia Mazon, Carmen Najera*
´
´
Departamento de Química Organica and Instituto de Síntesis Organica (ISO), Universidad de Alicante, Apartado 99,
03080 Alicante, Spain
Fax: (þ34)-96-590-3549, e-mail: cnajera@ua.es
Received: March 23, 2004; Accepted: June 7, 2004
Abstract: Cinchonidine, epicinchonidine, cinchonine meric catalysts can be easily recovered after the reac-
or quinine have been N-anchored to cross-linked poly- tion by simple filtration and reused.
styrene (Merrifield resin) or grafted polystyrene (Syn-
PhaseTM Lanterns) affording polymer-supported chi-
ral ammonium salts which are employed as phase- Keywords: alkylation; amino acids; ammonium salts;
À
transfer catalysts in the asymmetric alkylation of N- asymmetric synthesis; C C bond formation; organic
(diphenylmethylene)glycine esters. These new poly- catalysis; phase-transfer catalysis
Introduction
1970s N-methylephedrine and (R)-N,N-dimethyl-a-
methylbenzylamine were immobilized on cross-linked
chloromethylated polystyrene for different asymmetric
Optically active a-amino acidsare compoundsof well-
known interest, and their synthesis by simple and easily transformations under PTC conditions, although with
scalable procedures represents an important synthetic low ees.[16] Cinchona alkaloidsallow different sitesfor
challenge that hasboosted the development of numer-
polymer attachment. Thus, the bridgehead nitrogen of
ousmethodologies. [1] Amongst them, the enantioselec- quinine was quaternized with cross-linked polystyrenes
tive synthesis employing easily available and re-usable and the resulting polymers 1 (n¼1, 12; R¼OMe; X¼
chiral catalysts presents clear synthetic advantages for Cl, Br) were used in the enantioselective epoxidations
large-scale procedures. Probably, the phase-transfer cat- of chalcone with poor results.[17] Moreover, cinchonidine
alysis (PTC)[2] methodology applied to the asymmetric was anchored to the Merrifield resin and the resulting
alkylation[1r] of glycine and alanine Schiff bases is the polymeric ammonium salt 1 (n¼1, R¼H, X¼F) was
most simple and easy to scale-up. Thus, the advent in used as PTC catalyst in Michael additions albeit also
the early 1990 sof the enantioeslective alkylation of
amino acid iminesunder PTC conditionscatalyzed by
with low ees.[18]
The success of the mentioned OꢀDonnell-Corey-Lygo
quaternized Cinchona alkaloids,[3] pioneered by OꢀDon- enantioselective PTC alkylation of glycinate imines[4–6]
nell[4] and improved by Corey[5] and Lygo,[6] allowed one prompted the application of polymer-supported Cin-
to obtain impressive degrees of enantioselection using a chona alkaloid-derived ammonium salts to this proto-
very simple procedure. Moreover, dimeric,[7] trimeric[8] col. Thus, our group[19] and others[20] have anchored cin-
and even dendrimeric[9] Cinchona alkaloid-derived cat- chonidine to cross-linked polystyrene (1, n¼1, R¼H,
alysts, as well as non-Cinchona-derived species such as X¼Cl) for the asymmetric alkylation of benzophenone
spiro ammonium[10] and phosphonium salts,[11] TAD-
DOL[12a, b] and other tartaric derivatives,[12c, d] guanidini-
um salts,[12e] binaphthyl-derived amines[12b,13] and salen-
metal complexes[14] have also been used in this kind of
asymmetric PTC alkylations.
Attaching the alkaloid-derived chiral catalyst to a sol-
id support can be considered a step beyond in the devel-
opment of the PTC methodology due to the easiness of
its separation and possible recycling, the preparation
and uses of all kinds of supported reagents being consid-
ered nowadaysa fast-forward topic. [15] Thus, early in the Figure 1.
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DOI: 10.1002/adsc.200404093
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Polystyrene-Anchored Cinchona Ammonium Salts
FULL PAPERS
imine-derived glycine esters (up to 90% ee), whereas the polymer 1a was O-allylated by reaction with allyl
spacer chains of different lengths using cinchonidine bromide in the presence of aqueous KOH,[5a] affording
and quinine (1, n¼4, 6, 8; R¼H, OMe; X¼Cl, I) have polymeric salt 1b. Moreover, the cinchonine-derived
also been introduced achieving up to 81% ee.[21] In addi- Merrifield resin-supported ammonium salt 5 wasalso
tion, O-supported polymeric derivatives such as 2[22] obtained, ascinchonine hasbeen considered a pseudoe-
(R¼H, OMe; Ar¼9-anthryl) (up to 94% ee) aswell
as N- and O-alkylated polyethylene glycol (PEG) mon- ple way of achieving an opposite enantioselection.[4f]
omethyl ether ammonium salt derivatives such as 3[23a]
All these polymers 1 and 5 were tested as insoluble
nantiomer of cinchonidine, its use being therefore a sim-
(R¼H, OMe; Ar¼9-anthryl) (up to 71% ee) and 4 PTC catalysts (0.1 equiv.) in the triphase alkylation re-
[R¼H, OMe; Ar¼9-anthryl, oval¼MeOPEG5000
-
-
action of N-(diphenylmethylene)glycine esters 6 in an
organic solvent and using an aqueous base. The search
O2C-;[23a] R¼H, Ar¼9-anthryl, oval¼MeOPEG5000
O-C6H4-(CH2)3O-[23b]] (up to 81% ee), respectively, for the optimum reaction conditionswasperformed us-
have been obtained. Furthermore, a quinine-derived ing a model benzylation reaction of different iminic gly-
N-methylanthrylammonium salt attached to a PEG cine esters 6, and cinchonidine-supported salt 1a asPTC
chain at the 6-position of the quinoleine nucleus has catalyst (Table 1). The enantioselectivity of the reaction
been prepared,[23b] all these polymers being used for was measured by chiral GLC analysis (see Experimental
the asymmetric alkylation of glycinate imines although Section) of the corresponding N-trifluoroacetamide es-
achieving only up to 12% ee.
tersfrom 7.[24] In all cases (S)-7 wasobtained, itsabsolute
In thiscontext, and aspart of our ongoing studiesto-
configuration being determined by the sign of the specif-
wards the synthesis of polymeric PTC catalysts for the ic rotation of the phenylalanine,[25] obtained by hydroly-
asymmetric synthesis of a-amino acids,[19] we show in sis of 7 under refluxing 6 N HCl and treatment with pro-
thispaper the N-anchoring of some natural or modified pylene oxide.
Cinchona alkaloids to cross-linked or even grafted poly-
Thus, when using the ethyl or isopropyl esters 6a or 6b,
styrene, and the use of these supported ammonium salts respectively, in a system formed by toluene and a 25%
as chiral PTC catalysts in the enantioselective alkylation aqueousNaOH solution at room temperature, the cor-
of iminic glycine esters.
responding benzylated derivatives 7aa and 7ba were ob-
tained in 44 and 66% ee, respectively (Table 1, entries 1
and 2). However, when the reaction wascarried out with
the commercially available tert-butyl derivative 6c, the
reaction time wasconsiderably longer and product 7ca
Results and Discussion
Resin-supported ammonium salts 1a and 1c were ob- wasobtained in only 58% ee (Table 1, entry 3). Thus, de-
tained by reaction of cross-linked chloromethylated pol- rivative 6b[26a] was chosen as starting material for subse-
ystyrene (Merrifield resin, Fluka, cross-linked with 1% quent alkylation reactions.
of divinylbenzene, 200–400 mesh, 1.7 mmol Cl/g) with
an excess (2 equivs.) of cinchonidine and quinine, re-
spectively, in refluxing toluene. After filtration and
washing thoroughly with ethyl acetate, polymer-sup-
ported quaternary ammonium chlorides 1a and 1c
were obtained. The increase in the initial resin weight,
the new bandsin the IR spectra attributable to the alka-
loid structure and the presence of nitrogen in the ele-
mental analysis showed the incorporation of the alka-
loidsto the resin. In addition, and taking into account
the influence of substituting a hydroxy group by an ally-
loxy group in the catalytic performance of ammonium
Cinchona-derived ammonium salts in PTC reactions,[5] Figure 3.
Figure 2.
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Rafael Chinchilla et al.
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Toluene proved to be the solvent of choice (Table 1, ble 2, entries5 and 6). Furthermore, the above-men-
entry 2), the use of dichloromethane or tert-butyl methyl tioned consideration of cinchonine as a pseudoenan-
ether (Table 1, entries4 and 5) giving rise to lower ees,
whereasmore polar solventssuch asacetone or acetoni-
trile affording racemic 7ba (Table 1, entries6 and 7).
In addition, different aqueousalkaline basesin tol-
uene asorganic solvent at room temperature were ex-
amined (Table 1, entries2 and 8–10), 25% aqueous
tiomer of cinchonidine[4f] proved to be true when the
asymmetric benzylation reaction of 6b wascarried out
using polymer-supported cinchonine-derived ammoni-
um salt 5a, affording now the corresponding (R)-7ba, al-
though in a lower ee than when using its cinchonidine-
derived counterpart 1a (Table 2, compare entries1 and
NaOH affording the higher ee (Table 1, entry 2), where- 2 with entries7 and 8). Similarly to when using the O-al-
as the use of LiOH, KOH or especially CsOH gave low- lylated cinchonidine-derived ammonium salt 1b, the O-
er enantioselectivities. In addition, solid potassium car- allylated cinchonine-derived polymer 5b gave rise to a
bonate was also employed as base in acetonitrile as sol- lower enantioselection of (R)-7ba than itsOH-free
vent, although affording only 10% ee of compound 7ba counterpart 5a (Table 2, compare entries8 and 9).
(Table 1, entry 11). Finally, lowering the reaction tem-
Due to the low enantioselectivity achieved when using
perature gave place to a notable increment in the enan- the cinchonine-derived polymeric catalysts 5, we
tioselectivity. Thus, when the model benzylation reac- thought about the preparation of a polymeric ammoni-
tion wasperformed at 0 8C (bath temperature) the enan- um salt derived from cinchonidine but with an opposite
tioselection rose to 90% ee (Table 1, compare entries 2 configuration on the carbon bearing the OH group in the
and 12).
alkaloid moiety. Thus, we prepare epicinchonidine by
With all these optimized parameters, we performed OH mesylation ofcinchonidine and subsequentreaction
the enantioselective model benzylation of 6b using with refluxing water, according to the reported proce-
also polymeric PTC catalysts 1b, c and 5 (Table 2). The dure.[27] After N-quaternization of the epicinchonidine
O-allylation of the polymeric ammonium salt 1a seemed using the Merrifield resin, polymer-supported ammoni-
tolower itscapacity for enantioselection. Thus, when the
um salt 8 wasobtained and employed asPTC catalyst in
polymeric O-allylated cinchonidine-derived ammoni- the model benzylation reaction. However, the sense of
um salt 1b was used as PTC catalyst in the benzylation the enantioselectivity was not the expected and (S)-7
reaction of 6b, much lower eeswere obtained of ( S)- wasthe main enantiomer, the asymmetric induction be-
7ba compared to when the OH-intact polymeric catalyst ing very low (Table 2, entry 10). In all cases, the poly-
1a wasused (Table 2, compare entries1 and 2 with en-
tries3 and 4). Moreover, the polymeric ammonium
merswere recovered by filtration after the alkylation re-
action and reused up to three times without any loss of
salt from quinine 1c proved to be inferior to cinchoni- activity.
dine as PTC catalyst, as shown in the poor enantioselec-
tivitiesachieved for ( S)-7ba when 1c wasemployed (Ta-
We were also interested in anchoring the catalysts to a
type of support where a more mobile polymer is grafted
Table 1. Enantioselective benzylation of glycine derivatives 6 using polymeric catalyst 1a under PTC conditions.
Entry
R (No.)
Solvent
Base
T [8C]
t [h]
Product No.
Yield [%][a]
S/R ratio[b]
ee [%]
1
2
3
4
5
6
7
8
9
Et (6a)
PhMe
PhMe
PhMe
CH2Cl2
t-BuOMe
Acetone
MeCN
PhMe
PhMe
PhMe
MeCN
PhMe
25% aq. NaOH
25% aq. NaOH
25% aq. NaOH
25% aq. NaOH
25% aq. NaOH
25% aq. NaOH
25% aq. NaOH
25% aq. KOH
25% aq. CsOH
11% aq. LiOH[c]
K2CO3 (s)
25
25
25
25
25
25
25
25
25
25
25
0
4
4
36
4
2
1
2
3
10
23
36
17
7aa
7ba
7ca
7ba
7ba
7ba
7ba
7ba
7ba
7ba
7ba
7ba
85
90
80
95
75
86
85
94
80
90
60
90
72/28
83/17
79/21
77/23
75/17
50/50
50/50
79/21
68/32
80/20
55/45
95/5
44
66
58
54
58
0
i-Pr (6b)
t-Bu (6c)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
i-Pr (6b)
0
58
36
60
10
90
10
11
12
25% aq. NaOH
[a]
1
Crude yield determined by H NMR (300 MHz).
[b]
[c]
Determined by chiral GLC from the corresponding trifluoroacetamides (see text).
Solubility of LiOH in water.[26b]
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nal (S)-7ba wasobtained with an identical degree of
asymmetric induction as when using its Merrifield res-
in-attached counterpart 1a (Table 2, compare entries1
and 11), although lowering the reaction temperature af-
forded lower ee and high reaction time (Table 2, entry
12). Moreover, a similar enantioselectivity for (R)-7ba
was obtained using the cinchonine-supported Lantern
10 as catalysts aswhen using the Merrifield-derived ana-
logue 5a (Table 2, compare entries7 and 13). These Lan-
tern-attached ammonium salts 9 and 10 were tweezers-
separated after the reaction and reused up to three times
with almost no loss of activity (Table 2, see footnote[c]).
The next step was the use of other electrophiles in the
alkylation reaction of 6b using 1a asthe highest enantio-
selective supported PTC catalysts with 25% aqueous
NaOH asbase, toluene assolvent and at 0 8C. We per-
formed then the alkylation reaction using electrophiles
such as differently substituted benzyl bromides as well
asallyl and propargyl bromides(Table 3).
Figure 4.
Table 2. Enantioselective benzylation of glycine derivative
5b using polymeric catalysts 1, 5 or 8 – 10 under PTC condi-
tions.
Interestingly, all other electrophiles afforded lower
eesthan the formerly employed benzyl bromide (Ta-
ble 3, entry 1). Thus, a bulkytert-butyl group at the 4-po-
sition of the aromatic ring gave only 44% ee (Table 3,
entry 2). In addition, when different halogenswere
also at the 4-position of the nucleus (Table 3, entries 3,
4, 7 and 8), a certain dependence of the electronegativity
was observed, the presence of a fluorine atom giving
place to 72% ee (Table 3, entry 3), whereasan iodine
atom affording only 50% ee (Table 3, entry 8). The 2-,
3- or 4-position of the halogen on the aromatic ring
also influences the enantioselection (Table 3, en-
tries5–7). Thus, the presence of a bromine atom at
the 3- or 4-positions of the aromatic ring gave similar
ees(Table 3, entries6 and 7), whereasa bromine sub-
stituent at the 2-position lowered the enantioselectivity
Entry Cata- T [8C] t [h] Yield
S/R
ee [%]
lyst
[%][a] ratio[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1b
1b
1c
25
0
25
0
25
0
25
0
0
0
25
0
25
4
17
10
140
8
90
90
62
23
76
81
88
85
45
60
83
55
30
83/17
95/5
66
90
34
50
18
20
40
40
32
8
67/33
75/25
59/41
60/40
30/70
30/70
34/66
54/46
83/17
68/32
31/69
1c
96
4
5a
5a
5b
8
24
24
31
24
160
96
9[c]
9[c]
10[c]
66
36
38
[a]
[b]
1
Crude yield determined by H NMR (300 MHz).
Determined by chiral GLC from the corresponding tri- down to 20% ee (Table 3, entry 5). In addition, the pres-
fluoroacetamides(see text).
Reused up to three times with only 3% lowering in yield
and ee between first and third run.
ence of different groupson the aromatic ring did not
seem to influence remarkably the enantioselection.
Thus, when electron-withdrawing groups, such as nitro
or cyano, or electron-donating groups, such as methoxy,
were present the obtained ee was almost the same (Ta-
[c]
to a rigid plastic. Compared to cross-linked microporous ble 3, entries9–11). Finally, the use of allyl bromide
beads, which dominate the field of solid supports,[15] the (Table 3, entry 13) or propargyl bromide (Table 3, en-
use of these materials would allow great flexibility of de- try 14) gave rise to rather low ees, the (S)-enantiomer
sign, as plastics can be molded onto any particular being the main one in all cases.
shape.[28] We were interested in employing polystyr-
ene-grafted polypropylene in a particular shape called
“Lanterns”,[28] inspired by its use for the O-anchoring
of cinchonidine.[29] Thus, commercially available chloro-
methylated polystyrene-grafted polypropylene (chloro-
methylated SynPhaseTM Lanterns)[30] were used for the
N-quaternization of cinchonidine and cinchonine, af-
fording supported ammonium salts 9 and 10, respective-
ly. These derivatized Lanterns were added to the reac-
tion flask, being employed as PTC catalyst in the benzy-
lation of 6b. Thus, when the cinchonidine-supported
Lantern 9 wasused working at room temperature, the fi-
Figure 5.
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Rafael Chinchilla et al.
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Table 3. Enantioselective alkylation of glycine derivative 6b using polymeric catalyst 1a under PTC conditions.
Entry
RBr
t [h]
No.
Yield [%][a]
S/R ratio[b]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhCH2Br
17
7
7ba
7bb
7bc
7bd
7be
7bf
7bg
7bh
7bi
7bj
7bk
7bl
7bm
7bn
90
86
76
66
80
80
79
77
22
70
85
45
75
63
95/5
90
44
72
58
20
60
56
50
64
60
64
48
32
36
4-t-BuC6H4CH2Br
4-FC6H4CH2Br
4-ClC6H4CH2Br
2-BrC6H4CH2Br
3-BrC6H4CH2Br
4-BrC6H4CH2Br
4-IC6H4CH2Br
4-O2NC6H4CH2Br
4-NCC6H4CH2Br
4-MeOC6H4CH2Br
2-C10H7CH2Br
72/28
86/14
83/17
60/40
80/20
78/22
75/25
82/18
80/20
82/18
74/26
66/34[c]
68/32
10
10
13
12
14
14
26
19
10
6
¼
CH2 CHCH2Br
19
43
¼
CH CCH2Br
[a]
1
Crude yield determined by H NMR (300 MHz).
[b]
[c]
Determined by chiral GLC from the corresponding trifluoroacetamides (see text).
Assigned by the relative retention times of the (R/S)-isomers reported in the literature.[24]
tra were obtained at 70 eV on a Shimadzu QP-5000. HRMS
(EI) were recorded on a Finnigan MAT 95S. Microanalyses
were performed by the Microanalyses Service ofthe University
of Alicante. Merrifield resin (cross-linked with 1% of divinyl-
benzene, 200–400 mesh, 1.7 mmol Cl/g) was purchased from
Fluka. Chloromethylated SynPhaseTM-PS Lanterns(A-Series,
Conclusion
We have prepared chiral polymeric ammonium salts by
anchoring a number of Cinchona-derived alkaloidsto
different typesof commercially available polystyrene-
related supports, such as the Merrifield resin and poly-
styrene-grafted polypropylene (SynPhaseTM Lanterns).
All these ammonium salts have been employed as sol-
id-supported chiral PTC catalysts for the asymmetric
benzylation of N-(diphenylmethylene)glycine isopropyl
esters achieving moderate enantioselectivities. The best
eesof the ( S)-enantiomer were achieved using a Merri-
field resin-supported cinchonidinium salt, whereas cin-
chonine-derived salts gave rise to opposite (R)-enantio-
selectivity. In all cases higher ees were obtained when a
hydroxy group waspresent in the alkaloid moiety, their
O-allylated counterpartsgiving lower enantioselectivi-
ties. All these supported PTC catalysts could be easily
separated from the reaction mixture and reused.
17ꢀ6 mm, surface area¼7.2 cm2, loading¼75 mmol) are
[30]
available from MimotopesPty. Ltd.
Glycinimides 6a and
6c were commercially available (Aldrich), whereas 6b waspre-
pared according to the literature.[26a] The enantiomeric ratio of
products 7 were determined by chiral GLC analyses (Crown-
pack Chirasil-L-Val column, 25 mꢀ0.25 mm i.d.; conditions
A: P¼85 kPa, 1 min 85 8C, 2 8C/min to 180 8C; conditionsB:
P¼50 kPa, 1 min 85 8C, 10 8C/min to 180 8C) of their corre-
sponding N-trifluoroacetamide esters.[24] GLC reference race-
mic samples were prepared from the corresponding racemic 7,
which were obtained using n-tetrabutylammonium bromide as
PTC catalyst. Crude yields of compounds 7 were determined
by weighing the reaction crude containing excess electrophile
and measuring the ratio by 1H NMR.
Preparation of Merrifield Resin-Supported
Ammonium Salts 1a, 1c, 5a and 8
Experimental Section
To a suspension of cinchonidine, quinine, cinchonine, or epicin-
chonidine[27] (2 mmol) in toluene (10 mL) wasadded the Mer-
rifield resin (588 mg, 0.5 quivs.), and the mixture was stirred un-
der reflux for 24 h. The reaction wascooled to room tempera-
ture and the solid was filtered, washed with AcOEt (3ꢀ15 mL)
and dried under vacuum (15 Torr), affording the polymer-sup-
ported ammonium salts.
General Remarks
All the reagents and solvents employed were of the best grade
available and were used without further purification. IR spec-
tra were recorded on a Nicolet 510 P-FTand only the structur-
ally most important peaks are listed. The H and 13C NMR
1
spectra were recorded on a Bruker AC-300 at 300 and
75 MHz, respectively, using CDCl3 assolvent and TMS asinter-
nal standard. Low-resolution electron impact (EI) mass spec-
Polymeric ammonium salt 1a: IR (KBr): n¼3415 (br), 3060,
1596, 1430, 1220, 1100, 750 cmÀ1; microanalysis: % N¼3.25;
loading¼1.7 mmol gÀ1
.
1190
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Polystyrene-Anchored Cinchona Ammonium Salts
FULL PAPERS
Polymeric ammonium salt 1c: IR (KBr): n¼3398 (br), 3020,
615, 1497, 1455, 1241, 1012, 757 cmÀ1; microanalysis: % N¼
4.8 Hz), 6.60 (1H, m), 7.04–7.59 (13H, m), 7.80 (1H, d, J¼
7.9 Hz); GLC (N-trifluoroacetamide ester): Conditions A, tR
(R) 25.46 min, tR (S) 27.03 min.
3.06; loading¼1.6 mmol gÀ1
.
Polymeric ammonium salt 5a: IR (KBr): n¼3409 (br), 3080,
1590, 1440, 1231, 1103, 760 cmÀ1; microanalysis: % N¼3.25;
Isopropyl 3-(4-tert-butylphenyl)-2-(diphenylmethylene-
amino)propanoate (7bb): mp 137–138 8C; IR (KBr): n¼
3058, 3032, 1741, 1619 cmÀ1; 1H NMR: d¼1.21, 1.23 (6H, 2d,
J¼6.3 Hz), 1.28 (9H, s), 3.12 (1H, dd, J¼13.3, 9.2 Hz), 3.24
(1H, dd, J¼13.3, 4.3 Hz), 4.15 (1H, dd, J¼9.2, 4.3 Hz), 5.03
(1H, hept., J¼6.3 Hz), 6.56 (1H, d, J¼6.7 Hz), 6.97 (2H, d,
J¼8.2 Hz), 7.19–7.60 (10H, m), 7.80 (1H, d, J¼8.3 Hz);
13C NMR: d¼21.7, 31.4, 34.3, 39.0, 67.6, 68.2, 124.9, 125.7,
127.6, 127.9, 128.0, 128.1, 128.2, 128.7, 129.5, 130.0, 130.1,
132.4, 135.0, 136.2, 137.6, 139.5, 149.1, 170.3, 171.3; MS:
m/z¼427 (Mþ, 0.4), 340 (28), 281 (20), 280 (100), 239 (11),
238 (65), 194 (17), 193 (66), 192 (42), 166 (18), 165 (60), 163
(13), 147 (14), 117 (15), 91 (13), 57 (19); HRMS: calcd. for
C25H26N (Mþ – CO2Pr-i): 340.2065; found: 340.2036; GLC
(N-trifluoroacetamide ester): Conditions A, tR (R) 38.23 min,
tR (S) 39.18 min.
loading¼1.7 mmol gÀ1
.
Polymeric ammonium salt 8: IR (KBr): n¼3362 (br), 3029,
1598, 1454, 1233, 1038, 769 cmÀ1; microanalysis: % N¼3.25;
loading¼1.7 mmol gÀ1
.
Preparation of O-Allylated Merrifield Resin-
Supported Ammonium Salts 1b and 5b
To a suspension of 1a or 5a (0.5 mmol) in CH2Cl2 (3 mL) was
added allyl bromide (1.5 mmol, 86.5 mL) and 50% aqueous
KOH (2.5 mmol, 0.3 mL) and the mixture wastsirred for
24 h at room temperature. The solid was filtered and washed
with water (3ꢀ5 mL) and CH2Cl2 (3ꢀ5 mL), and dried under
vacuum (15 Torr) affording the corresponding polymers.
Polymeric ammonium salt 1b: IR (KBr): n¼3080, 1590,
1440, 1231, 1103, 760 cmÀ1; microanalysis: % N¼2.03;
Isopropyl 2-(diphenylmethyleneamino)-3-(4-fluorophe-
nyl)propanoate (7bc): IR (film): n¼3068, 1737, 1624, 1598,
1
1102 cmÀ1; H NMR: d¼1.21, 1.23 (6H, 2d, J¼6.2 Hz), 3.14
loading¼1.2 mmol gÀ1
.
(1H, dd, J¼13.4, 9.1 Hz), 3.23 (1H, dd, J¼13.4, 4.6 Hz), 4.15
(1H, dd, J¼9.1, 4.6 Hz), 5.04 (1H, hept, J¼6.2 Hz), 6.67 (1H,
d, J¼6.6 Hz), 6.88 (2H, m), 7.01 (2H, m), 7.26–7.38 (5H, m),
7.48 (1H, m), 7.58 (2H, m), 7.80 (1H, d, J¼8.1 Hz);
13C NMR: d¼21.7, 38.7, 67.3, 68.5, 127.6, 128.0, 128.2, 128.2,
Polymeric ammonium salt 5b: IR (KBr): n¼3016, 1607,
1487, 1454, 1110, 760 cmÀ1; microanalysis: % N¼1.82;
loading¼1.0 mmol gÀ1
.
128.4, 128.7, 130.0, 130.3, 131.2, 131.3, 132.4, 133.8, 136.2,
þ
¼
137.6, 139.3, 160.0, 163.2, 170.8, 171.0; MS: m/z 390 (M þ
Enantioselective Alkylation of Iminic Glycine Esters 6
using Polymers 1, 5 or 8 as Catalysts under PTC
Conditions
1, 0.1), 303 (13), 302 (55), 281 (20), 280 (100), 238 (58), 194
(20), 193 (80), 192 (46), 166 (27), 165 (96), 164 (11), 121 (12),
109 (30), 77 (14); HMRS: calcd. for C25H23NO2F (Mþ þ1):
388.1713; found: 388,1738; GLC (N-trifluoroacetamide ester):
Conditions A, tR (R) 23.44 min, tR (S) 24.87 min.
To a stirred suspension of 6 (0.5 mmol), the polymeric catalyst
1, 5 or 8 (0.1 equiv.) and the corresponding aqueous base
(4 mL) in the appropriate solvent (5 mL) at the selected tem-
perature (see Table 1), was added the corresponding bromide
(0.6 mmol). When the reaction was considered finished
(GLC), the mixture was filtered and the solid was washed
with AcOEt (25 mL), consisting of the recovered polymeric
catalyst. The filtrate was washed with water (3ꢀ15 mL) and
the organic phase was dried (MgSO4), filtered off and evapo-
rated (15 Torr) to give compounds 7. Data of known com-
poundsare given from thismixture. In the case of new com-
pounds, spectroscopic data are given from pure chromato-
graphed or crystallized or analytical samples.
Ethyl 2-(diphenylmethyleneamino)-3-phenylpropanoate
(7aa):[4a] 1H NMR: d¼1.24 (3H, t, J¼7.1 Hz), 3.18 (1H, dd,
J¼13.3, 9.2 Hz), 3.28 (1H, dd, J¼13.3, 4.4 Hz), 4.10–4.26
(3H, m), 6.59 (1H, d, J¼6.5 Hz), 7.03 (1H, m), 7.17 (2H, m),
7.23–7.39 (6H, m), 7.58 (2H, m), 7.80 (1H, m); GLC (N-tri-
fluoroacetamide ester): Conditions A, tR (R) 25.24 min, tR (S)
26.41 min.
Isopropyl 3-(4-chlorophenyl)-2-(diphenylmethyleneami-
no)propanoate (7bd): IR (film): n¼3062, 3027, 1737, 1619,
1
1096 cmÀ1; H NMR: d¼1.21, 1.23 (6H, 2d, J¼6.2 Hz), 3.12
(1H, dd, J¼13.4, 9.1 Hz), 3.22 (1H, dd, J¼13.4, 4.4 Hz), 4.15
(1H, dd, J¼9.1, 4.4 Hz), 5.04 (1H, hept, J¼6.2 Hz), 6.68 (2H,
d, J¼6.3 Hz), 6.80 (1H, d, J¼8.1 Hz), 6.98 (2H, d, J¼
8.4 Hz), 7.15 (2H, d, J¼8.4 Hz), 7.25–7.51 (4H, m), 7.57 (2H,
d, J¼8.1 Hz), 7.80 (1H, d, J¼8.1 Hz); 13C NMR: d¼21.7,
38.9, 67.1, 68.5, 127.6, 128.0, 128.2, 128.2, 128.4, 128.7, 128.9,
130.0, 130.3, 131.1, 131.9, 132.1, 132.4, 136.1, 136.7, 137.1,
137.9, 139.3, 170.8, 170.9; MS: m/z¼405 (Mþ, 0.04), 320 (13),
318 (37), 281 (19), 280 (95), 238 (57), 194 (19), 193 (85), 192
(44), 166 (28), 165 (100), 164 (11), 124 (22), 77 (17); HMRS:
calcd. for C21H17NCl (Mþ – CO2Pr-i): 318.1050; found:
318.1054; GLC (N-trifluoroacetamide ester): Conditions A,
tR (R) 35.84 min, tR (S) 36.97 min.
Isopropyl 3-(2-bromophenyl)-2-(diphenylmethyleneami-
no)propanoate (7be): IR (film): n¼3062, 3026, 1733, 1665,
1
1100 cmÀ1; H NMR: d¼1.22, 1.24 (6H, 2d, J¼6.1 Hz), 3.23
Isopropyl 2-(diphenylmethyleneamino)-3-phenylpropa-
noate (7ba):[9b] 1H NMR: d¼1.20, 1.22 (6H, 2d, J¼6.5 Hz),
3.17 (1H, dd, J¼13.1, 9.2 Hz), 3.27 (1H, dd, J¼13.1, 4.3 Hz),
4.19 (1H, dd, J¼9.2, 4.3 Hz), 5.04 (1H, hept, J¼6.1 Hz), 6.62
(1H, m), 7.03–7.60 (13H, m), 7.79 (1H, d, J¼7.9 Hz); GLC
(N-trifluoroacetamide ester): Conditions A, tR (R) 24.72 min,
tR (S) 26.00 min.
(1H, dd, J¼13.4, 9.8 Hz), 3.49 (1H, dd, J¼13.4, 4.2 Hz), 4.41
(1H, dd, J¼9.8, 4.2 Hz), 5.04 (1H, hept, J¼6.1 Hz), 6.61 (1H,
d, J¼6.1 Hz), 7.01–7.59 (12H, m), 7.81 (1H, d, J¼7.9 Hz);
13C NMR: d¼21.8, 39.5, 64.6, 68.5, 125.2, 126.9, 127.6, 127.9,
128.0, 128.1, 128.2, 128.3, 128.8, 130.0, 130.2, 131.3, 132.3,
¼
132.5, 132.7, 133.3, 136.0, 137.3, 139.3, 171.0; MS: m/z 370
(Mþ – Br, 26), 364 (20), 362 (21), 281 (11), 280 (51), 238 (40),
194 (13), 193 (54), 192 (32), 180 (24), 179 (12), 166 (27), 165
tert-Butyl 2-(diphenylmethyleneamino)-3-phenylpropa-
noate (7ca):[6e] 1H NMR d¼1.4 (9H, s), 3.15 (1H, dd, J 13.4,
¼
9.2 Hz), 3.24 (1H, dd, J 13.4, 4.8 Hz), 4.11 (1H, dd, J¼9.2,
(100), 164 (10), 77 (14); HRMS: calcd. for C25H24NO2 (Mþ
–
¼
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ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Rafael Chinchilla et al.
FULL PAPERS
Br): 370.1807; found: 370.1809; GLC (N-trifluoroacetamide es-
ter): Conditions A, tR (R) 38.57 min, (S) 39.65 min.
Isopropyl 3-(4-cyanophenyl)-2-(diphenylmethyleneami-
no)propanoate (7bj):[9b] 1H NMR: d¼1.21, 1.23 (6H, 2d, J¼
6.3 Hz), 3.24 (1H, dd, J¼13.3, 8.6 Hz), 3.31 (1H, dd, J¼13.3,
4.8 Hz), 4.20 (1H, dd, J¼8.6, 4.8 Hz), 5.04 (1H, hept, J¼
6.3 Hz), 6.70 (1H, d, J¼6.7 Hz), 7.18 (2H, d, J¼8.3 Hz),
7.26–7.62 (10H, m), 7.66 (1H, d, J¼8.4 Hz), 7.80 (1H, d, J¼
8.4 Hz); GLC (N-trifluoroacetamide ester): Conditions A, tR
(R) 53.43 min, tR (S) 54.20 min.
Isopropyl 3-(3-bromophenyl)-2-(diphenylmethyleneami-
no)propanoate (7bf): IR (film): n¼3063, 1731, 1660,
1
1107 cmÀ1; H NMR: d¼1.22, 1.24 (6H, 2d, J¼6.2 Hz), 3.14
(1H, dd, J¼13.3, 9.1 Hz), 3.22 (1H, dd, J¼13.3, 4.5 Hz), 4.17
(1H, dd, J¼9.1, 4.5 Hz), 5.05 (1H, hept, J¼6.2 Hz), 6.68 (1H,
d, J¼6.1 Hz), 7.02–7.57 (12H, m), 7.80 (1H, d, J¼7.9 Hz);
13C NMR: d¼21.8, 39.2, 66.9, 68.6, 122.1, 127.6, 128.0, 128.2,
128.4, 128.6, 128.7, 129.3, 129.6, 130.0, 130.3, 131.5, 132.4,
132.7, 136.1, 139.3, 140.5, 170.9, 171.0; MS: m/z¼449 (Mþ,
0.1), 364 (29), 362 (29), 281 (18), 280 (85), 238 (41), 194 (18),
193 (83), 180 (20), 179 (11), 166 (28), 165 (100), 102 (10), 77
(15); HRMS: calcd. for C21H17NBr (Mþ – CO2Pr-i): 362.0544;
found: 362.0540; GLC (N-trifluoroacetamide ester): Condi-
tions A, tR (R) 50.23 min, tR (S) 51.61 min.
Isopropyl
2-(diphenylmethyleneamino)-3-(4-methoxy-
phenyl)propanoate (7bk): IR (film): n¼3059, 3029, 1732,
1
1660, 1278, 1248 cmÀ1; H NMR: d¼1.21, 1.23 (6H, 2d, J¼
6.3 Hz), 3.11 (1H, dd, J¼13.5, 9.1 Hz), 3.21 (1H, dd, J¼13.5,
4.5 Hz), 3.75 (3H, s), 4.15 (1H, dd, J¼9.1, 4.5 Hz), 5.03 (1H,
hept, J¼6.3 Hz), 6.67 (1H, d, J¼6.9 Hz), 6.73 (2H, d, J¼
8.8 Hz), 6.97 (2H, d, J¼8.7 Hz), 7.25–7.37 (3H, m), 7.46 (2H,
m), 7.55 (2H, m), 7.79 (2H, m); 13C NMR: d¼21.8, 38.7, 55.2,
67.6, 68.3, 113.5, 127.6, 127.9, 128.1, 128.3, 128.4, 128.7, 130.0,
130.0, 130.7, 132.4, 136.4, 137.7, 139.5, 158.1, 170.5, 171.3; MS:
m/z¼401 (Mþ, 2), 314 (16), 281 (20), 280 (100), 238 (67), 194
(16), 193 (53), 192 (50), 166 (22), 165 (75), 121 (86), 91 (12),
77 (17); HRMS: calcd. for C26H27NO3: 401.1991; found:
401.1991; GLC (N-trifluoroacetamide ester): Conditions A,
tR (R) 37.34 min, tR (S) 38.28 min.
Isopropyl 3-(4-bromophenyl)-2-(diphenylmethyleneami-
no)propanoate (7bg): mp 97–98 8C; IR (KBr): n¼3065,
1
1731, 1623, 1110 cmÀ1; H NMR: d¼1.22, 1.24 (6H, 2d, J¼
6.1 Hz), 3.23 (1H, dd, J¼13.4, 9.8 Hz), 3.48 (1H, dd, J¼13.4,
4.0 Hz), 4.14 (1H, dd, J¼9.8, 4.0 Hz), 5.04 (1H, hept, J¼
6.1 Hz), 6.60 (1H, d, J¼6.1 Hz), 7.01–7.59 (12H, m), 7.81
(1H, d, J¼7.9 Hz); 13C NMR d¼21.8, 39.5, 64.6, 68.5, 125.2,
126.9, 127.6, 127.9, 128.0, 128.1, 128.24, 128.3, 128.8, 130.0,
130.2, 132.4, 132.5, 132.7, 133.3, 136.0, 137.3, 139.3, 171.0; MS:
m/z¼406 (Mþ – i-Pr, 0.05), 364 (17), 363 (18), 281 (18), 280
(92), 238 (50), 194 (18), 193 (78), 192 (40), 166 (29), 165
Isopropyl 2-(diphenylmethyleneamino)-3-(naphthalen-2-
yl)propanoate (7bl):[9b] 1H NMR: d¼1.21, 1.23 (6H, 2d, J¼
6.3 Hz), 3.33 (1H, dd, J¼13.3, 9.2 Hz), 3.47 (1H, dd, J¼13.3,
4.4 Hz), 4.31 (1H, dd, J¼9.2, 4.4 Hz), 5.04 (1H, hept, J¼
6.3 Hz), 6.54 (2H, d, J¼7.0 Hz), 7.14–7.81 (15H, m); GLC
(N-trifluoroacetamide ester): Conditions A, tR (R) 50.31 min,
tR (S) 51.08 min.
(100), 90 (10), 77 (16); HRMS: calcd. for C21H17NBr (Mþ
–
CO2Pr-i): 362.0544; found: 362.0593; GLC (N-trifluoroacet-
amide ester): Conditions A, tR (R) 41.11 min, tR (S) 42.10 min.
Isopropyl
2-(diphenylmethyleneamino)pent-4-enoate
(7bm): IR (film): n¼3063, 1747, 1660 cmÀ1; H NMR: d¼
1.22, 1.24 (6H, d, J¼6.2 Hz), 2.58–2.74 (2H, m), 4.08 (2H,
dd, J¼7.6, 5.5 Hz), 4.99–5.10 (3H, m), 5.64–5.78 (1H, m),
7.17 (1H, m), 7.29–7.50 (6H, m), 7.60 (2H, m); 13C NMR: d¼
21.7, 38.1, 65.3, 68.2, 117.4, 127.8, 127.9, 128.2, 128.4, 128.5,
128.8, 130.0, 130.2, 132.4, 134.4, 136.5, 137.5, 139.6, 170.4,
171.2; MS: m/z¼321 (Mþ, 22), 280 (51), 238 (51), 235 (21),
234 (96), 194 (15), 193 (50), 192 (67), 166 (25), 165 (100), 131
(25), 129 (15), 116 (12), 104 (13), 91 (27), 77 (13); HRMS: calcd.
for C21H23NO2: 321.1729; found: 321.1755; GLC (N-trifluoro-
acetamide ester): Conditions B, tR (R) 7.50 min, tR (S) 8.54 min.
1
Isopropyl
2-(diphenylmethyleneamino)-3-(4-iodophe-
nyl)propanoate (7bh): mp 106–107 8C; IR (KBr); n¼3068,
1
3022, 1742, 1624 cmÀ1; H NMR: d¼1.21, 1.23 (6H, 2d, J¼
6.3 Hz), 3.10 (1H, dd, J¼13.4, 8.9 Hz) 3.18 (1H, dd, J¼13.4,
4.3 Hz), 4.15 (1H, dd, J¼8.9, 4.3 Hz), 5.03 (1H, hept, J¼
6.3 Hz), 6.67 (1H, d, J¼6.3 Hz), 6.80 (1H, d, J¼7.9 Hz),
7.09–7.40 (6H, m), 7.45–7.59 (4H, m), 7.66 (1H, d, J¼
7.9 Hz), 7.80 (1H, d, J¼7.9 Hz); 13C NMR: d¼21.7, 39.0,
67.0, 68.5, 91.4, 125.2, 127.5, 128.0, 128.2, 128.2, 128.4, 128.7,
129.0, 130.0, 130.3, 130.8, 131.9, 132.4, 136.0, 137.1, 137.8,
137.9, 139.2, 170.8, 170.9; MS: m/z¼410 (Mþ – CO2Pr-i, 25),
281 (20), 280 (100), 238 (46), 194 (17), 193 (71), 192 (37), 180
(14), 179 (12), 166 (26), 165 (88), 90 (14), 77 (14); HRMS: calcd.
for C21H17NI (Mþ– CO2Pr-i): 410.0406; found: 410.0370; GLC
(N-trifluoroacetamide ester): Conditions A, tR (R) 45.19 min,
tR (S) 46.09 min.
Isopropyl
2-(diphenylmethyleneamino)pent-4-ynoate
(7bn): IR (film): n¼3296, 3065, 3031, 1734, 1623 cmÀ1
;
1H NMR: d¼1.21, 1.23 (6H, 2d, J¼6.2 Hz), 2.72–2.88 (3H,
m), 4.24 (1H, dd, J¼7.5, 6.5 Hz), 5.05 (1H, hept, J¼6.2 Hz),
7.25–7.56 (5H, m), 7.59 (1H, d, J¼7.2 Hz), 7.65 (2H, d, J¼
7.3 Hz), 7.80 (2H, d, J¼7.5 Hz); 13C NMR: d¼21.7, 23.3,
64.2, 68.8, 70.1, 81.0, 128.0, 128.2, 128.4, 128.6, 128.9, 130.0,
130.4, 132.4, 136.1, 137.6, 139.9, 169.9, 171.7; MS: m/z¼319
(Mþ, 18), 318 (70), 280 (26), 276 (15), 238 (29), 233 (16), 232
(82), 205 (12), 194 (13), 193 (49), 192 (77), 166 (23), 165
(100), 129 (19), 128 (37), 127 (24), 77 (14); HRMS: calcd. for
C21H21NO2: 319.1572; found: 319.1571; GLC (N-trifluoroacet-
amide ester): Conditions B, tR (R) 7.84 min, tr (S) 8.26 min.
Isopropyl
2-(diphenylmethyleneamino)-3-(4-nitrophe-
nyl)propanoate (7bi): mp 140–141 8C; IR (KBr): n¼3083,
1732, 1628 cmÀ1; 1H NMR: d¼1.22, 1.24 (6H, 2d, J¼6.2 Hz),
3.29 (1H, dd, J¼13.3, 8.5 Hz), 3.34 (1H, dd, J¼13.3, 4.9 Hz),
4.24 (1H, dd, J¼8.5, 4.9 Hz), 5.05 (1H, hept, J¼6.2 Hz), 6.71
(1H, d, J¼6.9 Hz), 7.23–7.39 (4H, m), 7.46–7.62 (4H, m),
7.81 (2H, m), 8.06 (1H, m), 8.26 (2H, m); 13C NMR: d¼21.8,
39.4, 66.5, 68.9, 126.4, 127.5, 127.5, 128.1, 128.3, 128.7, 130.0,
130.6, 130.7, 132.4, 135.9, 137.6, 139.0, 146.2, 170.5, 171.3; MS:
m/z¼329 (Mþ – CO2Pr-i, 63), 281 (11), 280 (53), 238 (32),
194 (15), 193 (66), 192 (37), 180 (17), 179 (17), 178 (12), 166
(26), 165 (100), 104 (12), 77 (18); HRMS: calcd. for
C21H17N2O2 (Mþ – CO2Pr-i): 329.1290; found: 329.1290; GLC
(N-trifluoroacetamide ester): Conditions A, tR (R) 53.02 min,
tR (S) 54.07 min.
Preparation of SynPhaseTM Lantern-Supported
Ammonium Salts 9 and 10
To a suspension of cinchonidine or cinchonine (0.5 mmol,
148 mg) in CH2Cl2 (8 mL) wasadded A-Serieschloromethylat-
1192
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asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1186–1194

Polystyrene-Anchored Cinchona Ammonium Salts
FULL PAPERS
ed SynPhaseTM Lantern (see General Remarks). The Lantern
wasshaken into thismixture for 7 d at room temperature under
an inert atmosphere, removed, rinsed with CH2Cl2 (10 mL) and
dried under vacuum (15 Torr). The alkaloid incorporation was
estimated as quantitative according to weight difference.
C. L. Liotta, M. Halpern, Phase-Transfer Catalysis,
Chapman & Hall, New York, 1994; c) Handbook of
Phase-Transfer Catalysis, (Eds.: Y. Sasson, R. Neumann),
Blackie Academic
& Professional, London, 1997;
d) Phase-Transfer Catalysis (Ed.: M. E. Halpern), ACS
Symposium Series 659, American Chemical Society,
Washington, DC, 1997; e) A. Nelson, Angew. Chem.
Int. Ed. 1999, 38, 1583–1585; f) M. Makosza, Pure
Appl. Chem. 2000, 72, 1399–1403; g) K. Maruoka, T.
Ooi, Chem. Rev. 2003, 103, 3013–3028.
Enantioselective Benzylation of Iminic Glycine ester
6b using SynPhaseTM Lantern-Supported Ammonium
Salts 9 or 10 under PTC Conditions
[3] For a review on synthetic uses of Cinchona alkaloidsand
derivatives, see: K. Kacprzak, J. Gawronski, Synthesis
2001, 961–998.
To a solution of 6b (0.35 mmol, 98 mg) in toluene (4 mL) was
added the Lantern-supported ammonium salt 9 or 10 from
above, 25% aqueousNaOH (3 mL) and benzyl bromide
(0.42 mmol, 72 mL). The mixture wasshaken at the appropriate
temperature (see Table 2) and when the reaction was finished
(GLC), the Lantern wasremoved and rinesd with toluene
(2 mL) which waspoured on the reaction mixture. The com-
bined organicswere wahsed with water (3 ꢀ15 mL), dried
(MgSO4), filtered off and evaporated (15 Torr) to give com-
pound 7ba. The separated Lantern was rinsed with CH2Cl2
(10 mL) and dried under vacuum (15 Torr) for further reuse.
[4] a) M. J. OꢀDonnell, R. L. Polt, J. Org. Chem. 1982, 47,
2663–2666; b) M. J. OꢀDonnell, W. D. Bennett, S. Wu,
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[5] a) E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997,
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[6] a) B. Lygo, P. G. Wainwright, Tetrahedron Lett. 1997, 38,
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Acknowledgements
´
We thank the Ministerio de Educacion y Cultura (MEC) of
Spain (DGICYT, research project BQU2001–0724-C02–01),
the Generalitat Valenciana (GV99-33-1-02) and the Universi-
dad de Alicante for financial support.
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