Chiral lithium amides on polymer support - Synthesis and use in deprotonation of ketones

Article abstract of DOI:10.1139/V06-006

A number of chiral secondary amines attached to Merrifield resin or to noncrosslinked (soluble) polystyrene support were synthesized. The corresponding lithium amides, generated from these amines by treatment with BuLi, react with tropinone, a model symme

Full text of DOI:10.1139/V06-006

257
Chiral lithium amides on polymer support —
Synthesis and use in deprotonation of ketones1
Marek Majewski, Agnieszka Ulaczyk-Lesanko, and Fan Wang
Abstract: A number of chiral secondary amines attached to Merrifield resin or to noncrosslinked (soluble) polystyrene
support were synthesized. The corresponding lithium amides, generated from these amines by treatment with BuLi, re-
act with tropinone, a model symmetrical ketone, to give the corresponding enolates enantioselectively (ee up to 75%).
The enolates were trapped either as the corresponding aldol adducts by a reaction with benzaldehyde or as ring-
opening products in a reaction with a chloroformate.
Key words: chiral lithium amides, polymer-supported reagents, deprotonation, enolates, tropinone.
Résumé : On a réalisé la synthèse d’un certain nombre d’amines secondaires chirales liées à une résine de Merrifield
ou à un support de polystyrène non réticulé (soluble). Les sels de lithium des amides correspondants obtenus à partir
de ces amines par traitement avec du BuLi réagissent avec la tropinone, une cétone symétrique modèle, pour conduire
d’une façon énantiosélective (ee allant jusqu’à 75 %) à la formation des énolates correspondants. Les énolates ont été
piégés sous la forme d’adduits aldoliques correspondants par réaction avec du benzaldéhyde ou sous la forme de pro-
duits d’ouverture par réaction avec un chloroformiate.
Mots clés : sels de lithium d’amides chiraux, réactifs supportés par un polymère, déprotonation, énolates, tropinone.
[Traduit par la Rédaction] Majewski et al. 268
Introduction
support would be compatible with highly reactive reagents
such as butyllithium or carbanions, since there had been
very few precedents (5). Fortunately, no major problems on
this score were encountered. The preliminary results of this
study have been reported in a communication (6). Recently,
other researchers have taken up the theme of lithium amides
on polymer support achieving very interesting and useful re-
sults in different systems (7). Below, we present a full ac-
count of the synthesis of a number of chiral lithium amides
on polymer support and their reactions as bases in selected
systems.
There is a lot of interest in developing chemistry that in-
volves reactants on polymer support that are often described
in terms of solid phase synthesis (SPS) for insoluble poly-
mers, and liquid phase synthesis (LPS) for soluble resins
(the differences between “solid-phase”, “liquid-phase” and
“solution-phase” chemistry were discussed in a seminal pa-
per by Janda in 1997) (1) and often the challenge involves
adaptation of solution-phase reactions to work on the resin
(2). As the popularity of the polymer-supported scaffolds
and reagents grows, the more difficult aspects of synthetic
chemistry such as stereoselective reactions, and especially
their catalytic versions, are developed in the SPS and LPS
context (3). It should be noted that applications of substrates
and reagents on polymer support are not limited to combina-
torial chemistry, there is also a number of potential benefits
that could arise from using such reagents including easy re-
covery of expensive chemicals, easier control of environ-
mental contamination, and new reactor design (2, 3).
Results and discussion
Synthesis of chiral amines on insoluble polymer
support
Chloromethyl polystyrene 1 (Merrifield resin, 200–400
mesh) was chosen as the solid support for the initial studies.
The general method elaborated for the direct attachment of a
chiral amine to the resin is shown in Scheme 1.
Replacement of chlorine in 1 with iodine was done using
the Finkelstein reaction (8). The N-alkylation of chiral pri-
mary amines (3–5) proceeded smoothly when the amine was
used in excess. After the reaction was completed, the resins
(6–8) were separated by filtration, washed with the follow-
We have been interested in development of chiral lithium
amide bases for several years (4). Analogous amides sup-
ported on a resin are interesting because of a potential con-
nection to solid phase synthesis. At the onset of this work it
was not clear if chemistry involving reagents on polymer
Received 4 July 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 17 March 2006.
Dedicated to Professor Arthur Carty in recognition of his contributions to chemistry and the sciences in Canada.
M. Majewski,2 A. Ulaczyk-Lesanko, and F. Wang. Department of Chemistry, University of Saskatchewan, Saskatoon, SK
S7N 5C9, Canada.
1This article is part of a Special Issue dedicated to Professor Arthur Carty.
2Corresponding author (e-mail: majewski@usask.ca).
Can. J. Chem. 84: 257–268 (2006)
doi:10.1139/V06-006
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
Scheme 1.
1. R*NH2 (3-5)
NaI
acetone
R*
N
2. Bu3SnH
Cl
I
H
P
P
P
1
2
6-8
R*
Ph
6: S - CHMePh
7: S - (CH2)3N(Boc)CHMePh
8: S.R - CH(Me)CH(OH)Ph
NH2
Ph
NH2
Ph
N
NH2
Boc
OH
3
4
5
ing solvents: THF, MeOH, aq. MeOH (50%), H2O, NaOH,
H2O, MeOH, Et2O, and were dried under vacuum to the
constant weight. The rather involved washing procedure re-
sults from the fact that the polymers of this type swell in
THF or Et2O, but do not swell in polar protic solvents such
as MeOH or H2O. Thus, the resins were washed with a
swelling solvent first, to remove organic impurities absorbed
on the polymer. The wash with THF was followed by wash-
ing with solvents that do not have good swelling properties,
but which remove inorganic and acidic impurities.
Scheme 2. Reagents and conditions: (a) NaI, Me2CO, reflux;
(b) 3a, K2CO3, THF, reflux; (c) Et3N, (Boc)2O, MeOH; (d) 95%
NH2NH2, EtOH.
O
I
Br
O
a
N
N
90%
O
9
O
10
57%
b
Next, a method for determination of the amount of nitro-
gen (loading) in the polymer-supported reagents had to be
elaborated. The Volhard titration method was tried first (9).
A known amount of standard HCl solution was added to the
polymer-supported amine sample, which gave the corre-
sponding salt. The chloride ions that were not trapped by the
amine moieties were precipitated by addition of a known ex-
cess of a standard solution of AgNO3. After several experi-
ments, it was found that HCl was being incorporated into the
polymer matrix and the apparent N-loading of the resin was
higher than the Cl-loading of the original Merrifield resin.
This absorption of HCl on the polymer was confirmed by
several “blind titration” experiments, i.e., the commercially
available Merrifield resin was treated with a known amount
of the standard HCl solution, the resin was separated by fil-
tration, and the filtrate was titrated using the Volhard
method. Overall, contrary to some reports (9b), the Volhard
method was not effective. Another method of titration that
was tried was the Fajans method, which works in a similar
fashion, but relies on the analysis of sulfate ions (9a). This
method allowed a reasonably accurate determination of the
amine loading.
The third method used for determination of the nitrogen
content in polymeric amines was elemental analysis. The
loading values of all insoluble polymer-supported amines
ranged between 0.4 and 1.1 mmol of NH per gram (cf., the
Experimental section). Nitrogen loading clearly indicated
that, in many cases, the N-alkylation reaction did not go to
completion. Since the halide groups attached to the polymer
could interfere with subsequent reactions, a dehalogenation
procedure was performed according to the method described
by Leznoff that involves using an excess of Bu3SnH (10). A
quick, qualitative test of amine incorporation into the poly-
mer structure was done by using a solution of bromophenol
blue, similar to the test developed by Lam to monitor prog-
ress of reactions of peptides connected to resin beads (11).
c,d
56%
N
H
Ph
H2N
N
Ph
Boc
4
11
7, which was envisaged as the precursor of the bidentate
chiral lithium amide, was synthesized as shown in Scheme 2.
Most of the reacting groups in an insoluble polymer-
supported reagent are situated inside the polymer bead.
These reacting sites are not easily accessible to reagents in
solution, but the situation could be improved by distancing
the reactive groups from the rigid polymer matrix by a
linker. Selection of the proper linker can be critical to the
success of SP chemistry (1, 2b). Initially, two simple linkers
derived from 1,3-propanediol (13) and 1,6-hexanediol (14)
were used. They were attached to the polymer-supported
benzyl chloride 1 by a modified literature method (12), in-
volving O-alkylation, followed by functional group manipu-
lation using reactions that are well-known in the context of
solution chemistry (Scheme 3) (13). Iodides 17 and 18
served as precursors for the polymer-supported amines 19
and 20, which were obtained by simple N-alkylation of (S)-
α-methylbenzyl amine (3) with these compounds.
Some examples of attaching a chiral amine moiety to an
insoluble polymer support via a linker that had been incor-
porated into the amine structure as the corresponding amino
alcohol were published by other groups working on develop-
ing catalysts for stereoselective addition of nucleophiles to
aldehydes (2a, 12, 14–16). We have synthesized amines 22
and 24 hoping that they might be effective in
enantioselective deprotonation (Scheme 4). Compound 22
seemed especially promising owing to its structural similar-
ity to the C2 symmetrical amine 25 — the lithium amide of
this amine is one of the most versatile and effective chiral
bases (4). Compounds 21 and 23 used in these studies were
synthesized from chiral primary amines by the reductive
Amine 4, needed for synthesis of the corresponding resin
© 2006 NRC Canada

Majewski et al.
259
Scheme 3. Reagents and conditions: (a) NaH, 0 °C, DMF; (b) 1, 60 °C; (c) PhP3, I2, imidazole, CH2Cl2, rt; (d) 3a; (e) Bu3SnH.
a,b
c
OH
HO
(CH2)n
OH
O
(CH2)n
I
O
(CH2)n
13: n = 1
14: n = 4
P
15: n = 1
16: n = 4
17: n = 1
18: n = 4
P
d,e
O
(CH2)n
N
H
Ph
19: n = 1
20: n = 4
P
Scheme 4. Reagents and conditions: (a) NaH, 0 °C, DMF; (b) 2, K2CO3; (c) Bu3SnH, THF.
O
N
H
Ph
HO
a,b,c
Ph
N
H
Ph
25
N
H
Ph
22
P
21
a,b,c
HO(H2C)3
O
N
N
H
H
24
P
23
Scheme 5. Reagents and conditions: (a) AIBN, benzene, 70 °C,
48 h; (b) NaI, acetone.
amination method (starting from 4-hydroxy-4-methyl-2-
pentanone or menthone, respectively).
a
Synthesis of chiral amines supported on a soluble
polymer
SP
+
Cl
Reagents that are bound to soluble polymers offer a num-
ber of advantages while suffering less from reactivity prob-
lems often associated with a two-phase system (1). The
soluble polymer supports selected for our studies were the
noncrosslinked copolymer of styrene and chloromethyl sty-
rene 26, which was synthesized by free radical polymeriza-
tion following the procedure of Narita (9b, 17) and the
corresponding iodo derivative 27 (Scheme 5).
26
b
Cl
SP
I
27
Compound 26 has a number of advantages: it can be eas-
ily prepared from the commercially available starting materi-
als; it is soluble in common organic solvents such as THF,
CH2Cl2, CHCl3, AcOEt, and benzene even at low tempera-
tures, but it is insoluble in MeOH and H2O. The products of
reactions involving this polymer can be purified using aque-
ous extraction and polymer precipitation. Chiral amines 3
and 30 (the latter was prepared as shown in Scheme 6, using
literature procedures, refs. 4b, 18) were attached to the poly-
mer backbone using the iodo derivative 27 analogously to
the method described above for compounds derived from the
Merrifield resin (Scheme 6; cf., Scheme 1). All reactions
were easy to carry out, and the resulting resins (31, 32) were
isolated by precipitation from cold MeOH.
Scheme 6.
NH2
NH2
O
NH2
N
N
Ph COOH
28
Ph
29
Ph
30
Ph
N
N
H
Ph
N
H
SP
SP
Attachment of chiral amines to the soluble support via
linkers was realized by a three-step procedure shown in
Scheme 7. The linker was attached first to the soluble poly-
mer (26 or 27) followed by the well-precedented functional
group manipulations and attachment of the chiral amine. The
linker was expected to distance the amine from the polymer
31
32
matrix and it was hoped that this should make it more acces-
sible to BuLi during the generation of the corresponding
lithium amide, and also should result in less steric hindrance
© 2006 NRC Canada

260
Can. J. Chem. Vol. 84, 2006
Scheme 7.
1. NaH, 0 oC, DMF
2. 26, 60 oC
imidazole, PhP3,
HO
OH
I2, CH2Cl2, rt.
SP
O
OH
n
n
13: n = 1
14: n = 4
33: n = 1
34: n = 4
3, THF, reflux
O
I
SP
SP
O
N
H
Ph
n
n
35: n = 1
36: n = 4
37: n = 1
38: n = 4
during the subsequent deprotonation step. Polymers 37 and
38 were synthesized according to the procedure analogous to
that described above for the insoluble amines 19 and 20.
Scheme 8.
O
N
Synthesis and reactions of polymer-supported lithium
amides
Me
After the synthesis of the series of polymer-supported
chiral amines was completed, the stage was set for genera-
tion of the corresponding lithium amides. Polymer-supported
reagents could offer several advantages over the chiral lith-
ium amides generated in solution. Some of these could in-
volve: simplified reaction procedures, possibility of easy
regeneration of the polymer bound reagent, and undesired
side reactions such as crosslinking could be suppressed by
using more solvent (the principle of high dilution) (2b).
Polymer-bound reagents are usually more stable, and a pos-
sibility for the automation of reactions exists when dealing
with polymer-supported chiral lithium amides. Generation of
lithium amides from secondary amines is a relatively simple
reaction in solution and numerous procedures have been de-
scribed. The reader’s attention is directed to a few recent ref-
erences that illustrate a certain variety of conditions (4, 19).
The procedure for generation of polymer-supported lithium
amides was designed by analogy with chemistry in solution
(cf., Experimental) and involved treatment of the parent
amine with BuLi at 0 °C in THF. In the case of insoluble
polymer-supported chiral lithium amides, it should be noted
that THF is the solvent that swells the polymer matrix the
most, which implies that the conditions of the subsequent re-
action should be similar to homogenous conditions.
39
1.
CLA
2. PhCHO
1.
2. Cl3CCH2OCOCl
CLA
O
OH
O
N
H
Ph
Me
N
Me
COOCH2CCl3
40
41
CLA: polymer-supported chiral lithium amide
and is also a useful scaffold for construction of tropane
alkaloids (4). The aldol addition of tropinone enolate to
benzaldehyde is well-known to give only one
diastereoisomer of the corresponding aldol (40), which sim-
plifies the analysis, and the enantioselectivity can by easily
1
and accurately measured by H NMR with chiral solvating
During the generation of both the insoluble and soluble
polymer-supported lithium amides from the corresponding
chiral amines, color changes were observed (the suspension
of the polymer changed color from yellow to light reddish-
brown in the case of insoluble reagents and to red or purple
in the case of soluble ones). This could be attributed to the
formation of unidentified by-products. It was determined ex-
perimentally that if the color change did not occur, the sub-
sequent reactions did not proceed well; if the color became
dark brown, the yield of the reaction was usually low.
agents such as (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol
(4). Tropinone enolate undergoes ring opening with
chloroformates to give cycloheptenone derivatives (41); the
enantiomer ratio of these products can be analyzed by NMR
or by HPLC (Scheme 8) (4e).
Developing proper conditions for reactions involving
polymer-supported reagents can be complicated because of a
number of variables. The polymer matrix could react with
the reagents in solution in an undesirable fashion giving rise
to by-products and microenvironmental effects of an un-
known nature could be present (20). The reagents that are
supported on a polymer have restricted mobility owing to
the rigidity of the polymer matrix, and, usually, longer times
are required for reactions in which such reagents are em-
ployed. After some experimentation we established that gen-
eration of lithium amides attached to insoluble polymer
supports (i.e., derived from amines 6 or 20) required up to
8 h, and the subsequent deprotonation of tropinone required
Deprotonation of carbonyl compounds
Chiral lithium amide bases are powerful reagents that are
often used for enantioselective deprotonation of symmetrical
cyclic ketones (4). The resulting enolates are usually trapped
by various electrophiles and the reaction selectivity is mea-
sured on the product. Tropinone (39), a bicyclic ketone of Cs
symmetry provides a good model for deprotonation studies
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Majewski et al.
261
Table 1. Deprotonation of tropinone with chiral lithium amides on polymer support, followed by the
aldol reaction of the corresponding enolate.
Entry
Lithium amide
Additive
Yield of 40 (%)
ee of 40a (%)
1
2
3
4
5
6
7
8
9
Li-6
—
—
38
40
45
30
35
83
51
35
40
14
20
24
10
20
75
70
26
35
Li-6b
Li-6
LiCl (1 equiv.)
—
Li-20
Li-20
Li-31
Li-32
Li-37
Li-38
LiCl (1 equiv.)
LiCl (2 equiv.)
LiCl (1 equiv.)
LiCl (1 equiv.)
LiCl (1 equiv.)
Note: All reactions were done in THF, the lithium amides were generated at 0 °C, and the aldol reaction was done
at –78 °C (cf., the Experimental).
aAll products were dextrarotatory and the absolute configuration is as drawn for structure 40.
bThe ketone was added slowly (over 45 min).
Fig. 1. Hypothetical structures of (a) a dimer involving the chiral lithium amide supported on soluble polymer and (b) mixed aggre-
gates involving lithium amide and LiCl connected to the polymer.
Without LiCl
With LiCl
CH2
N
CH2
N
CH2
CH2
CH2
N
CH2
N
CH2
N
CH2
N
N
N
Li
*R
Li
*R
Li
*R
Li
*R
Li
*R
*R
*R
Li
*R
Li
Li
Li
Li
Li
Li
Li
Cl
Cl
Cl
Li
Li
Cl
*R
*R
*R
N
N
N
(b)
CH2
CH2
CH2
(a)
up to 15 h to proceed to completion (detailed procedures are
described in the Experimental section). The analogous reac-
tions in solution are much faster (1 h and 1–2.5 h are usually
sufficient for the two steps, respectively).
AcOEt, and the aqueous layer was further extracted with
AcOEt. (cf., the Experimental section).
Lithium chloride appears to be a necessary additive in re-
actions involving amides on soluble polymeric support. In
some cases lithium amides could not be generated without
LiCl because of the formation of a gel, which made the reac-
tion mixture heterogeneous. This was especially evident in
experiments involving the lithium amide generated from
amine 31 — the reaction in the absence of LiCl did not work
at all because of gel formation, while when LiCl was added
the enantioselectivity increased (albeit slightly) with increas-
ing amounts of LiCl (at 0.5 equiv. of LiCl the ee was 66%
and at 2 equiv. of LiCl, it was 75%). This behaviour paral-
lels the reaction in solution (4a, 4e). It is possible that for-
mation of the gel could be caused by a noncovalent
crosslinking of the polymer chains owing to aggregation of
the lithium amide moieties. After addition of a LiCl solu-
tion, the gel disappears presumably because formation of the
mixed aggregates breaks the crosslinking (Fig. 1). The possi-
bility of such phenomena occurring in solution had been pre-
viously pointed out by Seebach (21).
The second task was to elaborate a proper workup for re-
actions involving polymer-supported amides. Aldol reactions
in solution are usually quenched with an aqueous solution of
a weak acid, followed by an extraction. However, with insol-
uble polymer-supported reagents the reaction mixture could
not be extracted before the removal of the polymeric re-
agent. In the end the following procedure proved to be effec-
tive: the reaction was quenched by addition of an aqueous
solution of NH4Cl, the polymers were separated off by filtra-
tion and washed with THF. The aqueous layer of the filtrate
was then extracted with Et2O. Both the insoluble polymer
reagents 6 and 20 and soluble amines (such as 30) were re-
cycled, purified, and could be reused without loss of reactivity.
In most cases, both the yield and the enantiomeric purity
of the tropinone aldol (40) were modest. As far as the insol-
uble polymers were concerned (Table 1, entries 1–5), we
speculated that the heterogeneous conditions were lowering
the efficiency and selectivity of the reaction. Soluble poly-
mers proved somewhat better (Table 1, entries 6–10). In this
case, the extraction was applied before the precipitation of
the polymer, which made the workup much easier. After
quenching the reaction, the mixture was simply diluted with
Another reaction of tropinone that had been studied is the
somewhat unusual ring opening with chloroformates
(Scheme 8) (4e). The reaction is easy to carry out in solu-
tion, and the methods for measuring the enantiomeric excess
of product 41 are known (4).
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Can. J. Chem. Vol. 84, 2006
Table 2. Deprotonation of tropinone with lithium amides on polymer support, followed by the ring opening of the
corresponding enolate.
Entry
Lithium amide
Additive
Yield of 41 (%)
ee of 41 (%)
2
59
1
2
3
4
5b
6
7
8
Li-6
Li-6
Li-7
Li-7
Li-8
Li-8
Li-8
Li-19
Li-19
Li-20
Li-20
Li-22
Li-22
Li-24
Li-32
—
13
37
10
15
5
LiCl (1 equiv.)
—
LiCl (1 equiv.)
—
–13a
36
–1.5a
–6.5a
–13a
3
6
2
22
–11a
9
3
30
—
7
LiCl (1 equiv.)
—
LiCl (1 equiv.)
—
LiCl (1 equiv.)
—
LiCl (1 equiv.)
—
10
42
48
22
25
5
11
5
57
9
10
11
12
13
14
15
LiCl (1 equiv.) and n-BuLi (1 equiv.)
Note: Enantioselectivity was measured with HPLC using a Chiralpack AD column and 15% isopropanol in hexane as the solvent
system. All reactions were done in THF, the lithium amides were generated at 0 °C, and the ring-opening reaction was done at 0 °C
(cf., the Experimental).
aLevorotatory enantiomer of 41 was the major product.
bThe reaction was done in 2,2,5,5-tetramethyltetrahydrofuran.
The yields and enantioselectivities varied from mediocre
observed by Seebach and co-workers (24) and others (25)
and usually appears during attempts to deuterate enolates re-
sulting in low deuterium incorporation. The process can, in
principle, manifest itself also when different electrophiles
are used. We had recovered substantial amounts of tropinone
from experiments that gave low yields of the ring-opening
products, suggesting that the internal proton return might be
the culprit.
In summary, we synthesized a number of chiral amines at-
tached to polymer supports that were either insoluble or sol-
uble in organic solvents. The corresponding lithium amides
were generated efficiently from these amines. The lithium
amides were used in the deprotonation of tropinone, result-
ing, in several cases, in an efficiency and enantioselectivity
similar to reactions in solution. These studies comprise a
preliminary step towards development of practical lithium
amide reagents on polymer support.
to low with only a few exceptions. The highest ee in this se-
ries of experiments was obtained with lithium amide derived
from amine 6 in the presence of LiCl (Table 2, entry 2). The
incorporation of a linker into amine structures, to separate
the chiral lithium amide moiety from the polymeric rigid
backbone, did not seem to make a difference. Obviously, the
steric hindrance that reagent 6 exhibits is necessary for the
reaction to proceed with a useful degree of selectivity.
Interesting results were obtained with lithium amides Li-7
(Table 2, entries 3 and 4) and Li-22 (Table 2, entries 12 and
13). In both cases, in the absence of LiCl, the major product
was the levorotatory enantiomer of 41; however, after the ad-
dition of LiCl the dextrarotatory enantiomer was the major
product. The mechanism of deprotonation of ketones with
chiral lithium amides is not well understood. It could be sug-
gested that the origins of the LiCl effects lie in a different
lithium amides species acting as the deprotonating agent
(22). There is much interest in identifying the role of differ-
ent possible aggregates in deprotonation (23). It should be
noted, however, that formation of a dimer by an insoluble,
polymer-supported lithium amide is unlikely because of the
rigid nature of the polymer matrix. The explanation why dif-
ferent enantiomers form at different conditions has to wait
for a detailed mechanistic study.
Table 2 contains only one entry that refers to a lithium
amide attached to soluble support (entry 15). We investi-
gated all the lithium amides corresponding to the chiral
amines attached to the soluble support in the ring-opening
reaction, however, the yields were uniformly very low. In a
few cases, such as that involving lithium amide Li-32, we
were able to improve the yield to a moderate level by adding
an extra equivalent of BuLi prior to addition of the electro-
phile. The overall low yields and the improvement that was
realized through addition of extra BuLi were rationalized by
the internal proton return. This phenomenon was had been
Experimental
General
For a general description of solvent and reagent purifica-
tion and ee measurements see the previous contributions
from our group (4b, 4c). Chiral amines used in this study
were either commercially available (compounds 3 and 5), or
were synthesized according to previously published proce-
dures (compound 30) (4b, 18), or are described in the fol-
lowing.
The insoluble resin used as polymer support was the com-
mercially available Merrifield resin (PS-Cl from Argonaut
Technologies) and the soluble noncrosslinked polystyrene resin
was synthesized as described before (9b). All NMR spectra
were acquired in CDCl3 on a 300 MHz instrument (Bruker).
© 2006 NRC Canada

Majewski et al.
263
Soxhlet extraction with a 1:1 mixture of THF and ethanol
(150 mL) for 4 h, and drying to the constant weight under
high vacuum (8.125 g). (Note: during the synthesis of solu-
ble noncrosslinked polymers 33 and 34, the product was
washed with water and then MeOH only in each case). The
loading, as determined by gravimetric analysis, was
General and typical procedures
Conversion of chlorobenzyl to the iodobenzyl moiety on
polymer support
Sodium iodide (5.00 g, 33.4 mmol) was added to the
preswollen (acetone) Merrifield resin (4.00 g, 4.00 mmol,
original loading: 1.00 mmol of Cl per gram) in acetone
(50 mL), and the resulting suspension was refluxed for 48 h.
The polymer was then separated by filtration and washed
with 100 mL of each of the following solvents: acetone,
THF, EtOH, MeOH, methanol–water (1:1), 2 N NaOH, wa-
ter, MeOH, and EtOH. (Note: in the case of soluble,
noncrosslinked polymer 27, the product was washed with
water and then MeOH). Polymer 2 was dried to constant
weight under high vacuum, yielding 3.862 g of the product.
1
0.825 mmol of OH per gram. H NMR δ: 8.57–6.30 (m,
24H, Ar), 4.28–3.37 (m, 8H, CH2Cl, polymer matrix, and
PhCH2O-, -OCH2 and -CH2OH, alcohol moiety), 2.18–1.09
(m, 8H, CH2, CH polymer matrix and CH2, alcohol moiety);
13C NMR δ: 128.4 (C-Ar), 68.1 (PhCH2O-), 62.5 (OCH2-),
40.5 (CH, polymer matrix), 25.8 (CH2).
Activation of the linker by iodination (typical procedure)
Imidazole (1.138 g, 16.74 mmol) was added to a solution
of triphenyl phosphine (4.386 g, 16.74 mmol) in dry CH2Cl2
(150 mL). Iodine (4.252 g, 16.74 mmol) was added next,
followed by the addition of polymer 15 (6.973 g,
5.753 mmol, 0.825 mmol of OH per gram). The reaction
mixture was protected from light and was stirred under N2
for 96 h. After the reaction was completed, the polymer was
separated by filtration and washed with 200 mL of each of
the following solvents: diethyl ether, benzene, water, metha-
nol, and diethyl ether. (Note: during the synthesis of soluble
noncrosslinked polymers 35 and 36, the product was washed
with water and then MeOH only in each case). Product 17
was dried to constant weight under high vacuum, yielding
7.210 g of the resin. The loading of the polymer was esti-
mated by gravimetric analysis and was 0.750 mmol of iodine
Amination (typical procedure)
S-(–)-α-Methylbenzyl amine (3.645 g, 3.880 mL,
30.12 mmol) was added to the preswollen polymer 2
(6.026 g, 6.026 mmol, original loading of 1.00 mmol of ha-
lide per gram) in THF (100 mL). The mixture was refluxed
under N2 for 48 h. After the reaction was completed, poly-
mer 6 was separated by filtration and washed with the fol-
lowing solvents (150 mL): THF, acetone, methanol,
methanol–water (1:1), water, NaOH, water, methanol, etha-
nol, and Et2O. The polymer was dried under high vacuum to
constant weight, and 6.000 g of the corresponding resin was
obtained. The loading of polymeric amine 6 was determined
by Fajans titration method and by elemetal analysis and was
1
0.604 mmol of N per gram. H NMR δ: 8.05–5.75 (m, 28H,
1
per gram of compound. H NMR δ: 8.50–5.90 (m, 148H,
Ar), 3.87–3.11 (m, 3H, PhCH2-N and CH-N), 2.14–0.44 (m,
12H, CH2, CH, polymer matrix, and CH3, amine moiety).
13C NMR δ: 145.8 (C-Ar), 128.1 (C-Ar), 126.9 (C-Ar),
125.9 (C-Ar), 58.1 (CH-N), 52.3 (PhCH2-N), 40.6 (CH,
polymer matrix), 24.7 (CH3). Found: C 81.43, H 6.55, N
1.83, which indicated loading to be 0.604 mmol/g.
Ar), 4.93–4.13 (m, 4H, CH2Cl, polymer matrix, and
PhCH2O-), 3.82–2.85 (m, 12H, -OCH2 and CH2I), 2.35–0.80
(m, 52H, CH2, CH, polymer matrix, and CH2, iodide moi-
ety). 13C NMR δ: 128.8 (C-Ar), 68.1 (PhCH2-O), 41.0 (CH,
polymer matrix), 33.8 (CH2), 3.7 (CH2I).
N-(3-Iodopropyl)phthalimide (10) (ref. 26)
Dehalogenation
A solution of N-(3-bromopropyl)phthalimide (0.500 g,
1.86 mmol) in acetone (2 mL) was added to a suspension of
sodium iodide (1.40 g, 9.30 mmol) in acetone (15 mL), and
the reaction mixture was refluxed for 2.5 h. Acetone was
evaporated and the residue was diluted with Et2O (35 mL),
and a saturated solution of Na2S2O3 (30 mL) was added. The
aqueous layer was extracted with Et2O (3 × 35 mL). The or-
ganic layers were combined, dried with MgSO4, and the sol-
vent was removed in vacuo giving the crude product
(0.600 g), which was purified by flash chromatography (hex-
ane, hexane–AcOEt 4:1) yielding pure 10 (0.530 g, 90%);
This procedure was applied in cases involving insoluble
polymers only. A solution of tributyltin hydride (3.645 g,
3.300 mL, 12.54 mmol) was added to a suspension of poly-
mer 6 (6.122 g, 4.180 mmol, loading of 0.604 mmol of N
per gram) in THF (125 mL), and the reaction mixture was
refluxed under N2 for 48 h. The polymer was separated by
filtration and washed with the following solvents (150 mL):
hexane, THF, methanol, methanol–water (1:1), water, 2 N
NaOH, water, methanol, ethanol, hexane, and Et2O. The
product was dried under reduced pressure to constant
weight, yielding 5.387 g of polymer-supported amine 6.
1
mp 84–86 °C (lit. value (26) mp 86–88 °C). H NMR δ:
7.85–7.57 (m, 4H), 3.71 (t, J = 6.76 Hz, 2H), 3.11 (t, J =
7.19 Hz, 2H), 2.19 (quint, J = 7.00 Hz). 13C NMR δ: 168.3,
134.1, 132.0, 123.4, 38.7, 32.6, 1.4.
Connection of the linker using a diol (typical procedure)
1,3-Propanediol (10.94 g, 10.40 mL, 144.0 mmol) was
added slowly to a suspension of NaH prewashed with dry
pentane (1.728 g, 75.13 mmol) in DMF (100 mL), and the
reaction mixture was stirred at 0 °C under N2 for 2 h.
Chloromethyl polystyrene 1 (8.00 g, 8.80 mol, 1.10 mmol of
Cl per gram) was then added and the reaction mixture was
refluxed under N2 for 48 h. The reaction was quenched by
the addition of water (100 mL) at 0 °C, and polymer 15 was
separated by filtration and washed with the following sol-
vents: water, methanol, ethanol, and Et2O, followed by
(S)-(–)-(3-Phthalimidopropyl)-1-phenylethylamine (11)
A
solution of (S)-α-methylbenzylamine (0.363 g,
3.00 mmol) in THF (5 mL) was added to a solution of iodide
10 (0.473 g, 1.50 mmol) in THF (15 mL). The reaction was
refluxed for 1.5 h and potassium carbonate (0.207 g,
1.50 mmol) was added. The reflux was continued overnight.
The reaction mixture was cooled down to room temperature, a
© 2006 NRC Canada

264
Can. J. Chem. Vol. 84, 2006
saturated solution of sodium bicarbonate (20 mL) was added,
and the mixture was extracted with Et2O (3 × 30 mL). The
organic layers were combined, washed with brine, and dried
with MgSO4. The solvent was removed in vacuo yielding the
crude product (0.650 g). The crude product was purified by
flash chromatography (hexane, hexane–AcOEt 1:1) yielding
(S)-N-(1-Phenylethyl-3-propyl)amino-1-propoxymethyl
polystyrene (19)
S-(–)-α-Methylbenzylamine (3.225 g, 3.43 mL, 26.65 mmol)
was added to a slurry of polymer 2 (5.331 g, 6.930 mmol) in
THF (150 mL). The reaction mixture was refluxed under N2
for 72 h. After the reaction was completed, polymeric amine
19 was separated by filtration and washed with the following
solvents (150 mL): THF, acetone, methanol, methanol–water
(1:1), water, NaOH, water, methanol, ethanol, and ether, and
then was dried under vacuum to constant weight and 5.00 g
of product was obtained. The loading of the polymer was
calculated from elemental analysis and was 0.636 mmol of
N per gram. Dehalogenation was conducted according to the
Dehalogenation procedure. The resulting pure polymeric
amine 19 was dried to constant weight under reduced pres-
sure and 4.85 g was obtained. The loading was determined
pure 11 (0.265 g, 57%); mp 82–85 °C. [α]25 –34.2° (c 1.15,
D
1
CH2Cl2). IR (cm–1): 2958, 1708, 1395. H NMR δ: 7.80–7.70
(m, 2H), 7.65–7.57 (m, 2H), 7.27–7.08 (m, 5H), 3.80–3.52
(m, 3H), 2.70–2.31 (m, 2H), 1.77 (quint., 2H, J = 6.65 Hz,
J = 13.39 Hz), 1.48 (br s, 1H, NH), 1.27 (d, 3H, J = 6.55 Hz).
13C NMR δ: 168.3, 145.7, 133.8, 132.1, 128.3, 126.7, 126.5,
123.0, 58.2, 44.6, 35.9, 28.8, 24.3. MS (EI): 293 (M – 1, 97),
231 (6), 188 (32), 160 (42), 134 (16), 105 (100), 79 (11).
Anal. calcd. for C19H20N2O2: C 74.00, H 6.54, N 9.08; found:
C 73.98, H 6.49, N 8.94.
1
to be the same as before the dehalogention procedure. H
NMR δ: 8.35–6.50 (m, 25H, Ar), 4.04–3.15 (m, 5H,
PhCH2O, O-CH2, CH-N), 2.10–0.70 (m, 10H, CH3, CH2, CH,
polymer matrix, and CH3, CH2, amine moiety). 13C NMR δ:
128.5 (C-Ar), 126.7 (C-Ar), 68.8 (PhCH2O-), 66.2 (OCH2),
58.6 (CH-N), 45.5 (CH2N), 40.6 (CH, polymer matrix), 31.0
(CH2), 24.7 (CH3). Found: C 87.68, H 7.57, N 0.92.
(S)-(–)-[N-tert-Butoxycarbonyl-(3-phthalimidopropyl)]-1-
phenylethylamine (12)
A solution of 30% Et3N in MeOH (2.5 mL) was added to
a solution of amine 11 (0.500 g, 1.62 mmol) in MeOH
(20 mL), followed by the addition of (Boc)2O (1.769 g,
8.110 mmol) in MeOH (10 mL) during which time the reac-
tion was stirred vigorously. The reaction mixture was
refluxed overnight. The mixture was cooled down to room
temperature and the solvent was removed in vacuo giving
the crude product (0.454 g), which was purified by DFC
(hexane, hexane–AcOEt 1:1), giving the pure product 12
(0.433 g, 70% yield); bp 150–152 °C at 0.05 Torr (1 Torr =
(S)-N-(1-Phenylethyl-6-hexyl)amino-1-hexoxymethyl
polystyrene (20)
The amine 20 was synthesized according to the procedure
described for amine 19. Loading was calculated from ele-
mental analysis and was 0.707 mmol of NH per gram.
Dehalogenation was conducted according to the procedure
133.322 4 Pa). [α]25 –56.3° (c 1.38, CH2Cl2). IR (cm–1):
D
1
for 19. H NMR δ: 7.60–6.13 (m, 32H, Ar, polymer matrix
1
2974, 1710, 1687, 1394, 1365. H NMR δ: 7.80–7.60 (m,
and amine moiety), 4.50–4.27 (br s, 2H, PhCH2O-), 3.95–
3.70 (br s, 1H, N-CH), 3.58–3.15 (br s, O-CH2), 2.70–0.70
(m, 25H, CH3, CH2, CH, polymer matrix, and CH3, CH2,
amine moiety). 13C NMR δ: 145.4 (C-Ar), 128.2 (C-Ar),
127.9 (C-Ar), 125.9 (C-Ar), 73.0 (PhCH2O-), 58.6 (CH-N),
45.4 (CH2N), 44.0 (CH2), 42.0 (CH2, polymer matrix), 40.7
(CH, polymer matrix), 29.9 (CH2), 26.4 (CH2). Found: C
86.25, H 7.80, N 0.903.
4H), 7.25–7.00 (m, 5H), 5.65–5.14 (br s, 1H), 3.53–3.36 (m,
2H), 3.03–2.85 (br s, 2H), 1.89–1.68 (m, 2H), 1.50–1.41 (d,
3H, J = 7.07 Hz), 1.41–1.30 (s, 9H). 13C NMR δ: 167.6,
155.2, 141.2, 133.5, 131.8, 127.9, 126.8, 122.7, 79.2, 59.8,
35.4, 28.0, 20.6, 16.9, 13.9. Anal. calcd. for C24H28N2O4: C
70.57, H 6.91, N 6.86; found: C 70.30, H 7.08, N 6.75.
(S)-(–)-3-[tert-Butoxycarbonylamino-(1-phenylethyl)]-1-
propylamine (4)
(S,S)-(+)-4-(1-Phenylethylamino)-2-methyl-1-pentanol (21)
This compound was prepared according to a general pro-
cedure for reductive amination of ketones (27). A solution of
4-hydroxy-4-methyl-2-pentanone (1.00 g, 1.07 mL, 8.62 mmol)
in MeOH (5 mL) was added to a solution of (S)-α-methyl-
benzylamine (0.949 g, 1.00 mL, 7.84 mmol) in MeOH
(25 mL), followed by the addition of NaBH3CN (0.518 g,
8.23 mmol). The reaction was stirred at room temperature
overnight. The solvent was removed in vacuo, a 10% solu-
tion of hydrochloric acid (50 mL) was added to the residue,
and the aqueous layer was extracted with Et2O (30 mL). The
acidic aqueous layer was cooled down to 0 °C and was made
basic by the slow addition of NaOH (ca. 4 g). The basic so-
lution was extracted with Et2O (3 × 50 mL). The organic
layers were combined, washed with brine (75 mL), and dried
with MgSO4. The solvent was removed in vacuo giving a
mixture of two products in a 5:1 ratio (GC). The products
were separated by chromatography (hexane, hexane–AcOEt
1:1), and the major one was obtained (0.866 g, 50% yield);
bp 135–139 °C at 6 mmHg (1 mmHg = 133.322 4 Pa). Only
A solution of 95% hydrazine (1 mL) was added to a solu-
tion of 12 (0.200 g, 0.490 mmol) in EtOH (10 mL), and the
reaction was stirred at room temperature overnight. A white
solid (phthalazine-1,4-dione) was filtered off and washed
with EtOH (10 mL). The filtrate was concentrated in vacuo.
The residue was diluted with Et2O (10 mL), and a saturated
solution of sodium bicarbonate was added (10 mL). The
aqueous layer was extracted with Et2O (2 × 10 mL). The or-
ganic layers were combined, washed with brine (30 mL),
and dried with MgSO4. The solvent was removed in vacuo,
and the crude product was obtained (0.150 g). The crude
product was purified by DFC (hexane, hexane–AcOEt 1:1),
giving pure 4 (0.110 g, 81% yield); bp 235 °C at 15 Torr.
[α]25D –77.3° (c 1.11, CH2Cl2). IR (cm–1): 2973, 2931, 1685,
1
1406, 1365, 699. H NMR δ: 7.45–7.09 (m, 5H), 5.59–4.98
(br s, 1H), 3.23–2.70 (m, 2H), 2.65–2.35 (m, 2H), 1.55–1.47
(d, 3H, J = 7.00 Hz), 1.47–1.23 (m, 11H). 13C NMR δ:
155.9, 141.9, 128.3, 127.0, 79.6, 53.7, 49.7, 41.4, 39.7, 33.7,
28.5, 17.5. Anal. calcd. for C16H26N2O2: C 69.03, H 9.41, N
10.06; found: C 69.07, H 9.16, N 9.99.
the major isomer was fully characterized. [α]26 +67.7°
D
© 2006 NRC Canada

Majewski et al.
265
(c 3.06, CH2Cl2). IR (cm–1): 3310, 2943, 2913, 2865, 1454,
1071. 1H NMR δ: 7.28–7.05 (m, 5H), 3.82 (q, 1H, J =
6.45 Hz), 3.20–3.04 (m, 1H), 1.41–1.33 (m, 2H), 1.28 (d,
3H, J = 6.45 Hz), 1.23 (s, 3H), 1.11 (s, 3H), 0.99 (d, 3H, J =
6.19 Hz). 13C NMR δ: 145.6, 128.5, 127.2, 126.3, 70.2, 54.7,
48.3, 31.8, 28.5, 22.1, 21.3. MS: (NH3): 222 (M + 1, 100),
148 (9), 105 (5). Anal. calcd. for C14H23NO: C 75.97, H
10.47, N 6.33; found: C 75.87, H 10.51, N 6.60.
C13H27NO: C 73.18, H 12.75, N 6.56; found: C 73.13, H
12.91, N 6.87.
(1S,2R,5S)-N-[(2-Isopropyl-5-methyl)cyclohexylamino]-3-
propyl-1-propoxymethyl polystyrene (24)
A solution of amine 23 (3.443 g, 16.20 mmol) in DMF
(10 mL) was added to a suspension of prewashed NaH
(0.450 g, 18.75 mmol) at 0 °C, and the reaction was stirred
under N2 for 2 h. The reaction was warmed up to room tem-
perature, and Merrifield resin (1) was added (6.50 g,
7.15 mmol, 1.1 mmol of Cl per gram), followed by the addi-
tion of dry K2CO3 (2.235 g, 16.20 mmol). The reaction mix-
ture was heated at 80 °C for 72 h. The reaction mixture was
cooled down to room temperature, and polymeric amine 24
was separated by filtration. The polymer was then washed
with water (500 mL), followed by the following solvents
(200 mL): 50% aq. MeOH, MeOH, EtOH, THF, MeOH,
Et2O, and THF, dried under vacuum to constant weight, and
7.0 g of the polymer were obtained. The loading of the poly-
mer was calculated from elemental analysis and was
(S,S)-(+)-4-(1-Phenylethylamino)-2-methyl-1-pentanol on
polystyrene support (22)
A solution of amine 21 (2.00 g, 9.05 mmol) in dry DMF
(5 mL) was added to a prewashed suspension of NaH
(0.350 g, 14.6 mmol) in DMF (80 mL) at 0 °C under N2.
The reaction mixture was stirred for 1 h at 0 °C, and the
polymer-supported benzyl iodide (2, 6.50 g, 7.15 mmol,
1.1 mmol of halide per gram) was added, followed by the
addition of dry K2CO3 (2.498 g, 18.10 mmol). The reaction
mixture was heated at 80 °C for 72 h. The mixture was
cooled down to room temperature, and polymer 22 was sep-
arated by filtration, washed with H2O (500 mL), followed by
washing with 150 mL of each of the following solvents:
MeOH, EtOH, THF, MeOH, and Et2O. Polymer 22 was
1
0.536 mmol of NH per gram. H NMR δ: 8.40–5.60 (m,
44H, Ar), 3.90–3.70 (m, 4H, CH2Cl, polymer matrix, and
PhCH2O-), 3.70–3.40 (m, 8H, OCH2 and CH2N), 2.70–1.42
(m, 4H, CH, polymer matrix, CH2 in the ring), 1.42–0.60
(m, 10H, CH2, polymer matrix, and CH3, CH2, CH, amine
moiety). 13C NMR δ: 128.1 (C-Ar), 66.0 (PhCH2O-), 54.5
(CH-i-Pr), 48.8 (CH-N), 45.5 (CH2N), 40.7 (CH, polymer
matrix), 25.8 (CH3), 15.5 (CH3). Found: C 88.70, H 8.42, N
0.75.
1
dried to constant weight under vacuum (7.0 g). H NMR δ:
8.55–4.80 (m, 105H, Ar and CH-N), 3.70–3.10 (m, 4H,
PhCH2-N and N-CH2), 2.64–0.00 (m, 110H, CH3, CH2, CH,
polymer matrix, and CH3, CH2, amine moiety). 13C NMR δ:
128.2 (C-Ar), 65.3 (C-O), 40.5 (CH, polymer matrix), 28.5
(CH3-C), 17.3 (CH3). Found: C 84.12, H 8.07, N 2.72,
which indicated the loading of the resin to be 0.414 mmol of
NH per gram.
Generation of the lithium enolate of tropinone using
polymer-supported chiral lithium amides
3-[(1R,2R,5S)-2-Isopropyl-5-methylcyclohexylamino]-1-
propanol (23)
Insoluble polymers
A solution of 3-aminopropanol (2.212 g, 2.250 mL,
29.50 mmol) in dry MeOH (10 mL) was added to a solution
of (–)-menthone (5.00 g, 5.60 mL, 32.5 mmol) in dry MeOH
(50 mL), followed by the addition of NaBH3CN (2.047 g,
32.50 mmol). The pH of the reaction was adjusted to 6 by
addition of glacial acetic acid, and the reaction mixture was
stirred at room temperature overnight. The mixture was di-
luted with water (30 mL), and Et2O (75 mL) was added. The
organic layer was extracted with a 10% solution of HCl (3 ×
50 mL). The acidic aqueous layers were made basic by slow
addition of solid NaOH. The basic solution was extracted
with Et2O (3 × 50 mL). The organic layers were combined,
dried with MgSO4, and the solvent was removed in vacuo
giving the crude product as two diastereomers in a 1:6 ratio
(determined by GC; 7.00 g). The crude product was purified
by chromatography (hexane, hexane–AcOEt 1:1) giving pure
A solution of n-BuLi in hexanes (1.45 mol/L, 1.4 mL,
2.049 mmol) was added to a slurry of an insoluble polymer-
supported chiral amine (2.049 mmol) in THF (20–25 mL) at
0 °C, and the resulting suspension was stirred for 8 h. Lith-
ium chloride in THF (0.63 mol/L, 2.95 mL, 1.86 mmol) was
added, and the stirring was continued for an additional 2 h.
After cooling to –78 °C, tropinone (0.258 g, 1.86 mmol) in
THF (2 mL) was added dropwise over ca. 3 min, and the re-
sulting mixture was stirred overnight.
Soluble polymers
A solution of n-BuLi in hexanes (1.9 mol/L, 0.58 mL,
1.1 mmol) was added to a solution of a soluble polymer-
supported chiral amine (1.1 mmol) in THF (25 mL) at 0 °C,
and the resulting solution was stirred for 2.5 h. Lithium
chloride in THF (1.0 mmol) was added, and the stirring was
continued for an additional hour. After cooling to –78 °C,
tropinone (0.139 g, 1.00 mmol) in THF (2 mL) was added
dropwise for over a period of 3 min, and the resulting mix-
ture was stirred for 3 h. If necessary, a second equivalent of
n-BuLi (1.9 mol/L, 0.58 mL, 1.1 mmol) was added at this
time, and the reaction mixture was warmed up to 0 °C. The
stirring was continued for 30 min, followed by cooling down
of the reaction mixture to –78 °C before the addition of an
electrophile.
23 (3.50 g, 55% yield); bp 145–147 °C at 7 mmHg. [α]29
D
+22.4° (c 1.14, CH2Cl2). IR (cm–1): 3250, 2969, 1600, 1374,
1
700. H NMR δ: 3.63 (dd, 2H, J = 5.15, 5.15 Hz), 2.86 (dt,
1H, J = 5.39, 11.20 Hz), 2.73 (d, 1H, J = 2.91 Hz), 2.47 (dt,
1H, J = 5.70, 11.50 Hz), 1.81 (dd, 1H, J = 2.43, 13.78 Hz),
1.61–1.48 (m, 4H), 1.48–1.35 (m, 1H), 1.30 (ddd, J = 6.63,
3.23, 13.21 Hz), 1.04–0.87 (m, 1H), 0.75 (d, 3H, J =
2.58 Hz), 0.74–0.69 (m, 9H). 13C NMR δ: 64.4, 54.3, 48.1,
47.9, 37.5, 35.2, 31.5, 28.9, 25.6, 24.8, 22.5, 21.4, 20.5. MS:
(CI, NH3): 214 (M + 1, 100), 128 (22). Anal. calcd. for
© 2006 NRC Canada

266
Can. J. Chem. Vol. 84, 2006
ganic layers were combined, dried with MgSO4, and the
bulk of the solvents were removed in vacuo. The residue
was added to cold (–45 °C) MeOH (300 mL) and polymer
33 precipitated and was separated by filtration, washed with
water (500 mL) and MeOH (750 mL). The polymer was
dried under vacuum to constant weight and 15.5 g were ob-
tained. The loading of 33 was calculated by gravimetric
Noncrosslinked (S)-N-(methyl-1-phenylethyl)amino
polystyrene (31)
A solution of (S)-(–)-α-methylbenzylamine (10.00 g,
10.64 mL, 82.64 mmol) in benzene (20 mL) was added to a
solution of polymer 27 (20 g, 20 mmol, 1.0 mmol of halide
per gram) in benzene (100 mL), and the reaction was
refluxed for 48 h. The reaction was cooled down to room
temperature, and the solvent was removed in vacuo. The res-
idue was cooled down to –45 °C and methanol was added
(300 mL). Amine 31 precipitated, was separated by filtration
and washed with water (100 mL) and MeOH (500 mL), and
then was dried to constant weight under vacuum and 20.5 g
were obtained. The loading of the polymer 31 was calcu-
lated from elemental analysis and was 0.69 mmol of N per
1
analysis (0.9 mmol of OH per gram). H NMR δ: 7.40–6.86
(m, 79 H, Ar), 6.86–6.30 (m, 50H, Ar), 4.55–4.35 (m, 2H,
CH2Cl), 3.89–3.73 (m, 2H, CH2OH), 3.73–3.55 (m, 2H, CH2O),
3.45–3.25 (m, 1H, OH), 2.35–2.10 (m, 10 H, CH2), 2.05–
1.73 (m, 25 H, CH, polymer matrix), 1.70–1.24 (m, 47 H,
CH2, CH3, polymer matrix). 13C NMR δ: 145.4 (C-Ar), 131.2
(C-Ar), 128.9 (C-Ar), 128.1 (C-Ar), 127.8 (C-Ar), 125.8 (C-Ar),
73.3 (CH2-OAr), 69.3 (-OCH2), 62.1 (CH2OH), 45.5 (CH2Cl),
44.0 (CH2, polymer matrix), 40.6 (CH, polymer matrix),
32.4 (CH2, alcohol moiety). Found: C 87.63, H 7.87.
1
gram. H NMR δ: 7.41–6.98 (m, 102 H, Ar), 6.98–6.45 (m,
66H, Ar), 4.74–4.54 (br s, 2H, CH2X), 4.29 (q, J = 6.4 Hz,
2H, CH-N), 4.01–3.55 (m, 9 H, CH2 and NH), 2.20–1.86 (m,
30H, CH, polymer matrix), 1.78–1.40 (m, 72H, CH3, amine
moiety and CH2, CH3, polymer matrix). 13C NMR δ: 145.2
(C-Ar), 128.8 (C-Ar), 128.6 (C-Ar), 128.4 (C-Ar), 128.1 (C-
Ar), 127.8 (C-Ar), 127.0 (C-Ar), 126.1 (C-Ar), 125.8 (C-
Ar), 57.6 (-CH-N), 51.1 (CH2N), 46.4 (CH2Cl), 43.9 (CH2,
polymer matrix), 40.5 (CH, polymer matrix), 24.4 (CH3,
amine moiety). Found: C 89.16, H 7.74, N 1.47
Noncrosslinked 6-hydroxy-1-hexoxymethyl polystyrene
(34)
A solution of 1,6-hexanediol (9.912 g, 84.00 mmol) in dry
DMF (30 mL) was added to a cold (0 °C) suspension of
prewashed NaH (1.2 g, 50 mmol) in DMF (150 mL), and the
reaction was stirred under N2 for 2 h. Soluble polymer 26
(12 g, 12 mmol, 1.0 mmol of Cl per gram) was added. The
reaction was heated at 80 °C for 48 h. The bulk of DMF was
distilled off under reduced pressure. The residue was cooled
down to –45 °C and MeOH (500 mL) was added. Polymer
34 precipitated and was separated by filtration, washed with
water (250 mL) and MeOH (500 mL), and dried under vac-
uum to constant weight and 12.5 g were obtained. The load-
ing of the polymer was calculated by the OH titration
Noncrosslinked (R)-[1-phenyl-2-(-1-
piperidino)ethylmethyl]amino polystyrene (32)
A solution of (R)-(1-amino-1-phenyl)ethyl-1-piperidine
(3.023 g, 15.00 mmol) in benzene (25 mL) was added to a
solution of soluble polymer-supported benzyl iodide 27
(15.0 g, 15.0 mmol, 1.0 mmol of halide per gram) in ben-
zene (150 mL), followed by the addition of K2CO3 (8.28 g,
60.0 mmol). The reaction mixture was refluxed under N2 for
48 h. The solvent was removed in vacuo, and the residue
was cooled down to –45 °C. Methanol (300 mL) was added
and amine 32 precipitated. Polymer 32 was separated by fil-
tration and washed with MeOH (200 mL), water (500 mL),
and MeOH (750 mL), and then dried to constant weight un-
der vacuum (16.099 g). The loading of amine 32 was esti-
mated by subtracting the molar amount of unreacted amine
from the total molar amount of amine used for the attach-
1
method and was 0.98 mmol of OH per gram. H NMR δ:
7.45–6.35 (m, 55H, Ar), 4.55–4.34 (m, 2H, CH2Cl), 3.75–
3.60 (m, 2H, O-CH2Ph), 3.55–3.30 (m, 4H, OCH2, CH2OH),
2.35–1.25 (m, 41H, CH2, CH, CH3, polymer matrix), 1.1–
0.85 (m, 8H, CH2). 13C NMR δ: 145.4 (C-Ar), 138.0 (C-Ar),
128.1 (C-Ar), 127.8 (C-Ar), 125.8 (C-Ar), 73.5 (CH2-OAr),
64.3 (OCH2), 63.0 (CH2OH), 45.5 (CH2Cl), 44.4 (CH2, poly-
mer matrix), 40.6 (CH, polymer matrix), 32.9 (CH2), 29.9
(CH2), 26.3 (CH2), 25.8 (CH2). Found: C 85.82, H 7.93.
1
ment to the polymer and was 0.944 mmol of N per gram. H
NMR δ: 7.25–6.25 (m, 70H, Ar), 3.90–3.65 (m, 2H, CH2-
N), 3.53–3.18 (m, 3H, CH2-N, CH-N), 2.83–2.58 (m, 2H,
CH2), 2.58–2.28 (m, 4H, CH2), 2.20–1.10 (m, 40H, CH2,
CH, polymer matrix and CH2 amine moiety). 13C NMR δ:
145.5 (C-Ar), 143.3 (C-Ar), 128.5 (C-Ar), 128.1 (C-Ar),
127.8 (C-Ar), 127.3 (C-Ar), 125.8 (C-Ar), 66.7 (CH2N),
55.1 (CH-N), 54.7 (CH2-N), 40.6 (CH, polymer matrix),
26.4 (CH2), 24.7 (CH2). Found: C 87.81, H 7.42, N 1.91.
Noncrosslinked 3-iodo-1-propoxymethyl polystyrene (35)
Imidazole (2.652 g, 39.00 mmol) was added to a solution
of triphenylphosphine (10.218 g, 39.00 mmol) in dry CH2Cl2
(200 mL), followed by the addition of iodide (9.906 g,
39.00 mmol) and polymeric alcohol 33 (10 g, 9.0 mmol,
0.9 mmol of OH per gram). The reaction was protected from
light and stirred under N2 at room temperature for 48 h. The
reaction mixture was extracted with a saturated solution of
Na2S2O3 (3 × 100 mL). The organic layers were dried with
MgSO4 and the bulk of CH2Cl2 was removed in vacuo. The
residue was cooled down to –45 °C and MeOH (500 mL)
was added. The polymer precipitated, was separated by fil-
tration, and washed with H2O (200 mL) and MeOH
(500 mL). The polymer was dried under vacuum to constant
weight (11.5 g). The loading of the polymer was not deter-
Noncrosslinked 3-hydroxy-1-propoxymethyl polystyrene (33)
A
solution of 1,3-propanediol (6.84 g, 6.58 mL,
90.0 mmol) in THF (20 mL) was added to a suspension of
prewashed NaH (1.2 g, 50 mmol) in THF (100 mL) at 0 °C
under N2. After stirring for 2 h, a solution of soluble poly-
mer 26 (15 g, 15 mmol, 1.0 mmol of Cl per gram) in THF
(75 mL) was added dropwise, and the reaction was refluxed
for 48 h. The reaction was cooled down to 0 °C and water
(50 mL) was added. The layers were separated and the aque-
ous layer was extracted with AcOEt (3 × 300 mL). The or-
1
mined at this stage. H NMR δ: 7.27–6.27 (m, 84 H, Ar),
4.55–4.33 (m, 2H, CH2Cl), 4.25–3.92 (m, 2H, CH2-OAr),
3.60–3.41 (m, 2H, OCH2), 3.39–3.20 (m, 2H, CH2I), 3.89–
3.50 (m, 2H, CH2), 2.15–1.18 (m, 44 H, CH, CH2, CH3,
© 2006 NRC Canada

Majewski et al.
267
polymer matrix). 13C NMR δ: 145.3 (C-Ar), 132.1 (C-Ar),
128.1 (C-Ar), 127.8 (C-Ar), 125.8 (C-Ar), 73.2 (CH2-OAr),
69.5 (O-CH2), 44.3 (CH2Cl), 42.0 (CH2, polymer matrix),
40.6 (CH, polymer matrix), 33.7 (CH2), 3.7 (CH2I). Found:
C 77.75, H 6.54.
58.5 (CH2N), 45.4 (CH2, polymer matrix), 40.6 (CH, poly-
mer matrix), 29.5 (CH2), 27.3 (CH2), 26.2 (CH3). Found: C
87.62, H 7.69, N 1.05.
(1S,2R,1′S)-2-(1′-Hydroxybenzyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (40) (ref. 28)
Noncrosslinked 6-iodo-1-hexoxymethyl polystyrene (36)
Compound 36 was prepared according to the procedure
described for polymer 35. The loading of starting alcohol 33
was 0.98 mmol of OH per gram. Polymer 36 was dried un-
der vacuum to constant weight and 10.68 g were obtained;
Synthesis using insoluble polymer-supported chiral
lithium amides
Benzaldehyde (0.217 g, 0.208 mL, 2.049 mmol) was
added to a solution of tropinone lithium enolate (1.86 mmol)
at –78 °C, generated as described previously, and the reac-
tion mixture was stirred for 4 h. The mixture was quenched
with a saturated solution of NH4Cl (10 mL). The polymer
was separated by filtration and washed with NH4Cl solution
and Et2O. The aqueous layer was separated and extracted
with Et2O (3 × 50.00 mL). The organic extracts were com-
bined and dried with MgSO4. The solvents were removed in
vacuo and the crude product was obtained. The crude prod-
uct was purified by chromatography (hexane–AcOH (4:1),
CH2Cl2–MeOH (85:15)) and the reaction yield and
enantioselectivity were determined as described before (28).
1
the loading was not determined at this stage. H NMR δ:
7.40–6.25 (m, 120H, Ar), 4.57–4.32 (m, 2H, CH2Cl), 4.3–
3.92 (m, 2H, O-CH2Ar), 3.62–3.35 (m, 2H, OCH2), 3.30–
3.11 (m, 2H, CH2I), 2.98–2.54 (m, 4H, CH2, alcohol moi-
ety), 2.38–1.05 (m, 80H, CH2, CH, polymer matrix, and CH2
alcohol moiety). 13C NMR δ: 145.4 (C-Ar), 132.2 (C-Ar),
128.6 (C-Ar), 128.0 (C-Ar), 127.8 (C-Ar), 125.8 (C-Ar),
73.0 (CH2-OAr), 70.3 (OCH2), 40.5 (CH, polymer matrix),
33.6 (CH2), 30.4 (CH2), 29.7 (CH2), 25.5 (CH2), 7.5 (CH2I).
Found: C 75.92, H 6.27.
Noncrosslinked (S)-N-[(1-phenylethyl-3-propyl)amino]-1-
propoxymethyl polystyrene (37)
Synthesis using soluble polymer-supported chiral lithium
amides
A solution of (S)-(–)-α-methylbenzylamine (4.588 g,
4.88 mL, 37.90 mmol) in benzene (10 mL) was added to a
solution of polymer 35 (6.321 g, 5.690 mmol, 0.9 mmol of
halide per gram) in benzene (150 mL), and the reaction was
refluxed under N2 for 48 h. The reaction was cooled down to
room temperature and the bulk of the benzene was removed
in vacuo. The residue was cooled down to –45 °C and
MeOH (300 mL) was added slowly. Polymeric amine 37
precipitated, was separated by filtration, and washed with
water (250 mL) and MeOH (300 mL), and then was dried to
constant weight under vacuum and 6.0 g were obtained. The
loading was determined from elemental analysis and was
Benzaldehyde (117 mg, 0.11 mL, 1.10 mmol) was added
to a solution of tropinone enolate at –78 °C (1.0 mmol) gen-
erated as described previously, and the reaction mixture was
stirred for 1 h. The mixture was quenched with a saturated
solution of NH4Cl (10 mL), and quickly extracted with
AcOEt (3 × 100 mL). The organic extracts were combined,
dried with MgSO4, and the solvents were removed in vacuo.
The residue was cooled down to –40 °C and MeOH (100 mL)
was added. A soluble polymer-supported amine precipitated
out, and was separated by filtration. The filtrate was concen-
trated in vacuo, and the crude product was obtained. The
crude product was purified by chromatography (hexane–AcOH
(4:1), CH2Cl2–MeOH (85:15)), and the reaction yield and
enantioselectivity were determined as described before (28).
1
0.985 mmol per gram. H NMR δ: 7.50–6.40 (m, 142 H,
Ar), 4.59–4.33 (m, 2H, CH2Cl), 4.28–4.16 (m, 1H, CH-
OAr), 3.98–3.80 (m, 1H, CH-OAr), 3.70–3.35 (m, 3H,
OCH2, CH-N), 2.85–2.57 (m, 2H, N-CH2), 2.53–1.13 (m,
80H, CH2, CH, CH3, polymer matrix and CH2, CH3, amine
moiety). 13C NMR δ: 145.3 (C-Ar), 135.0 (C-Ar), 128.6 (C-
Ar), 128.1 (C-Ar), 127.8 (C-Ar), 126.8 (C-Ar), 125.8 (C-
Ar), 72.9 (CH2-OAr), 68.9 (OCH2), 64.4 (CH-N), 58.7
(CH2-N), 45.4 (CH2Cl), 44.1 (CH2, polymer matrix), 40.5
(CH, polymer matrix), 30.0 (CH2), 24.5 (CH3). Found: C
87.50, H 8.03, N 1.17.
6-[N-(2,2,2-Trichloroethoxycarbonyl)-N-methyl]-amino-
2-cyclohepten-1-one (41) (ref. 4e)
With insoluble polymer-supported chiral lithium amides
2,2,2-Trichloroethyl chloroformate (0.434 g, 0.28 mL,
2.05 mmol) was added to a solution of tropinone lithium
enolate (1.86 mmol), generated as described previously, and
the reaction mixture was stirred for 8 h. The reaction was
quenched with a saturated solution of K2CO3 (10 mL), and
the polymeric amine was separated by filtration and washed
with a saturated solution of K2CO3 (100 mL) and Et2O
(100 mL). The aqueous layer was separated and extracted
with Et2O (3 × 50.00 mL). The organic extracts were com-
bined and dried with MgSO4. The solvents were removed in
vacuo, and the crude product was purified by DFC (hexane,
hexane–AcOEt 1:1) and pure 41 was obtained. Spectral
characterisctics of compound 41 and the method for measur-
ing ee were described before (4e).
Noncrosslinked (S)-N-[(1-phenylethyl-6-hexyl)amino]-1-
hexoxymethyl polystyrene (38)
Amine 38 was prepared according to the procedure de-
scribed for amine 37. The product was dried to constant
weight under vacuum and 9.5 g were obtained. The loading
of polymer 38 was calculated from elemental analysis and
1
was 0.742 mmol N per gram. H NMR δ: 7.25–6.25 (m,
179H, Ar), 4.60–4.35 (m, 2H, CH2Cl), 4.25–4.13 (m, 1H,
ArO-CH2), 3.95–3.70 (m, 1H, ArO-CH2), 3.55–3.30 (m, 4H,
OCH2, CH-N, NH), 2.65–0.90 (m, 115H, CH2, CH polymer
matrix, and CH2N, CH2, CH3, amine moiety). 13C NMR δ:
145.4 (C-Ar), 134.0 (C-Ar), 128.6 (C-Ar), 128.1 (C-Ar),
125.8 (C-Ar), 73.2 (CH2-OAr), 70.5 (OCH2), 64.3 (CH-N),
With soluble polymer-supported chiral lithium amides
2,2,2-Trichloroethyl chloroformate (277 mg, 0.18 mL,
1.30 mmol) was added to a solution of tropinone lithium
© 2006 NRC Canada

268
Can. J. Chem. Vol. 84, 2006
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ture was stirred for 2 h. The mixture was quenched with a
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Acknowledgements
The authors thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the University of
Saskatchewan, Saskatoon, Saskatchewan, for financial sup-
port.
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© 2006 NRC Canada