Polymer-supported organocatalysts: Asymmetric reduction of imines with trichlorosilane catalyzed by an amino acid-derived formamide anchored to a polymer

Article abstract of DOI:10.1021/jo800094q

(Chemical Equation Presented) Asymmetric reduction of ketimines 1a-e with trichlorosilane can be catalyzed by the N-methylvaline-derived Lewis basic formamide anchored to a polymeric support (5a and 5b) with good enantioselectivity (≤82% ee) and low catal

Full text of DOI:10.1021/jo800094q

Polymer-Supported Organocatalysts: Asymmetric Reduction of
Imines with Trichlorosilane Catalyzed by an Amino Acid-Derived
Formamide Anchored to a Polymer†
Andrei V. Malkov,* Marek Figlus, and Pavel Kocˇovský*
Department of Chemistry, WestChem, Joseph Black Building, UniVersity of Glasgow,
Glasgow G12 8QQ, Scotland, U.K.
amalkoV@chem.gla.ac.uk; paVelk@chem.gla.ac.uk
ReceiVed January 15, 2008
Asymmetric reduction of ketimines 1a-e with trichlorosilane can be catalyzed by the N-methylvaline-
derived Lewis basic formamide anchored to a polymeric support (5a and 5b) with good enantioselectivity
(e82% ee) and low catalyst loading (typically 15 mol %) at room temperature. This protocol represents
a considerable simplification of the isolation procedure and is particularly suitable for a parallel synthesis
of chiral amines 2a-e. The polymer-supported catalysts retain full activity after a multiple use.
Introduction
synthesis of amines of high enantiopurity. However, aside from
the leaching problems and the difficulties associated with the
quantitative recovery of the catalyst, it is the need of high
pressure that makes this method less attractive in view of the
technical demands. This applies in particular to high-throughput
parallel chemistry and scaling up.
Asymmetric reduction of prochiral ketimines 1 represents an
attractive route to chiral amines 2 (Scheme 1), which serve as
valuable building blocks for pharmaceutical and other fine
chemical industries. Catalytic hydrogenation, employing a
variety of metals and chiral ligands, has evolved, over the years,
into an established method1–4 and is regarded as an advanced
alternative to stoichiometric processes, such as hydride reduc-
tion, for which the enantioselective version1 is less economical.
Since both atoms of the H2 molecule are transferred to the
product, hydrogenation can serve as a prime example of atom
economy. However, the potential leaching of the transition-metal
catalyst requires special attention, since the allowed contamina-
tion of the product in pharmaceutical industry is at the ppm
level. Iridium-catalyzed asymmetric hydrogenation5 has now
been generally accepted as the champion method for the
Metal-free organocatalysis6 has now emerged as a novel
synthetic philosophy with the ambition to replace, whenever
possible, the traditional transition metal catalysis. The past few
years have witnessed the development of organocatalytic
(2) For recent reports on catalytic hydrogenation (with Ti, Ir, Rh, and Ru),
see refs 1b–d and the following: (a) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed.
2001, 40, 3425. (b) Jiang, X. B.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.;
Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G. Org.
Lett. 2003, 5, 1503. (c) Cobley, C. J.; Henschke, J. P. AdV. Synth. Catal. 2003,
345, 195. (d) Okuda, J.; Verch, S.; Stürmer, R.; Spaniol, T. S. J. Organomet.
Chem. 2000, 605, 55. (e) Guiu, E.; Muñoz, B.; Castillón, S.; Claver, C. AdV.
Synth. Catal. 2003, 345, 169. (f) Cobbley, C. J; Foucher, E.; Lecouve, J.-P.;
Lennon, I. C.; Ramsden, J. A.; Thominot, G. Tetrahedron: Asymmetry 2003,
14, 3431. (g) Chi, Y.; Zhou, Y. G.; Zhang, X. J. Org. Chem. 2003, 68, 4120.
(h) Bozeio, A. A.; Pytkowicz, J.; Côté, A.; Charette, A. B. J. Am. Chem. Soc.
2003, 125, 14260. (i) Trifonova, A.; Diesen, J. S.; Chapman, C. J.; Andersson,
P. G. Org. Lett. 2004, 6, 3825. (j) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.;
Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886. For the Ru-catalyzed transfer
hydrogenation, see: (k) Samec, J. S. M.; Bäckvall, J. E. Chem. Eur. J. 2002, 8,
2955. For Rh-catalyzed hydrogenation of enamides, see the following: (l) Hu,
X.-P.; Zheng, Z. Org. Lett. 2004, 6, 3585.
† Dedicated to Dr. Vladimír Hanusˇ on the occasion of his 85 birthday.
(1) For a general overview of the reduction of imines, see the following: (a)
Morrison, J. D. Asymmetric Synthesis; Academic Press: New York, 1983; Vol.
2. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley & Sons:
New York, 1994. (c) Ojima, I. Catalytic Asymmetric Synthesis; 2nd ed.; J. Wiley
and Sons: New York, 2000. (d) James, B. R. Catal. Today 1997, 37, 209. (e)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (f) Cho, B. T. Tetrahedron
2006, 62, 7621.
10.1021/jo800094q CCC: $40.75
Published on Web 04/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3985–3995 3985

Malkov et al.
CHART 1. Catalysts for the Asymmetric Reduction of
SCHEME 1. Asymmetric Reduction of Selected Ketimines
Imines
reduction with Cl3SiH,7–10 Hantzsch ester,11 and most recently,
even with H2 in the absence of a transition metal (though the
latter one is yet awaiting its enantioselective version).12
Matsumura, 9 Sun,10 and we7 have developed a series of chiral
organocatalysts derived from R-amino acids to promote asym-
metric reduction of prochiral imines7,9,10 and ketones8 with
trichlorosilane (Scheme 1). This methodology is tolerant of
various substitution patterns and the enantioselectivities regularly
exceed 90% ee.
In general, most of the organocatalytic procedures developed
to date require a rather high catalyst loading, with 20–30 mol
% (or even more) of the catalyst being more the rule rather
than an exception.6 Organocatalysts are cheaper than their
counterparts containing a precious transition metal coordinated
to an expensive ligand, so that there is less economic pressure
on the reduction of catalyst loading. Nevertheless, separation
of copious quantities of an organocatalyst from the desired
organic product is not a trivial task on a large scale and may
also become a nuisance in high-throughput parallel chemistry.
Our amino acid derived formamide-type catalysts 3a-d
(Chart 1)7 proved to be very efficient and, as a result, the loading
was reduced to 1–5 mol % (Table 1, entries 1 and 2).7,13
Nevertheless, even this considerably reduced amount still
appears as a contaminant in the product that has to be separated.
Recently, we have introduced a fluorous tag to the catalyst
(4a-c),7c which simplified the separation to an ordinary filtration
through a pad of fluorous silica gel that retained the catalyst,
whereas the product was eluted. Subsequent change of the
solvent resulted in elution of the catalyst that could be reused.
The classical chromatography of the crude mixture after the
workup was thus avoided. The introduction of the fluorous tag
proved to have little effect on the catalytic activity (Table 1;
compare entries 1 and 2 with 3).7c Herein, we describe a further
simplification of the product isolation by attaching the catalyst
to a solid support (5).14
(3) For hydrosilylation, see, e.g. (a) Reding, M. T.; Buchwald, S. L J. Org.
Chem. 1998, 63, 6344. (b) Verdaguer, X.; Lange, U. E. W.; Buchwald, S. L.
Angew. Chem., Int. Ed. 1998, 37, 1103. (c) Hansen, M. C.; Buchwald, S. L.
Org. Lett. 2000, 2, 713. (d) Vedejs, E.; Trapencieris, P.; Suna, E. J. Org. Chem.
1999, 64, 6724. (e) Nishikori, H.; Yoshihara, R.; Hosomi, A. Synlett 2003, 561.
(f) Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am. Chem. Soc. 2001, 123,
12917. (g) Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228.
(4) For transfer hydrogenation, see, e.g., ref 2j and the following: Kadyrov,
R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.
(5) Schinder, P.; Kock, G.; Pretot, R.; Wang, G.; Bohnen, F, M.; Kruger,
C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887.
(6) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Berkessel,
A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (d)
Dalko, P. I. EnantioselectiVe Organocatalysis; Wiley-VCH:Weinheim, 2007.
(7) (a) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocˇovský, P. Org.
Lett. 2004, 6, 2253. (b) Malkov, A. V.; Stoncˇius, S.; MacDougall, K. N.; Mariani,
A.; McGeoch, G. D.; Kocˇovský, P. Tetrahedron 2006, 62, 264. (c) Malkov,
A. V.; Figlus, M.; Stoncˇius, S.; Kocˇovský, P. J. Org. Chem. 2007, 72, 1315. (d)
Malkov, A. V.; Stoncˇius, S.; Kocˇovský, P. Angew. Chem., Int. Ed. 2007, 46,
3722.
Results and Discussion
(8) Malkov, A. V.; Stewart Liddon, A. J. P.; Ramírez-López, P.; Bendová,
L.; Haigh, D.; Kocˇovský, P. Angew. Chem., Int. Ed. 2006, 45, 1432.
(9) (a) Iwasaki, F.; Omonura, O.; Mishima, K.; Kanematsu, T.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525. (b) Onomura, O.; Kouchi, Y.;
Iwasaki, F.; Matsumura, Y Tetrahedron Lett. 2006, 47, 3751. For a related
reduction of ketones, see: (c) Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 1999, 40, 7507. (d) Matsumura, Y.; Ogura,
K.; Kouchi, Y.; Iwasaki, F.; Onomura, O. Org. Lett. 2006, 8, 3789.
(10) (a) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett.
2006, 8, 999. (b) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett.
2006, 8, 3045. See also: (c) Zheng, H.; Deng, J.; Lin, W.; Zhang, X. Tetrahedron
Lett. 2007, 48, 7934.
As the next step toward developing a user-friendly methodo-
logy for the reduction of imines with Cl3SiH, we resolved to
anchor the catalyst to a polymer (5) by employing the ether
link that proved suitable previously in the case of fluorous tag7c
(Chart 2). While the previous reductions were all carried in a
homogeneous solution (with toluene as an optimal solvent or
in CHCl3 or CH2Cl2),7 the solid-supported catalysts operate in
a heterogeneous system, which creates problems in its own
right.14 The choice of the type of polymer, to which the catalyst
is to be anchored, is not trivial, and a number of factors have
to be considered, including the swelling properties, the acces-
(11) (a) Singh, S.; Batra, U. K. Indian J. Chem., Sect. B 1989, 28, 1. (b)
Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005,
7, 3781. (c) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem.,
Int. Ed. 2006, 6383. (d) Rueping, M.; Antonchik, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 6751. (e) Yang, J. W.; Hechavarria-Fonesca, M. T.;
List, B. Angew. Chem., Int. Ed. 2004, 43, 6660. (f) Yang, J. W.; Hechavarria-
Fonesca, M. T.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (g)
Yang, J. W.; Hechavarria-Fonesca, M. T.; List, B. J. Am. Chem. Soc. 2005,
127, 15036. (h) Hoffman, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed.
2005, 44, 7424. (i) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193.
(j) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128, 13074.
(k) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368. (l) Zhou, J.;
List, B. J. Am. Chem. Soc. 2007, 129, 7498. (m) Ouellet, S. G.; Tuttle, J. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. (n) Storer, R. I.; Carrera,
D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (o) Tuttle,
J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662.
(12) (a) Case, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem.,
Int. Ed. 2007, 46, 8050. For a highlight, see: (b) Kenward, A. L.; Piers, W. E.
Angew. Chem., Int. Ed. 2008, 47, 38.
(13) In our earlier work, we used 10 mol % loading, which was recently
reduced to 0.5–1.0 mol %. Matsumura9 and Sun10 have typically used 10 mol
% loading.
(14) (a) For reviews on polymer-supported catalysts, see, e.g.: McNamara,
C. A.; Dixon, M. J.; Bradley, M Chem. ReV. 2002, 102, 3275. (b) Heitbaum,
M.; Glorius, F.; Escher, I. Angew. Chem., Int. Ed. 2006, 45, 4732. (c) Cozzi, F.
AdV. Synth. Catal. 2006, 348, 1367.
3986 J. Org. Chem. Vol. 73, No. 11, 2008

Polymer-Supported Organocatalysts
TABLE 1. Reduction of Ketimine 1a with Trichlorosilane,
Catalyzed by the Valine-Derived N-Methylformamides (S)-3b,d,
(S)-4b, and (S)-5a-fa
CHART 2. L-Valine-Derived Formamide Anchored to
Polymers with a Varying Spacer
entry
catalyst (mol %)
solvent
run
yieldb (%)
2ac % eed
1
2
3
4
5
6
7
8
9
3b (10)
3d (1)
toluene
toluene
toluene
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CHCl3
CHCl3
toluene
toluene
CHCl3
toluene
toluene
CHCl3
toluene
CHCl3
toluene
CHCl3
1
1
1
1
1
2
3
4
5
6
1
2
3
4
5
6
1
2
1
1
2
3
4
5
6
1
2
3
1
2
3
1
2
3
1
1
1
1
1
1
1
85
92
90
84
80
81
82
80
81
78
87
84
85
83
84
83
90
92
86
83
76
77
76
76
74
34
53
52
74
68
69
72
69
72
72
82
71
87
88
94
81
91e
93e
91e
63
76
82
81
82
82
81
77
82
81
81
82
81
78
81
20
73
78
79
77
77
77
22
61
68
73
77
76
47
47
63
30
45
51
91
88
86
86
4b (10)
5a (25)
5a (25)
5a (25)
5a (25)
5a (25)
5a (25)
5a (25)
5b (15)
5b (15)
5b (15)
5b (15)
5b (15)
5b (15)
5b (35)
5b (35)
5c (20)f
5c (20)f
5c (20)f
5c (20)f
5c (20)f
5c (20)f
5c (20)f
5c (40)g
5c (40)g
5c (40)g
5d (15)f
5d (15)f
5d (15)f
5d (25)g
5d (25)g
5d (25)g
5e (5)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
5e (5)h
5f (30)
10 (10)
10 (10)
11 (10)
22 (10)
a The reaction was carried out on a 0.4 mmol scale with 2.0 equiv of
Cl3SiH at 25 °C for 16 h unless stated otherwise. b Isolated yield. c The
absolute configuration was established from the optical rotation
(measured in CHCl3) by comparison with the literature data (see the
Experimental Section) and by HPLC via comparison with an authentic
sample; the resulting amines 2a was found to be (S)-configured.
d Determined by chiral HPLC. e Reference 7c. f Prepared by Williamson
etherification. g Prepared by Mitsunobu reaction. h The polymer was
acetylated with CH3COCl prior to the reaction.
of the sequence in a homogeneous solution. Therefore, protec-
tion was required in the beginning.
In our previous work, an ether link was selected to connect
the catalyst with the fluorous tag,7c and a similar strategy was
employed in the present study. The ether link was constructed
by using the catalyst precursor equipped with a free phenolic
group (ArOH) and the alkylating agent RfX. Optimization in
our previous work led to the use of RfOH as the alkylating agent
under Mitsunobu conditions.7c An alternative that would require
nucleophilic substitution at the aromatic ring of the catalyst with
RfOH serving as a nucleophile turned out to be much less
efficient.7c This previous work thus set the scene for the present
study.
sibility of the catalyst surrounded by the mass of atoms of the
polymeric chain, the compatibility of the polymer with the
reaction conditions, etc. The nature and the length of the link
between the polymer and the catalyst is another factor that has
to be considered.14 Of the plethora of commercially available
resins compatible with the intended chemistry of anchoring the
catalysts,14 we have selected the series summarized in Chart 2,
which included the most common Merrifield and Wang resin,
TentaGel, etc.
In the synthesis of the catalyst carrying the fluorous tag,7c
all of the chemistry involved was going to occur in a
homogeneous solution, so that the tag could be introduced in
an early stage of the synthesis.7c By contrast, in the present
study, we resolved to construct the link between the catalyst
and the polymer in the very last step in order to carry out most
Synthesis of the Catalytic Moiety Suitable for
Immobilization. The phenolic derivative 11 (Scheme 2) was
selected as a suitable catalyst precursor to be attached to the
polymer. Its synthesis commenced with the protection of
nitrophenol 6 by benzylation, and the resulting nitro ether 7
J. Org. Chem. Vol. 73, No. 11, 2008 3987

Malkov et al.
resulting acid 17 with LiAlH4 (95%).17 Mitsunobu reaction was
then employed to effect the alkylation of nitro phenol 6 with
alcohol 18 and the resulting nitro derivative 19 (84%) was
reduced with SnCl2 to furnish amine 20 (51%). Acylation of
the latter amine with the BOC-protected N-methylvaline7b
provided amide 21 (76%), whose deprotection (TFA), followed
by formylation (HCO2H, Ac2O), gave formamide 22 (87%). The
final hydrogenation released phenol 23 (95%).
SCHEME 2. Synthesis of the Catalyst with an Attachment
Point
Anchoring the Catalyst to a Polymer. Immobilization of
the catalyst in form of 5a,b (Scheme 5) was effected by
alkylation of the phenolic hydroxyl in 11 with polymeric benzyl
chlorides 24 and 25, respectively,18 using the modified Will-
iamson method (CsOH, DMF, 60 °C, 48 h), which afforded 5a
(0.75 mmol/g; 80%) and 5b (0.53 mmol/g; 51%).19,20 For the
preparation of the derivatized Wang polymer 5c, two approaches
were investigated, namely the alkylation of phenol 11 with the
bromo-Wang polymer 26 using the Williamson method (CsOH,
DMF, 60 °C, 48 h; 0.71 mmol/g; 57%) and alkylation of 11
with alcohol 27 via Mitsunobu reaction (1.31 mmol/g; 64%).
Similarly, this dual approach was utilized in the synthesis of
the derivatized TentaGel polymer 5d: the Williamson alkylation
with bromide 28 (CsOH, DMF, 80 °C, 67 h) produced 5d in
16% yield (0.21 mmol/g), whereas the Mitsunobu reaction with
alcohol 29 was slightly more effective, affording 5d in 39%
yield (0.33 mmol/g). The reaction of the phenolic Marshall
polymer 30 with the alkyl chloride 15 under Williamson
conditions (CsI, CsOH, THF, 45 °C, 48 h) afforded 5e (0.26
mmol/g; 20%). Finally, the extended Merrifield polymer 5f was
prepared by alkylation of phenol 23 with the benzylic chloride
24 under the Williamson conditions (0.69 mmol/g, 75%).
Asymmetric Reduction of Imines with Trichlorosilane
Catalyzed by Solid-Supported Formamides. The activity of
our immobilized catalysts in the reduction of imines was
investigated by using the reaction conditions adopted from the
homogeneous catalysis; catalyst 5a was employed in the pilot
reduction of imine 1a (R ) Ph). The reaction was carried out
as follows: a small porous polypropylene reactor vessel (2.4
mL internal volume) with 5a and imine 1a was left in toluene
for 30 min to ensure a proper swelling of the polymer, after
which Cl3SiH was added at 0 °C and the reduction was left to
proceed at room temperature overnight. After separation from
the mother liquor, the porous reactor vessel with the immobilized
catalyst was washed with toluene to elute the rest of the product,
followed by further washing with CH2Cl2, MeOH, and Et2O to
regenerate the immobilized catalyst. Aqueous workup of the
toluene solution7c afforded pure amine 2a (84% yield, 63% ee;
Table 1, entry 4). Switching to chloroform as the solvent had a
positive effect on the activity of 5a (76% ee; entry 5).
(89%)15 was reduced with SnCl2 under our standard conditions7c
to afford the aniline derivative 8 (43%). Extension of the reaction
time at the same temperature resulted in the formation of a
significant amount of the debenzylated product, whereas at lower
temperature the reaction did not proceed to completion. Acy-
lation of the latter product with the BOC-protected
N-methylvaline7b by using the carbodiimide method furnished
amide 9 (77%), whose deprotection with trifluoroacetic acid,
followed by formylation in one pot with a mixed anhydride
generated from formic acid and acetic anhydride, gave rise to
formamide 10 (85%). Finally, the protecting benzyl group was
removed by catalytic hydrogenation to produce the desired
phenol 11 (85%).
While phenol 11 could be used directly for the anchoring to
some of the resins, as in the case of 5a-d, others required
further modification before the final attachment (5e,f). Thus,
the chloropropyl ether 15 (Scheme 3) was prepared as a
precursor of the catalyst anchored to the Marshall polymer (5e).
Its synthesis differed from that of 11 in that the phenolic
hydroxyl in 6 was first derivatized by alkylation with 3-chlo-
ropropan-1-ol under Mitsunobu conditions to afford ether 12
(79%), in which the chloropropyl group served both as a
protection and as the final moiety to be used for the attachment.
The rest of the synthesis followed the original scheme: the nitro
derivative 12 was reduced with SnCl2 and the resulting amine
13 (65%) was converted into amide 14 (86%) by the carbodi-
imide method. The one-pot deprotection with TFA and formy-
lation with HCO2H and Ac2O afforded 15 (96%).
(17) Henley-Smith, P.; Whiting, D. A.; Wood, A. F. J. Chem. Soc., Perkin
Trans. 1 1980, 614.
(18) The following resins were employed in this study: (a) Chloromethyl-
polystyrene (24) 1.23 mmol/g 75–150 µm (StratoSphere), obtained from Polymer
Laboratories. (b) 5-[4-(Chloromethyl)phenyl]pentyl]styrene (25), polymer-bound
0.75–1.25 mmol/g 100–200 µm, obtained from Aldrich. (c) Bromo-
methylphenoxymethyl polystyrene (26) 1.40 mmol/g (StratoSphere) 150–300
µm, obtained from Polymer Laboratories. (d) 4-Hydroxymethylphenoxymethyl
polystyrene (27) 1.70 mmol/g (StratoSphere) 150–300 µm, obtained from
Polymer Laboratories. (e) TentaGel HL Br resin (28), 0.43 mmol/g, 110 µm,
obtained from Rapp Polymere GmbH. (f) TentaGel HL OH resin (29) 0.43
mmol/g 110 µm, obtained from Rapp Polymere GmbH. (g) 4-Hydroxytiophenol
resin (30), 1.58 mmol/g, 150–300 µm (StratoSphere), obtained from Polymer
Laboratories.
Synthesis of the extended polymer 5f required the elongated
phenol 23 as a precursor (Scheme 4). In its synthesis, alcohol
18 was selected as the electrophilic reagent to alkylate phenol
6. Alcohol 18 itself was prepared in two steps from the phenolic
acid 16, involving protection of the hydroxyl by benzylation
(BnBr, NaOH, EtOH; 56%),16 followed by reduction of the
(19) The yields were calculated by comparing the actual and theoretical
increase of the mass of the product. The mmol/g content of the active catalyst
anchored to a polymer was established by elemental analysis.
(15) When THF was used as solvent, the yield dropped to 30%.
(16) Doherty, D. G. J. Am. Chem. Soc. 1955, 77, 4887.
3988 J. Org. Chem. Vol. 73, No. 11, 2008

Polymer-Supported Organocatalysts
SCHEME 3
SCHEME 4
Repeated use of the regenerated catalyst 5a has demonstrated
retention of the activity (with chloroform as solvent; entries
6–10). Interestingly, the enantioselectivity turned out to be
slightly higher in runs 2–6 than in the first cycle (82 vs 76% ee
in the second vs first run; entries 6 and 5), which suggests that
“conditioning” of the catalyst was required to attain its optimal
performance.
Catalyst 5b (∼15 mol %) exhibited similar reactivity and
selectivity (entries 11–16) as its lower “homologue” 5a with a
shorter spacer. An attempt to improve the catalytic performance
by increasing the catalyst load to 30 mol % was fruitless (entries
17 and 18).
the next runs (entries 22–25). Interestingly, 5c prepared by
Mitsunobu reaction exhibited inferior results (entries 26–28).
However, a considerable improvement was attained in the
second and third run (entries 27 and 28), suggesting that the
polymer was contaminated by impurities, which were partly
removed during the first run.
The catalyst immobilized on TentaGel by Williamson etheri-
fication (5d) exhibited a similar level of activity as 5a (compare
entries 29–31 with 4–9), whereas the catalyst constructed via
Mitsunobu reaction appeared to be slightly less active (entry
34) with significantly worse results attained in toluene (entries
32 and 33).
With the Wang resin 5c, prepared by the Williamson reaction,
a dramatic dependence on the solvent was observed. Thus, while
the reduction of 1a in toluene exhibited mere 20% ee (entry
19), the reaction in chloroform gave 73% ee (entry 20). The
second run, as in the previous case, gave an improved result
(78% ee; entry 21), and this remained practically constant in
The catalyst anchored to the Marshall resin (5e) exhibited
rather low selectivity and can be regarded as a failure (entry
(20) The reaction carried out at 45 °C gave 5a in 62% yield, whereas at 80
°C the yield decreased to 31%. The use of THF or various mixtures of THF and
DMF as solvent, gave inferior results.
J. Org. Chem. Vol. 73, No. 11, 2008 3989

Malkov et al.
SCHEME 5. Attaching the Catalyst to a Polymera
TABLE 2. Asymmetric Reduction of Imines 1a-e with
Trichlorosilane Catalyzed by the Reused 5b (30 mol %) in CHCl3
a
run
imine
R1
yield in %b
2c % eed
2
3
4
5
6
1a
1b
1c
1d
1e
Ph
82
72
67
62
67
81e
79
81
77
78
2-naphthyl
4-CF3C6H4
4-MeOC6H4
2,5-Me2-3-furyl
a The reaction was carried out on a 0.4 mmol scale with 2.0 equiv of
Cl3SiH at 25 °C for 16 h unless stated otherwise. b Isolated yield. c The
absolute configuration was established from the optical rotation
(measured in CHCl3) by comparison with the literature data (see the
Experimental Section) and/or by HPLC via comparison with authentic
samples. All amines 2a-e were (S)-configured. d Determined by chiral
HPLC. e See also Table 1, entry 18.
TABLE 3. Reduction of Imine 1a with Trichlorosilane Catalyzed
a
by Resins 24–30
entry
resinb (mol %)
run
solvent
conversionc (%)
1
2
3
4
5
6
7
8
9
24(40)
24(40)
24(40)
25(30)
26(40)
27(40)
28(30)
29(30)
30(35)
1
2
3
1
1
1
1
1
1
CHCl3
CHCl3
toluene
CHCl3
toluene
CHCl3
CHCl3
CHCl3
toluene
15
10
40
6
70
7
9
9
85
a The reaction was carried out on a 0.4 mmol scale with 2.0 equiv of
Cl3SiH at 25 °C for 16 h. b The mol % loading of the resin relates to
the mmol/g content of the active group in the resin (ref 19).
c Established by 1H NMR spectroscopy of the isolated crude mixture of
the starting material and product.
a Williamson: CsOH, DMF, 60–80 °C, 48–67 h. Mitsunobu: Ph3P,
DEAD, THF, rt, 65–68 h.
runs. Therefore, we first “conditioned” the catalyst with 1a in
run 1; Table 2 shows runs 2–6 with the “conditioned” catalyst.
As expected, little variation of the yield and enantioselectivity
was observed for 1a–e (77–81% ee), which is consistent with
the results obtained for homogeneous solution.
35). Acetylation of any possible unfunctionalized phenolic
groups on the polymer with acetyl chloride and using this
product as a modified catalyst had only a marginal effect on
the activity (entry 36).
Finally, catalyst 5f also turned out to be rather inefficient, as
it facilitated the reduction of 1a with 51% ee (entry 37) even in
chloroform.
The Effect of the Solid Support and the Solvent on the
Reactivity and Selectivity. The solid-supported catalysts 5con-
sistently exhibited lower enantioselectivity (by ca. 10% ee) than
their soluble counterparts 3 and 4 (compare, e.g., entries 1 in
Tables 1 and 2), suggesting that either the polymeric backbone
affects the catalyst selectivity in an adverse way or that the
background, nonenantioselective reaction is faster in the het-
erogeneous system than in a homogeneous solution. To shed
light on this issue, control experiments with resins 24–30 (i.e.,
those lacking the catalytic formamide moiety) were carried out
(Table 3). It turned out, indeed, that the free resins did catalyze
the reaction, though at a considerably lower rate. In toluene
(Table 3, entries 3, 5, and 9), this background reaction proved
to be faster than in chloroform (entries 1, 2, 4, 6–8), which can
account for the inferior enantioselectivities obtained in toluene
(vide supra). Hence, it can be concluded that the lower
enantioselectivities observed for the heterogeneous systems
originate from the enhanced rate of the nonenantioselective,
background reaction, catalyzed by the polymeric backbone.
Furthermore, comparison of the catalytic activity of the Mer-
rifield resin 24 in chloroform in the first and second run (entries
1 and 2) could explain the changes observed between the first
Intermediates in the synthesis of the polymer-supported
catalysts, namely 10, 11, and 22, also proved to catalyze the
reduction (entries 38–41), generally at the level attained with
the original catalysts 3 (entries 1 and 2), i.e., by ∼10% ee higher
than those typical for the solid-supported catalysts 5. Again, as
with 3, slightly better results were obtained when toluene was
used as solvent (compare entries 38 and 39). These observations
show that the modification within the core of the original
catalysts 3 had little effect on its activity. Hence, the lower
selectivity, characterizing the solid-supported catalysts, must
originate from the polymeric framework and heterogeneous
conditions.
The scope of the imine reduction with Cl3SiH, catalyzed by
3a-d and 4a-c under homogeneous conditions (Scheme 1), is
relatively broad and spans from a range of aromatic to
heteroaromatic and some aliphatic substrates.7 In order to verify
if this is also the case with the solid-supported catalysts 5, a
brief screening was carried out with the aid of representative
imines, including electron-rich and electron-poor aromatics and
a heteroaromatic 1a-e (Table 2). As shown above, our solid-
supported catalysts retained their activity when reused. There-
fore, this series (Table 2) was run with the same batch of catalyst
5b. However, the previous experiments also demonstrated that
the first run gave consistently poorer results than the subsequent
(21) Dichloromethane behaved in a similar way as chloroform, exhibiting
only slightly lower enantioselectivities. On the other hand, solvents such as THF
or MeCN proved to be unsuitable for homogeneous solutions and were, therefore,
excluded from this study.
3990 J. Org. Chem. Vol. 73, No. 11, 2008

Polymer-Supported Organocatalysts
drying afforded a brownish solid (160 mg, 80%): IR (KBr) ν 3444,
2919, 1942, 1869, 1802, 1661, 1602, 1541, 1491, 1450 cm-1. Anal.
Found: C, 84.77; H, 7.15; N, 2.11. This corresponds to 0.75 mmol/g
loading.
and second run, i.e., the chemical background of the “condition-
ing” (vide supra). In the case of the reaction performed in
toluene, the Merrifield resin exhibited a relatively high catalytic
activity even after the “conditioning” (entry 3), which shows
that this solvent is not suitable for the heterogeneous reduction.21
The actual mechanism of the “conditioning” is intriguing.
With the polymers originally containing hydroxy groups prior
to anchoring the catalyst (27, 29, and 30), it can be speculated
that some of these groups remained unreacted and could then
interfere in the first run of the catalytic reduction. Their
exposition to the excess Cl3SiH would then lead to their
“capping” or ‘disabling’ for the second run, which would result
in an improved asymmetric induction. However, this mechanism
would not apply to the benzyl chloride type resins (24–26 and
28), indicating that the mechanism must be different. Interest-
ingly, after the first run with the supported catalyst 5a and
decomposition of the excess Cl3SiH, followed by rigorous drying
of the recovered catalyst, we noticed an increase of its weight
by about 25%, which was not repeated after the following runs.
The latter increase apparently stems from the formation of a
small amount of a gel by decomposition of Cl3SiH during the
workup. This gel, being itself an oligomer, could not be removed
from the polymer and its presence is apparently associated with
the improved enantioselectivity in the n + 1 runs. However,
the chemical basis of its action remains obscure. The infrared
spectra of the catalyst 5a, taken before and after the first run,
exhibit characteristic differences: thus, two strong additional
vibrations could be detected in the spectrum of the regenerated
catalyst, namely at 841 cm-1 (Si-O) and 2253 cm-1 (Si-H),
which is consistent with the mass increase.
Modified Merrifield Resin-Supported Catalyst 5b. Cesium
hydroxide monohydrate (57 mg, 0.34 mmol) was added to a reaction
tube with a solution of phenol 11 (90 mg, 0.32 mmol) in DMF (3
mL), followed by shaking at 60 °C for 30 min. A small porous
polypropylene reactor vessel (2.4 mL internal volume and 74 µm
pore size) with [5-[4-(chloromethyl)phenyl]pentyl]styrene, polymer-
bound 25 [0.75–1.25 mmol/g (130 mg, 0.097–0.16 mmol)] was
placed into the reaction tube, and the shaking was continued at 60
°C for 48 h. The porous reactor vessel was then removed from the
organic solution and successively washed with MeOH (2 × 25 mL),
a 1:1 mixture of MeOH and H2O (2 × 25 mL), a 1:1 mixture of
THF and H2O (2 × 25 mL), and then alternately with MeOH and
CH2Cl2 (4 × 25 mL of each solvent), and ether (25 mL). Vacuum
drying afforded a brownish solid (142 mg, 51%): IR (KBr) ν 3317,
2916, 1942, 1871, 1803, 1694, 1600, 1547, 1490, 1449, 1372 cm-1
.
Anal. Found: C, 85.08; H, 7.76; N, 1.49; this corresponds to 0.53
mmol/g loading.
Wang Resin-Supported Catalyst 5c. Method A. Cesium
hydroxide monohydrate (57 mg, 0.34 mmol) was added to a reaction
tube with a solution of phenol 11 (90 mg, 0.32 mmol) in DMF (3
mL), followed by shaking at 60 °C for 30 min. A small porous
polypropylene reactor vessel (2.4 mL internal volume and 74 µm
pore size) with bromomethylphenoxymethyl polystyrene 26 [1.40
mmol/g (114 mg, 0.16 mmol)] was placed into the reaction tube,
and shaking was continued at 60 °C for 48 h. The porous reactor
vessel was then removed from the organic solution and successively
washed with MeOH (2 × 25 mL), a 1:1 mixture of MeOH and
H2O (25 mL), a 1:1 mixture of THF and H2O (25 mL), and then
alternately with MeOH and CH2Cl2 (4 × 25 mL of each solvent)
and ether (25 mL). Vacuum drying afforded a brownish solid (130
mg, 57%): IR (KBr) ν 3431, 3024, 2920, 1943, 1877, 1805, 1725,
1674, 1602, 1550, 1512, 1451 cm-1. Anal. Found: C, 82.30; H,
7.55; N, 1.98; this corresponds to 0.71 mmol/g loading.
Conclusions
In conclusion, an effective methodology for asymmetric
reductions of imines 1a-e with trichlorosilane, promoted by
organocatalysts immobilized on a solid support (5), has been
developed. The methodology simplifies the recovery of the
catalyst while enabling the preparation of chiral amines in good
chemical yields and with good enantioselection, regardless of
the substitution pattern in the substrate. The catalysts can be
reused at least 5 times without any loss of activity, which
demonstrates their suitability for multiple and parallel use. The
highest level of catalytic activity and enantioselectivity (e82%
ee) was attained with the catalysts directly attached to the
polymer (5a) or via a suitable spacer (5b). A strong influence
of the solvents on the catalytic performance was observed; the
best results were obtained for chloroform, whereas toluene
proved to be much less suitable. Further improvements of these
polymer-supported catalysts are underway and will be reported
in due course.
Method B. Diethyl azodicarboxylate (80 µL, 0.51 mmol) was
added to a reaction tube containing a small porous poypropylene
reactor vessel (2.4 mL internal volume and 74 µm pore size) with
hydroxymethylphenoxymethyl polystyrene 27 [1.70 mmol/g (100
mg, 0.17 mmol)], phenol 11 (142 mg, 0.51 mmol), and triph-
enylphosphine (134 mg, 0.51 mmol) in THF (3 mL) at 0 °C. The
mixture was shaken at 25 °C for 65 h, and the porous reactor vessel
was then removed from the organic solution and washed alternately
with MeOH and THF (4 × 25 mL of each solvent), then CH2Cl2
(3 × 25 mL), and ether (25 mL). Vacuum drying afforded a white
solid (128 mg, 64%): IR (KBr) ν 3315, 3061, 2337, 1944, 1876,
1799, 1600, 1512, 1493, 1454 cm-1. Anal. Found: C, 79.10; H,
7.25; N, 3.68; this corresponds to 1.31 mmol/g loading.
TentaGel Resin-Supported Catalyst 5d. Method A. Cesium
hydroxide monohydrate (57 mg, 0.34 mmol) was added to a reaction
tube with a solution of phenol 11 (90 mg, 0.32 mmol) in DMF (3
mL), followed by shaking at 80 °C for 30 min. A small porous
polypropylene reactor vessel (2.4 mL internal volume and 74 µm
pore size) with TentaGel HL Br resin 28 [0.43 mmol/g (300 mg,
0.13 mmol)] was placed into the reaction tube, and the shaking
was continued at 80 °C for 67 h. The porous reactor vessel was
then removed from the organic solution and successively washed
with MeOH (2 × 25 mL), a 1:1 mixture of MeOH and H2O (2 ×
25 mL), a 1:1 mixture of THF and H2O (2 × 25 mL), and then
alternately with MeOH and CH2Cl2 (4 × 25 mL of each solvent)
and ether (25 mL). Vacuum drying afforded a brownish solid (304
mg, 16%): IR (KBr) ν 3448, 2917, 2870, 1664, 1602, 1492, 1453,
1106 cm-1. Anal. Found: C, 67.67; H, 8.56; N, 0.59; this
corresponds to 0.21 mmol/g loading.
Experimental Section
Merrifield Resin-Supported Catalyst 5a. Cesium hydroxide
monohydrate (57 mg, 0.34 mmol) was added to a reaction tube
with a solution of phenol 11 (90 mg, 0.32 mmol) in DMF (3 mL),
followed by shaking at 60 °C for 30 min. A small porous
polypropylene reactor vessel (2.4 mL internal volume and 74 µm
pore size) with chloromethylpolystyrene 24 [1.23 mmol/g (130 mg,
0.16 mmol)] was placed into the reaction tube, and the shaking
was continued at 60 °C for 48 h. The porous reactor vessel was
then removed from the organic solution and successively washed
with DMF (2 × 25 mL) and then alternately with MeOH and
CH2Cl2 (4 × 25 mL of each solvent) and ether (25 mL). Vacuum
Method B. Diethyl azodicarboxylate (55 µL, 0.35 mmol) was
added to a reaction tube containing a small porous polypropylene
reactor vessel (2.4 mL internal volume and 74 µm pore size) with
J. Org. Chem. Vol. 73, No. 11, 2008 3991

Malkov et al.
TentaGel HL OH resin 29 [0.43 mmol/g (300 mg, 0.129 mmol)],
phenol 11 (90 mg, 0.32 mmol), and triphenylphosphine (92 mg,
0.35 mmol) in THF (3.5 mL) at 0 °C. The mixture was shaken at
25 °C for 68 h, and the porous reactor vessel was then removed
from the organic solution and washed with THF (2 × 25 mL), then
alternately with MeOH and CH2Cl2 (4 × 25 mL of each solvent)
and ether (25 mL). Vacuum drying afforded a white solid (314
mg, 39%): IR (KBr) ν 3509, 2869, 1948, 1733, 1695, 1601, 1492,
1453, 1349 cm-1. Anal. Found: C, 67.69; H, 8.56; N, 0.93; this
corresponds to 0.33 mmol/g loading.
Marshall Resin-Supported Catalyst 5e. A solution of forma-
mide 15 (90 mg, 0.25 mmol) in THF (3 mL) was added dropwise
to a reaction tube containing a small porous polypropylene reactor
vessel (2.4 mL internal volume and 74 µm pore size) with
4-hydroxytiophenol resin 30 [1.58 mmol/g (80 mg, 0.13 mmol)],
cesium hydroxide monohydrate (27 mg, 0.16 mmol), and cesium
iodide (44 mg, 0.17 mmol), and the mixture was shaken at 45 °C
for 48 h. The porous reactor vessel was then removed from the
organic solution and successively washed with THF (20 mL), a
1:1 mixture of THF and water (2 × 20 mL), a 1:1 mixture of THF
and 1 M HCl (2 × 20 mL), and alternately with MeOH and CH2Cl2
(4 × 25 mL of each solvent) and ether (25 mL). Vacuum drying
afforded a brownish solid (88 mg, 20%): IR (KBr) ν 3429, 2920,
1944, 1873, 1804, 1655, 1599, 1580, 1491, 1451 cm-1. Anal.
Found: C, 77.67; H, 6.67; N, 0.72; this corresponds to 0.26 mmol/g
loading.
Merrifield Resin-Supported Catalysts with a Long Spacer
5f. Cesium hydroxide monohydrate (57 mg, 0.34 mmol) was added
to a reaction tube with a solution phenol 23 (132 mg, 0.32 mmol)
in DMF (3 mL), followed by shaking at 60 °C for 30 min. A small
porous polypropylene reactor vessel (2.4 mL internal volume and
74 µm pore size) with chloromethylpolystyrene 24 [1.23 mmol/g
(130 mg, 0.16 mmol)] was placed into the reaction tube and shaking
was continued at 60 °C for 65 h. The porous reactor vessel was
then removed from the organic solution and successively washed
with MeOH (2 × 25 mL), a 1:1 mixture of MeOH and H2O (25
mL), a 1:1 mixture of THF and H2O (25 mL), and then alternately
with MeOH and CH2Cl2 (4 × 25 mL of each solvent) and ether
(25 mL). Vacuum drying afforded a brownish solid (177 mg, 75%):
IR (KBr) ν 3318, 2915, 1942, 1872, 1803, 1694, 1599, 1546, 1489,
1448, 1374 cm-1. Anal. Found: C, 84.20; H, 7.46; N, 1.93; this
corresponds to 0.69 mmol/g loading.
CH2Cl2 to afford contaminated 8 (530 mg) as a red oil. The oil
was dissolved in Et2O (20 mL), followed by the addition of 1 M
hydrochloric acid (10 mL). The white solid amine salt thus formed
was isolated by filtration and washed with Et2O to remove impurities
and then dissolved in a mixture of Et2O (20 mL), water (10 mL),
and saturated NaHCO3 (10 mL) and stirred for 10 min. The organic
phase was separated, dried over MgSO4, and evaporated to afford
pure
8 (340 mg, 43%) as a yellowish oil: Rf ) 0.25
1
(CH2Cl2-petroleum ether 2:1); H NMR (400 Hz, CDCl3) δ 2.24
(s, 6H), 4.75 (s, 2H), 6.44 (s, 2H), 7.32–7.49 (m, 5H); 13C NMR δ
16.4 (CH3), 74.3 (CH2), 115.9 (CH), 127.8 (CH), 127.8 (CH), 128.
Five (CH), 131.8 (C), 137.9 (C), 141.1 (C), 148.9 (C); MS (EI)
m/z (%) 227 (M·+, 19), 136 (100), 108 (18), 91 (28); HRMS (EI)
227.1311 (C15H17NO requires 227.1310).
Amide (S)-(-)-9. Triethylamine (0.32 mL, 2.30 mmol) was
added to a solution of (S)-BOC-N-methylvaline (390 mg, 1.69
mmol) in dry CH2Cl2 (8 mL) at 0 °C. To the resulting clear solution
were successively added a solution of aniline 8 (340 mg, 1.50 mmol)
in CH2Cl2 (3 mL), 1-hydroxybenzotriazole (HOBt; 230 mg, 1.70
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (EDCI; 330 mg, 1.72 mmol). The reaction mixture was
stirred at 0 °C for 1 h and then at room temperature for 23 h. The
mixture was then diluted with ethyl acetate (70 mL) and washed
successively with water (30 mL), cold 0.5 M HCl (2 × 30 mL),
saturated NaHCO3 (2 × 30 mL), and brine (30 mL) and dried over
MgSO4 and evaporated. The residue (680 mg) was purified by
chromatography on a column of silica gel (50 g) with a mixture of
petroleum ether and ethyl acetate (8:1) to afford pure amide (S)-
(-)-9 (510 mg, 77%) as a white solid: mp 132–134 °C; Rf ) 0.50
(petroleum ether-AcOEt, 6:1); [R]D –81.6 (c 0.5, EtOH); 1H NMR
(400 Hz, CDCl3) δ 0.91 (d, J ) 6.5 Hz, 3H), 1.02 (d, J ) 6.5 Hz,
3H), 1.49 (s, 9H), 2.28 (s, 6H), 2.32–2.41 (m, 1H), 2.83 (s, 3H),
4.10 (d, J ) 10.7 Hz, 1H), 4.76 (s, 2H), 7.20 (s, 2H), 7.33–7.49
(m, 5H), 8.07 (br s, 0.78H); 13C NMR δ 16.5 (CH3), 18.6 (CH3),
19.9 (CH3), 25.9 (CH), 28.4 (CH3), 30.4 (CH3), 66.0 (CH), 74.2
(CH2), 80.6 (C), 120.2 (CH), 127.8 (CH), 128.0 (CH), 128.5 (CH),
131.6 (C), 133.7 (C), 137.5 (C), 152.2 (C), 157.4 (CO), 168.6 (CO);
MS (EI) m/z 440 (M•+, 22), 214 (36), 158 (95), 136 (100), 91 (54),
57 (49); HRMS (EI) 440.2674 (C26H36N2O4 requires 440.2675).
Formamide (S)-(-)-10. Trifluoroacetic acid (18.5 mL) was
added dropwise to a solution of the BOC derivative 9 (1.62 g, 4.40
mmol) in CH2Cl2 (30 mL) at 0 °C and stirring continued at the
same temperature for 1 h. The acid was removed under reduced
pressure, and the residue was coevaporated with toluene (2 × 20
mL) to afford a TFA salt of the deprotected amine as a brownish
oil, which was used in the following step without further purifica-
tion. The crude amine salt was dissolved in formic acid (20.7 mL),
and the resulting solution was cooled to 0 °C. Acetic anhydride
(15.4 mL) was then added dropwise and the mixture was allowed
to stir at room temperature for 15 h. The volatiles were then
evaporated and the residue (1.58 g) was purified by chromatography
on a column of silica gel (75 g) with a mixture of CH2Cl2 and
MeOH (99:1) to afford formamide (S)-(-)-10 (1.15 g; 85%) as a
light orange solid: mp 123–124 °C; Rf ) 0.62 and 0.37 (two spots;
CH2Cl2-MeOH, 49:1); [R]D –153.40 (c 0.5, CHCl3); 1H NMR (400
Hz, CDCl3, a mixture of rotamers in ca. 4:1 ratio; the signals for
the minor rotamer are marked with an *) δ 0.92 (d, J ) 6.5 Hz,
3H), 1.05 (d, J ) 6.5 Hz, 3H), 2.27 (s, 6H), 2.41–2.54 (m, 1H),
2.98 (s, 0.59H*), 3.00 (s, 2.36H), 3.68 (d, J ) 10.95, 0.16H*),
4.37 (d, J ) 11.0, 0.86H), 4.76 (s, 2H) 7.21 (s, 1.86 H), 7.24 (s,
0.13 H*), 7.32–7.47 (m, 5H), 8.01 (s, br. 0.85H), 8.15 (s, 0.91H),
8.50 (s, 0.16H); 13C NMR δ 16.5 (CH3), 18.6 (CH3), 19.6 (CH3),
25.2 (CH), 31.6 (CH3), 63.2 (CH), 74.2 (CH2), 120.4 (CH), 127.8
(CH), 128.0 (CH), 128.5 (CH) 131.7 (C), 133.2 (C), 137.5 (C),
152. Five (C), 164.0 (CO), 167.0 (CO); IR (KBr) ν 3459, 3317,
3069, 2965, 1658, 1613, 1551, 1482, 1411, 1211 cm-1; MS (EI)
m/z 368 (M·+, 9), 277 (17), 164 (12), 142 (91), 114 (100), 91 (75)
86 (23), 55 (13), 42 (11); HRMS (EI) 368.2103 (C22H28 N2O3
requires 368.2100).
4-Benzyloxy-3,5-dimethylnitrobenzene 7. Benzyl bromide (3.56
mL, 29.99 mmol) and K2CO3 (5.00 g, 36.20 mmol) were consecu-
tively added to a stirred solution of 2,6-dimethyl-4-nitrophenol 6
(2.00 g, 11.96 mmol) in dry acetone (50 mL), and the mixture was
refluxed for 19 h. The mixture was then evaporated, the residue
was partitioned between ether (80 mL) and water (40 mL), and the
organic phase was additionally washed with a 1 M aqueous solution
of NaOH (40 mL). The organic solution was dried over MgSO4
and evaporated to afford the crude product (6.05 g), which was
purified by chromatography on a column of silica gel (50 g) with
a mixture of petroleum ether and CH2Cl2 (5:1) to remove benzyl
bromide. Continued elution with a mixture of CH2Cl2 and petroleum
ether (2:1) afforded 7 (2.74 g, 89%) as a white solid: mp 68–69
1
°C; Rf ) 0.25 (petroleum ether-CH2Cl2, 5:1); H NMR (400 Hz,
CDCl3) δ 2.24 (s, 6H), 4.88 (s, 2H), 7.36–7.47 (m, 5H), 7.94 (s,
2H); 13C NMR δ 16.7 (CH3), 74.4 (CH2), 124.3 (CH), 127.9 (CH),
128.5 (CH), 128.7 (CH), 132.7 (C), 136.5 (C), 143.6 (C), 161.1
(C); MS (EI) m/z 257 (M·+, 4), 91 (100), 89 (5), 65 (27), 39 (9);
HRMS (EI) 257.1053 (C15H15NO3 requires 257.1052).
4-Benzyloxy-3,5-dimethylaniline 8. Tin(II) chloride dihydrate
(3.16 g, 14 mmol) was added to a solution of nitro ether 7 (900
mg, 3.5 mmol) in ethanol (20 mL), and the mixture was refluxed
for 9 h. The mixture was then cooled, a saturated aqueous solution
of NaHCO3 (50 mL) was added to reach pH 10, and the product
was extracted with ether (3 × 150 mL). The organic phase was
dried over MgSO4 and evaporated, and the residue (820 mg) was
purified by chromatography on a column of silica gel (30 g) with
3992 J. Org. Chem. Vol. 73, No. 11, 2008

Polymer-Supported Organocatalysts
Formamide (S)-(-)-11. A mixture of the benzyl derivative 10
(280 mg, 0.76 mmol) and 10% palladium on activated charcoal
(80 mg, 10 mol%) in absolute ethanol (14 mL) was stirred under
a hydrogen atmosphere for 9 h. The mixture was then filtered
through Celite, and the solvent was evaporated. The residue (220
mg) was purified by chromatography on a column of silica gel (30
g) with a mixture of CH2Cl2 and MeOH (49:1) to afford (S)-(-)-
11 (180 mg, 85%) as an enamel: Rf ) 0.37 and 0.25 (two spots;
CH2Cl2-MeOH, 49:1); [R]D –141.30 (c 1.0, CHCl3); 1H NMR (400
Hz, CDCl3, a mixture of rotamers in ca. 4:1 ratio; the signals for
the minor rotamer are marked with an *) δ 0.91 (d, J ) 6.5 Hz,
3H), 1.04 (d, J ) 6.5 Hz, 3H), 2.18 (s, 6H), 2.39–2.50 (m, 1H),
2.92 (s, 0.60H*), 3.00 (s, 2.35H), 3.51 (d, J ) 10.5 Hz, 0.19H*),
4.40 (d, J ) 11.2, 0.78H), 5.18 (s, 0.77H), 5.25 (s, 0.20H), 7.07 (s,
0.36 H*), 7.10 (s, 1.59H), 8.10 (s, br. 0.81H), 8.13 (s, 0.89H), 8.21
(s, 0.23H); 13C NMR δ 16.1 (CH3), 18.5 (CH3), 19.5 (CH3), 25.3
(CH), 31.6 (CH3), 62.9 (CH), 120.7 (CH), 123.8 (C), 129.8 (C),
149.3 (C), 163.9 (CHO), 167.0 (CO); IR (KBr) ν 3433, 3086, 3069,
2965, 1655, 1557, 1490, 1469, 1410, 1210 cm-1; MS (EI) m/z 278
(M•+, 39), 137 (66), 114 (100), 86 (38) 55 (19), 42 (19); HRMS
(EI) 278.1632 (C15H22N2O3 requires 278.1630).
4-(3′-Chloro-1′-propyloxy)-3,5-dimethylnitrobenzene 12. Triph-
enylphosphine (980 mg, 3.74 mmol), 3-chloropropanol (0.31 mL,
3.70 mmol), and 97% diethyl azodicarboxylate (0.59 mL, 3.73
mmol) were added consecutively to a stirred solution of 2,6-
dimethyl-4-nitrophenol 6 (500 mg, 2.99 mmol) in THF (7 mL) at
0 °C. The resulting mixture was stirred at 25 °C for 21 h, and the
solvent was then evaporated to afford the crude product (2.04 g),
which was purified by chromatography on a column of silica gel
(40 g) with a mixture of petroleum ether and CH2Cl2 (4:1) to give
12 (580 mg, 79%) as a white solid: mp 53–55 °C; Rf ) 0.42
(petroleum ether-CH2Cl2, 5:1); 1H NMR (400 Hz, CDCl3) δ 2.27
(pent, 2H, J ) 5.9 Hz), 2.36 (s, 6H), 3.84 (t, 2H, J ) 6.2 Hz), 3.97
(t, J ) 5.8 Hz, 2H), 7.92 (s, 2H); 13C NMR δ 16.5 (CH3) 33.0
(CH2), 41.2 (CH2), 68.3 (CH2), 124.3 (CH), 132.4 (CH), 143.6 (C),
160.9 (C); MS (CI) m/z (%) 243 (M·+, 37), 167 (86), 137 (77),
121 (15), 91 (54), 82 (100), 47 (59); HRMS (EI) 243.0658
(C11H14ClNO3 requires 243.0662).
yellowish oil: Rf ) 0.27 (petroleum ether-ethyl acetate, 8:1); [R]D
1
–81.6 (c 0.5, CHCl3); H NMR (400 Hz, CDCl3) δ 0.90 (d, J )
6.5 Hz, 3H), 1.00 (d, J ) 6.5 Hz, 3H), 1.48 (s, 9H), 2.22 (pent, J
) 6.0 Hz, 2H) partly overlapped with 2.25 (s, 6H), 2.31–2.41 (m,
1H), 2.82 (s, 3H), 3.83 (t, J ) 6.3 Hz, 3H), 3.85 (t, J ) 5.7 Hz,
2H), 4.09 (d, J ) 11.1 Hz, 1H), 7.18 (s, 2H), 8.08 (s, 0.87 H); 13
C
NMR δ 16.3 (CH3), 18.6 (CH3), 19.8 (CH3), 25.9 (CH), 28.4 (CH3),
30.4 (CH3), 33.2 (CH2), 41.6 (CH2), 65.9 (CH), 68.1 (CH2), 80.6
(C), 120.2 (CH), 131.4 (C), 133.6 (C), 151.9 (C), 157.4 (CO), 168.6
(CO); MS (CI) m/z 426 (M•+, 25), 213 (75), 136 (79), 130 (100),
82 (92), 57 (95); HRMS (EI) 426.2291 (C22H35ClN2O4 requires
426.2285).
Formamide (S)-(-)-15. Trifluoroacetic acid (3.5 mL) was added
dropwise to a solution of the BOC derivative 14 (300 mg, 0.70
mmol) in CH2Cl2 (6 mL) at 0 °C, and stirring was continued at the
same temperature for 1 h. The acid was removed under reduced
pressure, and the residue was coevaporated with toluene (2 × 10
mL) to afford a TFA salt of the deprotected amine as a brownish
oil, which was used in the following step without further purifica-
tion. The crude amine salt was dissolved in formic acid (4 mL),
and the resulting solution was cooled to 0 °C. Acetic anhydride (3
mL) was then added dropwise and the mixture was allowed to stir
at room temperature for 19 h. The volatiles were then evaporated,
and the residue (290 mg) was purified by chromatography on a
column of silica gel (40 g) with a mixture of CH2Cl2 and MeOH
(70:1) to afford formamide (S)-(-)-15 (230 mg; 96%) as a white
solid: mp 117–119 °C; Rf ) 0.50 and 0.42 (two spots;
CH2Cl2-MeOH, 49:1); [R]D –154.20 (c 0.5, CHCl3); 1H NMR (400
Hz, CDCl3 a mixture of rotamers in ca. 4:1 ratio; the signals for
the minor rotamer are marked with an *) δ 0.91 (d, J ) 6.5 Hz,
3H), 1.04 (d, J ) 6.5 Hz, 3H), 2.21 (pent, J ) 6.0 Hz, 2H) partly
overlapped with 2.24 (s, 6H), 2.40–2.52 (m, 1H), 2.98 (s, 0.6 H*),
2.99 (s, 2.42 H), 3.74 (d, J ) 10.6 Hz, 0.18H*), 3.82 (t, J ) 6.3
Hz, 2H), 3.85 (t, J ) 5.7 Hz, 2H), 4.37 (d, J ) 11.3 Hz, 0.83H)
7.18 (s, 1.69H), 8.05 (s, br, 0.74 H), 8.14 (s, 0.86 H), 8.57 (s, 0.29
H); 13C NMR δ 16.3 (CH3), 18.5 (CH3), 19.5 (CH3), 25.2 (CH),
31.6 (CH3), 33.2 (CH2), 41.6 (CH2), 63.1 (CH), 68.2 (CH2), 120.4
(CH), 131.5 (C), 133.2 (C), 162.2 (C), 164.0 (CO), 167.0 (CO);
IR (KBr) ν 3285, 3215, 3148, 3081, 2965, 2875, 1658, 1613, 1555,
1485, 1411, 1215 cm-1; MS (EI) m/z 354 (M•+, 54), 213 (96), 166
(15), 142 (82), 114 (100), 86 (52), 55 (28), 41 (28); HRMS (EI)
354.1715 (C18H27ClN2O3 requires 354.1710).
4-(3′-Chloro-1′-propyloxy)-3,5-dimethylaniline 13. Tin(II) chlo-
ride dihydrate (4.30 g, 19.04 mmol) was added to a solution of the
nitro ether 12 (1.16 g, 4.76 mmol) in a 1:1 mixture of THF and
EtOH (24 mL), and the resulting solution was stirred at 40 °C for
23 h. The mixture was then cooled, and a saturated aqueous solution
of NaHCO3 (70 mL) was added to reach pH 10. The product was
extracted with ether (3 × 200 mL) and the organic phase was dried
over MgSO4 and evaporated. The residue (1.15 g) was purified by
chromatography on a column of silica gel (50 g) with CH2Cl2 to
afford aniline 13 (660 mg, 65%) as a brownish solid: mp 62–63
4-[3′-(4′′-Benzyloxyphenyl-1′′-propyl)oxy]-3,5-dimethylni-
trobenzene 19. Triphenylphosphine (4.31 g, 16.42 mmol), alcohol
18 (3.98 g, 16.42 mmol), and diethyl azodicarboxylate (2.58 mL,
16.42 mmol) were added successively to a stirred solution of 2,6-
dimethyl-4-nitrophenol 6 (2.22 g, 13.28 mmol) in THF (30 mL) at
0 °C, and the resulting mixture was stirred at 25 °C for 19 h. The
solvent was evaporated, and the residue was purified by chroma-
tography on a column of silica gel (100 g) with a mixture of
petroleum ether and dichloromethane (3:2) to afford a slightly
contaminated product as a brownish solid. The solid was washed
with ether (2 × 15 mL) to give pure ether 19 (4.36 g, 84%) as a
yellowish solid: mp 97–99 °C; Rf ) 0.3 (petroleum ether-CH2Cl2,
1
°C; Rf ) 0.40 (CH2Cl2); H NMR (400 Hz, CDCl3) δ 2.20–2.23
(m, 8H), 3.54 (s, br, 1.94 H), 3.83 (t, J ) 6.4 Hz, 2H), 3.84 (t, J
) 5.8 Hz, 2H), 6.38 (s, 2H); 13C NMR δ 16.2 (CH3) 33.3 (CH2),
41.8 (CH2) 68.3 (CH2), 115.5 (CH), 131.7 (C), 141.5 (C), 148.4
(C); MS (CI) m/z 213 (M•+, 45), 136 (100), 120 (9), 108 (52), 93
(38), 91 (19), 41 (52); HRMS (EI) 213.0916 (C11H16CION requires
213.0920).
1
3:2); H NMR (400 MHz, CDCl3) δ 2.09–2.17 (m, 2H), 2.33 (s,
6H), 2.81 (t, J ) 7.7 Hz, 2H), 3.84 (t, J ) 6.4 Hz, 2H), 5.06 (s,
2H), 6.93 (d, J ) 8.6 Hz, 2H), 7.15 (d, J ) 8.6 Hz, 2H), 7.33–7.45
(m, 5H), 7.91 (s, 2H); 13C NMR δ 16.7 (CH3), 31.3 (CH2), 32.1
(CH2), 70.1 (CH2), 71.9 (CH2), 114.9 (CH), 124.2 (CH), 127.4 (CH),
127.9 (CH), 128.6 (CH), 129.3 (CH), 132.3 (C), 133.5 (C), 137.1
(C), 143.4 (C), 157.2 (C), 161.6 (C); MS (EI) m/z 391 (M•+, 82),
285 (8), 256 (9), 225 (5), 197 (7), 167 (6), 133 (8), 91 (100), 86
(100), 47 (93); HRMS (EI) 391.1781 (C24H25NO4 requires 391.1784).
4-[3′-(4′′-Benzyloxyphenyl-1′′-propyl)oxy]-3,5-dimethylani-
line 20. Tin(II) chloride dihydrate (4.82 g, 21.36 mmol) was added
to a solution of nitro ether 19 (2.00 g, 5.11 mmol) in a 1:1 mixture
of ethanol and THF (30 mL), and the mixture was refluxed for
9 h. The mixture was then cooled, and a saturated aqueous solution
of NaHCO3 (75 mL) was added to reach pH 10. The product was
Amide (S)-(-)-14. Triethylamine (0.16 mL, 1.15 mmol) was
added to a solution of (S)-BOC-N-methylvaline (210 mg, 0.91
mmol) and aniline 13 (180 mg 0.84 mmol) in dry CH2Cl2 (6 mL)
at 0 °C. To the resulting clear solution were consecutively added
1-hydroxybenzotriazole (HOBt; 160 mg, 1.18 mmol) and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI;
210 mg, 1.09 mmol). The reaction mixture was stirred at 0 °C for
1 h and then at room temperature for 22 h. The mixture was then
diluted with ethyl acetate (35 mL), washed successively with water
(20 mL), cold 0.5 M HCl (2 × 20 mL), saturated NaHCO3 (2 ×
20 mL), and brine (20 mL), dried over MgSO4, and evaporated.
The residue (430 mg) was purified by chromatography on a column
of silica gel (40 g) with a mixture of petroleum ether and ethyl
acetate (8:1) to afford pure amide (S)-(-)-14 (310 mg, 86%) as a
J. Org. Chem. Vol. 73, No. 11, 2008 3993

Malkov et al.
extracted with ethyl acetate (3 × 125 mL), and the organic phase
was dried over MgSO4. The solvent was evaporated, and the residue
(2.60 g) was purified by chromatography on a column of silica gel
(70 g) with CH2Cl2 to afford aniline 20 (950 mg, 51%) as a reddish
solid: mp 53–55 °C; Rf ) 0.20 (CH2Cl2);1H NMR (400 MHz,
CDCl3) δ 2.03–2.10 (m, 2H), 2.20 (s, 6H), 2.78 (t, J ) 7.8 Hz,
2H), 3.72 (t, J ) 6.4 Hz, 2H), 5.05 (s, 2H), 6.47 (s, 2H), 6.92 (d,
(C) 137.2 (C), 152.8 (C) 157.1 (C), 163.9 (CHO), 167.0 (CO); IR
(KBr) ν 3448, 2925, 1655, 1552, 1509, 1484, 1215 cm-1; MS (EI)
m/z 502 (M•+, 18), 361 (25), 276 (10), 233 (100), 231 (40), 121
(47), 78 (92), 44 (55); HRMS (EI) 502.2831 (C31H38N2O4 requires
502.2832).
Formamide (S)-(-)-23. A mixture of the benzyl derivative 22
(870 mg, 1.73 mmol) and a 10% palladium on activated charcoal
(180 mg, 10 mol%) in absolute ethanol (40 mL) was stirred under
a hydrogen atmosphere for 8 h. Ethanol (300 mL) was then added,
and the mixture was filtered through Celite and evaporated. The
residue (720 mg) was purified by chromatography on a column of
silica gel (70 g) with a mixture of CH2Cl2 and MeOH (49:1) to
afford (S)-(-)-23 (670 mg, 95%) as an enamel: Rf ) 0.37 and 0.25
(two spots, CH2Cl2-MeOH, 49:1); [R]D –140.60 (c 0.5, CHCl3);
1H NMR (400 Hz, CDCl3, a mixture of rotamers in ca. 4:1 ratio;
the signals for the minor rotamer are marked with an *) δ 0.90 (d,
J ) 6.6 Hz, 3H), 1.02 (d, J ) 6.5 Hz, 3H), 2.02–2.09 (m, 2H),
2.21 (s, 6H), 2.40–2.50 (m, 1H), 2.75 (t, J ) 7.7 Hz, 2H), 2.94 (s,
0.43H*), 3.02 (s, 2.60H), 3.51 (d, J ) 10.4 Hz, 0.14H*), 3.71 (t,
J ) 6.4 Hz, 2H), 4.37 (d, J ) 11.2 Hz, 0.86H), 6.37 (br s, 0.96H),
6.79 (d, J ) 8.5 Hz, 2H), 7.07 (d, J ) 8.5 Hz, 2H), 7.14 (s, 0.14H*),
7.16 (s, 1.69H), 8.03 (br s, 0.12H*), 8.14 (s, 0.93H), 8.19 (s, 0.78H),
8.25 (s, 0.13H*); 13C NMR δ 16.4 (CH3), 18.5 (CH3), 19.4 (CH3),
25.4 (CH), 31.4 (CH2), 31.7 (CH3), 32.2 (CH2), 63.1 (CH), 71.7
(CH2), 115.3 (CH), 120.5 (CH), 129.4 (CH), 131.5 (C), 132.8 (C),
133.5 (C), 152.8 (C) 154.0 (C), 164.1 (CHO), 167.0 (CO); IR (KBr)
ν 3396, 2960, 2871, 1654, 1549, 1517, 1480, 1218 cm-1; MS (CI)
m/z 413 ([MH]•+, 40), 412(68), 271 (27), 143 (90), 115 (100), 88
(28); HRMS (CI) 413.2436 (C24H33N2O4 [MH]•+ requires 413.2440).
General Procedure for the Asymmetric Reduction of
1a-e, Catalyzed by 5a-f or 24–30. The imine 1 (100 mg, 4.44
mmol) was added to a reaction tube containing a small porous
polypropylene reactor vessel (2.4 mL internal volume and 74 µm
pore size) with an immobilized catalyst or resin (for the number of
mmol, see Tables 1 and 3) in a solvent (4 mL), and the tube was
shaken at room temperature for 30 min. Trichlorosilane (100 µL)
was added at 0 °C, followed by overnight shaking at room
temperature. The porous reactor vessel was separated from the
mother liquor and washed with chloroform (2 × 30 mL). Combined
organic solutions were quenched with a saturated aqueous solution
of NaHCO3 (25 mL), the layers were separated, and the aqueous
layer was additionally extracted with chloroform (60 mL). Com-
bined chloroform solutions were dried over MgSO4, and the solvent
was evaporated to give a crude product, which was purified by
chromatography on a column of silica gel (15 g) to afford pure
amines 2. The results are summarized in the Tables 1 and 3.
Regeneration of Immobilized Catalysts. After separation from
the mother liquor and washing with chloroform, the porous reactor
vessel with immobilized catalyst was alternately washed with
methanol and CH2Cl2 (4 × 25 mL of each solvent) and ether (25
mL). An overnight drying under vacuum afforded the regenerated
catalyst, which was used for the next transformation without further
purification.
J ) 8.6 Hz, 2H), 7.16 (d, J ) 8.6 Hz, 2H), 7.31–7.45 (m, 5H); 13
C
NMR δ 16.3 (CH3), 31.6 (CH2), 32.2 (CH2), 70.0 (CH2), 71.8 (CH2),
114.7 (CH), 116.5 (CH), 127.5 (CH), 127.9 (CH), 128.5 (CH), 129.3
(CH), 131.8 (C), 134.2 (C), 137.1 (C), 139.2 (C), 149.8 (C), 157.0
(C); MS (EI) m/z 361 (M•+, 55), 136 (69), 91 (100), 84 (19), 65
(13); HRMS (EI) 361.2044 (C24H27NO2 requires 361.2042).
Amide (S)-(-)-21. Triethylamine (0.85 mL, 6.12 mmol) was
added to a solution of (S)-BOC-N-methylvaline (850 mg, 3.68
mmol) in dry CH2Cl2 (25 mL) at 0 °C. To the resulting clear
solution were consecutively added aniline 20 (950 mg, 2.63 mmol),
1-hydroxybenzotriazole (HOBt; 630 mg, 4.66 mmol), and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI;
780 mg, 4.07 mmol), and the reaction mixture was stirred at 0 °C
for 1 h and then at room temperature for 24 h. The mixture was
then diluted with ethyl acetate (150 mL) and washed successively
with water (75 mL), cold 0.5 M HCl (2 × 75 mL), saturated
NaHCO3 (2 × 75 mL), and brine (75 mL), dried over MgSO4, and
evaporated. The residue (1.92 g) was purified by chromatography
on a column of silica gel (100 g) with a mixture of petroleum ether
and ethyl acetate (8:1) to afford pure amide (S)-(-)-21 (1.15 g,
76%) as an orange oil: Rf ) 0.42 (petroleum ether-AcOEt, 6:1);
[R]D –70.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.91 (d,
J ) 6.6 Hz, 3H), 1.01 (d, J ) 6.5 Hz, 3H), 1.49 (s, 9H), 2.04–2.11
(m, 2H), 2.24 (s, 6H), 2.32–2.41 (m, 1H), 2.79 (t, J ) 7.7 Hz, 2H),
2.83 (s, 3H), 3.73 (t, J ) 6.4 Hz, 2H), 4.09 (d, J ) 11.0 Hz, 1H),
5.05 (s, 2H), 6.92 (d, J ) 8.6 Hz, 2H), 7.15 (d, J ) 8.6 Hz, 2H)
partly overlapped with 7.16 (s, 2H), 7.30–7.45 (m, 5H), 8.05 (br s,
0.84H); 13C NMR δ 16.4 (CH3), 18.6 (CH3), 19.9 (CH3), 25.9 (CH),
28.4 (CH3), 30.5 (CH3), 31.5 (CH2), 32.2 (CH2), 66.0 (CH), 70.1
(CH2), 71.7 (CH2), 80.6 (C), 114.8 (CH), 120.1 (CH), 127.5 (CH),
127.9 (CH), 128.5 (CH), 129.3 (CH), 131.5 (C), 133.4 (C), 134.1
(C) 137.2 (C), 152.5 (C) 157.1 (C), 157.4 (CO), 168.6 (CO); MS
(EI) m/z 574 (M•+, 26), 361 (53), 130 (54), 91 (100), 86 (69), 57
(44); HRMS (EI) 574.3404 (C35H46N2O5 requires 574.3407).
Formamide (S)-(-)-22. Trifluoroacetic acid (10.1 mL) was
added dropwise to a solution of the BOC derivative 21 (1.15 g,
2.00 mmol) in CH2Cl2 (17 mL) at 0 °C and stirring continued at
the same temperature for 1 h. The acid was removed under reduced
pressure, and the residue was coevaporated with toluene (2 × 20
mL) to afford a TFA salt of the deprotected amine as a brownish
oil, which was used in the following step without further purifica-
tion. The crude amine salt was dissolved in formic acid (12.1 mL),
and the resulting solution was cooled to 0 °C. Acetic anhydride (9
mL) was then added dropwise, and the mixture was allowed to stir
at room temperature for 25 h. The volatiles were then evaporated,
and the residue was coevaporated with toluene (2 × 10 mL). The
latter residue (940 mg) was purified by chromatography on a column
of silica gel (100 g) with a mixture of CH2Cl2 and MeOH (90:1)
to afford formamide (S)-(-)-22 (870 mg; 87%) as a colorless oil:
Rf ) (2 spots 0.70 and 0.50) (CH2Cl2-MeOH, 49:1); [R]D –95.20
(c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3, a mixture of rotamers
in ca. 4:1 ratio; the signals for the minor rotamer are marked by an
*) δ 0.91 (d, J ) 6.6 Hz, 3H), 1.05 (d, J ) 6.5 Hz, 3H), 2.04–2.11
(m, 2H), 2.23 (s, 6H), 2.39–2.52 (m, 1H), 2.78 (t, J ) 7.7 Hz, 2H),
2.93 (s, 0.41H*), 2.99 (s, 2.55H), 3.49 (d, J ) 10.3 Hz, 0.11H*),
3.73 (t, J ) 6.4 Hz, 2H), 4.38 (d, J ) 11.2 Hz, 0.83H), 5.05 (s,
2H), 6.92 (d, J ) 8.6 Hz, 2H), 7.15 (d, J ) 8.6 Hz, 2H), 7.17 (s,
2H), 7.30–7.45 (m, 5H), 7.76 (s, 0.12H*), 8.02 (br s, 0.83H), 8.14
(s, 0.86H), 8.24 (s, 0.13H*); 13C NMR δ 16.4 (CH3), 18.5 (CH3),
19.5 (CH3), 25.2 (CH), 31.5 (CH2), 31.6 (CH3), 32.2 (CH2), 63.1
(CH), 70.1 (CH2), 71.7 (CH2), 114.8 (CH), 120.3 (CH), 127.4 (CH),
127.9 (CH), 128.5 (CH), 129.3 (CH), 131.5 (C), 133.0 (C), 134.1
Amine (S)-(-)-2a. Purified by column chromatography on silica
gel with a hexane-ethyl acetate mixture (10:1, Rf ) 0.3): [R]D
1
–4.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 1.50 (d, J )
6.7 Hz, 3H), 3.70 (s, 3H), 3.79 (br s, 1H), 4.42 (q, J ) 6.7 Hz,
1H), 6.46–6.50 (m, 2H), 6.68–6.72 (m, 2H), 7.20–7.25 (m, 1H),
7.30–7.38 (m, 4H) in agreement with data for an authentic sample;7
chiral HPLC (Chiracel OD-H, hexane/2-propanol 99:1, 0.9 mL/
min) showed 81% ee (tR ) 21.6 min, tS ) 24.4 min).
Amine (S)-(-)-2b. Purified by column chromatography on silica
gel with a hexane-ethyl acetate mixture (10:1): [R]D -23.2 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.58 (d, J ) 6.7 Hz, 3H),
3.68 (s, 3H), 3.90 (br s, 1H), 4.57 (q, J ) 6.7 Hz, 1H), 6.50–6.54
(m, 2H), 6.66–6.70 (m, 2H), 7.41–7.52 (m, 3H), 7.79–7.83 (m, 4H)
in agreement with literature data;11a–c chiral HPLC (Chiracel OD-
H, hexane/2-propanol 99:1, 0.9 mL/min) showed 79% ee (tR ) 27.4
min, tS ) 33.4 min).
3994 J. Org. Chem. Vol. 73, No. 11, 2008

Polymer-Supported Organocatalysts
Amine (S)-(+)-2c. Purified by column chromatography on silica
gel with a petroleum ether-ethyl acetate mixture (9:1): [R]D +6.5
46.4 (CH), 55.8 (CH3), 104.6 (CH), 114.8 (2 × CH), 114.9 (2 ×
CH), 123.6 (C), 141.8 (C), 144.9 (C), 149.7 (C), 152.1 (C); IR ν
3398, 2964, 2921, 1583, 1511, 1450, 1234 cm-1; MS (EI) m/z 245
(M•+, 25), 123 (100), 86 (35), 84 (54), 83 (25), 51 (24), 49 (77),
43 (35); HRMS (EI) 245.1414 (C15H19NO2 requires 245.1416);
HPLC analysis (Chiralpak IB, hexane-propan-2-ol (99:1), 0.75 mL/
min,) showed 79% ee (tminor ) 12.782 min, tmajor ) 14.546 min).
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 1.51 (d, J ) 6.7
Hz, 3H), 3.70 (s, 3H), 3.83 (br s, 1H), 4.46 (q, J ) 6.7 Hz, 1H),
6.41–6.45 (m, 2H), 6.67–6.71 (m, 2H), 7.48 (d, J ) 8.2 Hz, 2H),
7.57 (d, J ) 8.2 Hz, 2H) in agreement with literature data;11a–c
chiral HPLC (Chiracel OD-H, hexane/2-propanol 95:5, 0.9 mL/
min) showed 81% ee (tR ) 15.7 min, tS ) 21.8 min).
Acknowledgment. We thank the EPSRC for Grant No. GR/
S87294/01, the University of Glasgow for a graduate fellowship
to M.F., and Polymer Laboratories (now part of Varian, Inc.)
and Rapp Polymere GmbH for a donation of polymers. We are
particularly indebted to Dr. Richard Hartley for sharing with
us his expertise in solid-supported chemistry and some of his
equipment.
Amine (S)-(-)-2d. Purified by column chromatography on silica
gel with a petroleum ether-ethyl acetate mixture (9:1): [R]D -16.1
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 1.47 (d, J ) 6.7
Hz, 3H), 3.70 (s, 3H), 3.78 (s, 3H), 4.37 (q, J ) 6.7 Hz, 1H),
6.46–6.70 (m, 2H), 6.67–6.71 (m, 2H), 6.84–6.87 (m, 2H),
7.25–7.29 (m, 2H) in agreement with literature data;11a–c chiral
HPLC (Chiracel OD-H, hexane/2-propanol 98:2, 0.6 mL/min)
showed 77% ee (tR ) 28.8 min, tS ) 33.9 min).
Amine (S)-(-)-2e. Purified by column chromatography on silica
gel with a petroleum ether-ethyl acetate mixture (10:1): [R]D –4.5
Supporting Information Available: General experimental
methods and 1H and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
(c, 2, CHCl3); H NMR (400 MHz, CDCl3) δ 1.42 (d, J ) 6.7,
3H), 2.21 (br s, 3H), 2.25 (br s, 3H), 3.36 (br s, 1H), 3.74 (s, 3H),
4.29 (q, J ) 6.6 Hz, 1H), 5.88 (br s, 1H), 6.53–6.57 (m, 2H),
6.73–6.77 (m, 2H); 13C NMR δ 11.9 (CH3), 13.6 (CH3), 23.2 (CH3),
JO800094Q
J. Org. Chem. Vol. 73, No. 11, 2008 3995