Synthesis of tunable diamine ligands with spiro indane-2,2′- pyrrolidine backbone and their applications in enantioselective henry reaction

Article abstract of DOI:10.1021/jo402631u

Novel diamine ligands with spiro indane-2,2′-pyrrolidine scaffold were synthesized starting from Seebach's oxazolidinone 6 and were subsequently employed in asymmetric Henry reaction. Following the initial experimental findings, further synthesis resulted

Full text of DOI:10.1021/jo402631u

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Article
Synthesis of Tuneable Diamine Ligands with Spiro Indane-2,2'-pyrrolidine
Backbone and Their Applications in Enantioselective Henry Reaction
Rafa# #wiek, Piotr Niedziejko, and Zbigniew Ka#u#a
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo402631u • Publication Date (Web): 18 Jan 2014
Downloaded from http://pubs.acs.org on January 20, 2014
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Synthesis of Tuneable Diamine Ligands with Spiro Indane-2,2’-
pyrrolidine Backbone and Their Applications in Enantioselective Henry
Reaction
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a
a
a
Rafał Ćwiek, Piotr Niedziejko, Zbigniew Kałuża *
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224, Warsaw, Poland
Fax: (+48)-22-632-6681; e-mail: zbigniew.kaluza@icho.edu.pl
Abstract
Novel diamine ligands with spiro indane-2,2’-pyrrolidine scaffold were synthesized starting from
Seebach’s oxazolidinone 6 and were subsequently employed in asymmetric Henry reaction.
Following the initial experimental findings, further synthesis resulted in two types of spiro
diamines, with varying substituents at both nitrogen atoms. Ligands of type A, containing a small
substituent at N-1’ atom, and a large group at N-1 atom gave predominantly the S-configured β-
nitroalcohol, while ligands of type B, with the reversed location of small and large substituents
furnished the R-configured product. Both types of ligands turned out to be versatile catalysts for
the Henry reaction between nitromethane and assortment of aryl as well as alkyl aldehydes
offering either S- (lig. A) or R-configured (lig. B) nitroalcohols in a good to high chemical yield and
an excellent enantioselectivity up to 99% ee.
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Introduction
The chiral ligands with spiro-backbone, owing to their excellent catalytic efficiency in a variety of
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mechanistically dissimilar reactions fulfill the requirements for “privileged” ligands, a term coined
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by Jacobsen.
Figure 1. Representative example of privileged spiro ligands, where X = metal coordination groups
such as -PAr , -OPAr , -NHPAr , oxazoline, etc.
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2
The most prominent and successful spiro ligands have rigid C -symmetrical skeleton and metal
coordination groups attached to the phenyl ring (predominantly) or to the spiro[4.4]nonane
moiety (Figure 1). These mono or bidentate privileged ligands typically contain either phosphorus
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or/and sp -hybridized nitrogen donor atoms. Chiral amines, in comparison with phosphorus
ligands, hold several well-known advantages such as easy availability in enantiomerically pure
form, chemical robustness, particularly a substantially higher resistance to air oxidation, and
ability to form stable complexes with transition as well as alkali metals. Although, for the reasons
given above, the primary, secondary, and tertiary diamines are widely applied in the catalytic
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,4
asymmetric syntheses,
the diamine ligands that contain spiro-backbone are relatively
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uncommon and have only been reported recently.
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Figure 2. Spiro diamine ligands currently known.
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b
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The synthesis of proline derived diamines 1 and 2 with C -symmetric spirobi(indane) skeleton
was reported by Zhou in 2006 (Figure 2). These diamines were shown to be a promising
organocatalysts for the asymmetric aldol reaction. The preparation of spirobi(chromane) diamines
5c
3 and 4 and isolation of their enantiopure forms were presented by Frexia. The catalytic
effectiveness of ligands 3 and 4 was tested in palladium catalyzed oxidative kinetic resolution of 1-
phenylethanol, displaying a low to moderate stereo-selectivity. The last example of spirodiamine
ligand comes from Royer’s group: an eleven steps synthesis, employing (S)-naphthylethylamine as
a chiral auxiliary, furnished diamine 5 with the C
1
-symmetrical 1-azaspiro[4.4]nonane scaffold in
5
a
1
9% overall yield. The rigid diamine 5 was demonstrated to be an effective catalyst for the
asymmetric Michael addition to nitroolefines.
The presented above three examples of literature reports concerning the synthesis and
applications of asymmetric spiro-diamines show that this field remains mostly unexplored.
Moreover, the limited number of compounds with spiro-backbone used for the preparation of
efficient ligands or organocatalysts indicates that the continuation of research in this area may
lead to further progress.
Herein, we report our work targeting the design and synthesis of novel diamines that contain the
1
C -symmetrical spiro[indane-2,2'-pyrrolidine] core.
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Results and Discussion
In a continuation of our study on design and synthesis of diamine ligands for asymmetric
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catalysis, we focused our efforts on the preparation of new compounds with a rigid spiro-
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backbone. Additionally, we anticipated that such spiro-diamines must fulfill the following
requirements: their synthesis as well as further structure diversification must be simple, efficient,
and provide a variety of derivatives in enantiopure form. A literature search for the suitable
scaffold revealed Crooks’ report, presenting the synthesis of racemic aminoketone with the
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spiro[indane-2,2'-pyrrolidine] backbone. To the best of our knowledge, spirodiamine ligands with
such skeleton were never previously described.
Inspired by this work, we proposed the asymmetric synthesis of spiro-diamines of general
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structure X starting from the easily available Seebach’s oxazolidinone 6 (Scheme 1). Such
diamines with cis-arrangement of amino groups with respect to the indane parent, should offer a
good metal chelation ability, while the chiral spiro-skeleton should assure an effective asymmetric
induction.
Scheme 1. Retrosynthesis of diamines of type X from Seebach’s oxazolidinone 6.
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We expected that the highly stereoselective alkylation (self-reproduction of chirality) of
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compound 6 with o-iodo benzyl bromide, followed by Parham’s cyclization of 7 should provide
aminoketone 8, a suitable starting material for the preparation of diamines of type X via standard
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carbonyl group transformation.
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To verify this idea, the oxazolidinone 6 was alkylated with o-iodobenzyl bromide using Seebach
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procedure. (Scheme 2).
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Scheme 2. Synthesis of aminoketone 8a from oxazolidinone 6. Reagents and conditions: a) LDA, THF, -
7
0
8°C, 0.5 h, then o-iodobenzyl bromide, -78 →-30°C, 3 h; b) n-BuLi, THF, -78°C, 0.5 h; c) t-BuLi, THF, -78°C,
.5 h; d) o-bromobenzyl bromide, THF -78 → -30°C.
The isolated product 7a was treated with n-BuLi to generate organolithium species 7b, which
spontaneously cyclized furnishing aminoketone 8a in an excellent yield (96%) and a high optical
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purity (~99% ee). In order to simplify the preparation of 8a, we examined also a one-pot two-
step procedure with the sequential addition of organolithium reagent. The first equivalent of t-
BuLi deprotonated oxazolidinone 6 to facilitate the alkylation with o-bromobenzyl bromide, then
the in situ generated derivative 7c was treated with another equivalent of t-BuLi to effect the
bromine-lithium exchange, thus enabling cyclization step, leading to final aminoketone 8a.
Although the overall yield of 8a, using unoptimized one pot synthesis (62%) is lower than that of
the original two-step preparation (75%), the use of an inexpensive o-bromobenzyl bromide and a
simplified procedure makes the one-pot synthesis a reasonable alternative.
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The initial effort to prepare diamines from aminoketone 8a using reductive amination was
unsuccessful. Consequently, we focused our attention on the alternative oxime approach for the
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generation of amine. Thus, we converted the aminoketone 8a into corresponding oxime 9a and
examined its palladium-catalyzed hydrogenation (Scheme 3).
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Scheme 3. Synthesis of spiro-diamine 10. Reagents and conditions: a) Boc O, 50°C, 0.5 h, 96%; b) NH OH,
Py/EtOH, reflux, 1-3 days; c) H , Pd/C, MeOH/AcOH, 24 h; d) COCl , DIEPA, DCM, 0 → RT, 3h.
2
2
An initial testing led to a mixture of epimeric diamines 10a (cis) and 11a (trans), isolated in about
:18 ratio, respectively. The cis-configuration of amine 10a was corroborated by an easy formation
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of cyclic derivative 12 in reaction with phosgene. The major reduction product, trans-isomer 11a
did not react with phosgene.
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(R)
Re
Re favored
1(S)
N
R
NH2
R= Boc
N
R
N
Si favored
OH
R= H
2(R)
Si
1(R)
N
R
NH2
Figure 3. Palladium-catalyzed hydrogenation of spiro-oxime. The dependence of amine R-
substituent size and reduction product stereochemistry
Based on the Crooks report that the reduction of N-benzoylated racemic spiro-ketone 8 yields
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predominantly the respective α-alcohol , we speculated that the protection of pyrrolidine nitrogen
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atom with a bulky protective group will shield the Si-face of oxime, and the Re-face addition of
hydrogen should be favored (Figure 3). In order to examine this assumption, we prepared the N-
Boc protected oxime 9b in two steps from ketone 8a (Scheme 3). The catalytic hydrogenation of
9b furnished the expected cis-amine 10b in 87% yield. The unwanted trans-isomer 11b was barely
detectable by TLC, in agreement with our expectation. With enantiopure mono-protected diamine
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1
0b in hand, we synthesized several diamine derivatives with various substituents at both nitrogen
atoms (Scheme 4). All syntheses were executed using standard reactions such as reductive
amination with mono and dialdehydes, amine alkylation and Boc removal.
Scheme 4. Synthesis of spiro-diamine derivatives 13-16. Reagents and conditions: a) HCHO, NaBH
DCM/AcOH, RT; b) TFA, DCM; c) PhCHO, NaBH CN, DCM/AcOH, MeOH/AcOH, 24 h; d) 1,4-dibromobutane,
Na CO , NaI, MeCN, reflux; e) Benzene-1,2-dicarbaldehyde, NaBH CN, DCM/AcOH, 24 h;
3
CN,
3
2
3
3
Complexes of chiral diamines with copper salts are widely utilized in asymmetric Henry reaction, a
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useful C−C bond-forming process with a strong industrial relevancy. We have selected this
process to evaluate the catalytic efficiency of new ligands 13a-c, 14a-c, and 15a-b. Until now,
many catalytic systems for the Henry reaction have been developed. A literature search revealed,
that screening the catalytic performance of a new ligands in nitroaldol reactions, the catalyst (Cu-
1
3a
12f, 12g
12i
diamine complex) is used at first in 5, 10
or even 20 mol%. For the most effective ligands,
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optimization of the reaction conditions allows to reduce the amount of catalyst down to 2.5
13c-d
12p
mol%.
The reactions are performed mainly in an alcohol solution using iso-propanol, n-
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12q
13c
13d
propanol or ethanol. However, other solvents as THF or diethyl ether are also suitable
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for this process. Depending on copper complex, nitroaldol reaction proceeds smoothly without an
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external base,
or the base, typically tertiary amine is required to activate the nitromethane,
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thus increasing the reaction rate.
In certain catalytic systems, tertiary amine is applied up to
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2m, 13c
equimolar amount without effecting the stereoselectivity.
However, a large amount of a
base can decrease stereoselectivity, therefore it is used in the same as a catalyst amount or
1
2f
lower. Taking into account the above literature information, we carried out a model reaction
between nitromethane and benzaldehyde in iso-propanol solution at 0°C, using complexes of
copper(II) acetate with a series of new ligands (10 mol% each) and triethylamine (5 mol%). In
result, corresponding nitroalcohol was isolated in good chemical yield and with a low to moderate
enantioselectivity (ee 13-45%; Table 1) with notable exception of ligand 14a that offered a
substantially higher enantioselectivity (ee 77%, entry 4).
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a
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Table 1. Asymmetric Henry reaction catalyzed by Cu(OAc) complexes with diamines 13-15.
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b
Entry Ligand R
Time Yield Ee Conf.
[
h]
[%]
[%]
1
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8
13a
13b
13c
14a
14b
14c
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15b
H
24
78
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78
76
85
45
13
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77
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S
Me 6
R
R
S
Bn 24
H
3
Me 4
S
Bn 16
R
S
H
4
Me 24
R
a)
.
.
Reaction conditions: Cu(OAc) Lig generated in DCM from Cu(OAc) H O (0.05 mmol, 10 mol%),
2
2
2
o
benzaldehyde (0.5 mmol), i-PrOH (2 mL), nitromethane (5 mmol), TEA (0.025 mmol, 5 mol%), 0 C.
b)
The ee’s and absolute configurations were determined by chiral HPLC analysis using OD-H
1
2n
Chiralpack column as described in the literature.
Considering the fact that new ligands possess both the same spiro-skeleton and configuration
1S,2R), we noticed interesting changes in the direction of asymmetric induction in a standard test
(
reaction. A thorough analysis of reaction results has shown an intriguing regularity in the product
configuration that could be reasonably associated with the characteristics of substituents at both
nitrogen atoms within the ligand. For example, in the reaction catalyzed by diamines with
unsubstituted pyrrolidine nitrogen atom (13a, 14a, 15a), the S-configured product dominated in all
cases. The enantiomeric excess observed in each case depends, however, on the bulkiness of
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substituent on the second nitrogen atom (entry 1, 4, 7). When N-1’-methyl or benzyl analogues
were used, the R nitro alcohol was obtained (entry 2, 3, 6, 8). Only in the case of diamine 14b, the
S-enantiomer still dominated, but in comparison with ligand 14a, the enantiomeric excess was
considerably reduced from 77% ee (S) to 18% ee (S), (entry 4 and 5). Considering the above results
we formulated a working hypothesis correlating the relationship between the steric bulkiness of
substituents at both nitrogen atoms within ligand and the configuration of product as well as the
extent of observed enantiomeric excess.
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Our proposed hypothesis is that ligands A with a small substituent at N-1’atom, and a large group
at N-1 atom should furnish predominantly the S-configured β-nitroalcohol (Figure 4).
Figure 4. The relationship between ligand structure and product configuration in Henry reaction.
On the other hand, ligands B with the reverse location of small and large substituent favour the
formation of R-configured product. The extent of observed enantiomeric excess depends to some
degree on the relative difference of steric bulkiness of substituents at both nitrogen atoms. This
hypothesis is strongly supported by the results of test reaction using ligands 13c (47% ee, S) and
1
4a (77% ee, R), (Table 1, entry 3, and 4).
To verify the above hypothesis we decided to synthesize an array of diamines of type A and B,
then explore in-depth their structure-properties relationship. The ligands of type A (compounds
16a-d) were prepared by analogy to compounds 13-15 (Scheme 5). The N-Boc-protected diamine
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10b was subjected either to the alkylation with appropriate terminal di-bromide (16a, 16b, 16d),
or benzyl bromide (16c). Finally, the Boc group was removed to give ligands 16a-d. The diamine
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6e was obtained from 10b in four step reaction sequence: acylation with 2-(2-
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bromophenyl)acetyl chloride, deprotection of secondary amine followed by the aluminium
hydride reduction of amide group, and finally intramolecular palladium catalyzed amine arylation
to give the title compound.
Scheme 5. Synthesis of spiro-diamines type A, 16a-e. Reagents and conditions: a) ligands 16a-d
were obtained as shown in Scheme 4. b) 2-(2-bromophenyl)acetyl chloride, TEA, DCM, -30°C → RT,
0.5 h, 83%; c) TFA; d) AlH
toluene, 100°C.
3 2 4 2 3
, THF/E O, 0°C → RT, 3h; e) Pd(PPh) (10 mol%), K CO , t-BuONa,
The initial ligand screening indicated that the highest enantiomeric excess (47% ee) of R-
configured nitroalcohol was obtained when ligand 13c with benzyl substituent at N-1’atom and
dimethylamine at C-1 carbon atom was used (Table 1, entry 3). Consequently, hoping to improve
the R-selectivity of type B ligands, we decided to prepare several similar diamines with a bulky
substituent at N-1’atom, and ethyl or methyl group at the second nitrogen atom.
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Scheme 6. Synthesis of spiro-diamines type B, 21a-d, 24a-e and 25. Reagents and conditions: a) Ac O, Py; b) TFA, RT,
0.5 h; c) RCH
2 2 3 3 4
Cl, Na CO , NaI, MeCN, reflux; d) RCHO, NaBH CN, MeOH, AcOH; e) LiAlH , THF, reflux; f) CbzCl, TEA,
DCM; g) H , Pd/C, MeOH, AcOH. h) Yield calculated for two steps from 22.
2
The synthesis of type B ligands is shown on Scheme 6. Amine 10b was acetylated and crude amide
was treated with TFA. The pure product was isolated via crystallization as an easy to handle
trifluoroacetate salt 19. The initial attempts to introduce bulky substituents at N-1’ atom by
alkylation with active secondary bromides such as benzhydryl bromide, or by reductive amination
with pivaloyl aldehyde or several ketones were unsuccessful, probably due to the steric hindrance.
An alkylation of pyrrolidine nitrogen atom in 19 was accomplished by either the use of apropriate
benzyl chloride or by applying reductive amination with aromatic aldehyde (For details see
4
experimental section). Finally, the reduction of acetamide 20a-d with LiAlH led to a series of
ethylamine substituted ligands 21a-d. A number of corresponding diamines with methylamine
group at C-1 carbon atom, i.e., compounds 24a-e, were prepared following a similar strategy. The
reaction sequences differ only at the first step, namely the Cbz protection of primary amine in
common substrate 10b. A newly synthesized ligands of type A and B were subsequently examined
in a model reaction between nitromethane and benzaldehyde, carried out under the same
conditions as described above (see Table 1). The collected results are listed in Table 2.
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a
Table 2. Asymmetric Henry reaction catalyzed by Cu(OAc)
2
complexes with diamines 16, 21 and 24
Entry Ligand Time Yield Ee Conf.
[h]
[%]
[%]
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
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
5
6
7
8
9
1
1
1
16a
16a
16a
16b
16c
16d
16e
21a
21b
21c
21d
24a
24a
25
24
48
72
8
85
68
33
78
0
92
93
97
83
-
S
b
c
S
S
S
d
24
8
-
80
70
79
85
84
80
86
84
72
73
82
81
85
74
30
82
74
91
90
87
93
99
94
81
96
98
96
91
S
24
6
S
R
R
R
R
R
R
R
R
R
R
R
R
3
0
1
2
24
8
3
c
13
24
8
1
4
5
1
24b
24c
24c
24d
24e
24
24
48
24
24
16
c
1
7
8
1
19
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
a)
b)
Reagents, reaction conditions, and ee assignment are as described in Table 1 unless otherwise noted.
o
c)
o
d)
Reaction was run at -20 C. Reaction was run at -40 C. A fast decomposition of copper complex was
observed
.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ligands of type A, i.e., compounds 16a-b and 16d-e gave predominantly the S-configured products
in all cases. For diamine 16c we did not observe any reaction, probably due to the fast
decomposition of copper complex (Entry 5). The highest enantiomeric excess (92% ee) was
achieved with piperidine derivative 16a. The reaction catalyzed with morpholine analog 16b
proceeded much faster, but with a lower stereoselectively (only 83% ee). The last two examples
(
entry 1 and 4) clearly show that apart from the size of nitrogen substituent, also its electronic
properties play an important role. The reaction catalyzed with the best ligand in this series,
o
o
diamine 16a, was run at -20 C and -40 C to give corresponding nitroalcohol with a high
selectivity, 93% and 97% ee, respectively. However, both the reaction rate and its yield were
reduced considerably (Entry 2 and 3). In agreement with the expectation, ligands of C-1-
ethylamine series 21a-d furnished exclusively the R-configured product in a high enantiomeric
purity (Entry 8-11). The highest enantiomeric excess (91% ee) was achieved for the
pentamethylbenzyl derivative 21b. The use of a more sterically congested 2,4,6-triisopropylbenzyl
analog 21c led to the same level of selectivity (90% ee), but the reaction was much slower than
that catalyzed with ligand 21b (Entry 9 and 10). The methylamine analogs 24a-e gave excellent
results in terms of both the stereoselectivity and the yield of nitroaldol reaction. When the
o
reaction was carried out at 0 C, all ligands, with exception of compound 24b, furnished 2-nitro-1-
phenylethanol with enantiomeric excess between 91-96% ee. Considering the enantioselectivity of
ligands with the same pentamethylbenzyl substituent at pyrrolidine nitrogen atom (21b, 24a, 25),
we can clearly see a simple relationship: smaller N-1-substituent induces formation of R-
configured product with a higher ee. For instance, for ethyl derivative the 91% ee was observed
(entry 9), 93% for methyl (entry 12), and 94% for primary amine (entry 14). The best ligand in
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terms of R-selectivity, the primary amine 25, however, showed a slower reaction rate in
comparison with its secondary amine analogs 21b, 24a, and the formation of unidentified side
o
products was observed. For the best ligands in this series, we repeated the reaction at –40 C, and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
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39
40
41
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46
47
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49
50
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52
53
54
55
56
57
58
59
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observed an excellent stereoselectivity for pentamethylbenzyl derivative 24a (99% ee), and 2-
methyl-naphthyl 24c (98% ee).
The high ee’s achieved for several ligands in a test reaction (Table 2) indicate that initially selected
reaction conditions were suitable, nonetheless we decided to undertake further optimization. The
results are given in Table 3. Firstly, a series of copper salts (10 mol%) were evaluated in complexes
with ligand 16a (10 mol%) in iso-propanol at 0 °C for a specified time.
Table 3. Optimization of the enantioselective Henry reaction between benzaldehyde and nitromethane
catalysed by Cu(II) complexes with diamines 16a. The influence of copper(II) salt, solvent and amount of
a
tiethylamine on the reaction yield and product ee.
Entry Copper salt
Solvent
TEA
Time
[h]
Yield
[%]
85
Ee
[%]
92
[
mol%]
1
2
Cu(OAc)
2
i-PrOH
i-PrOH
5
5
24
.
Cu(OAc)
CuCl
CuBr2
2
H O
24
83
92
2
3
4
2
i-PrOH
i-PrOH
EtOH
5
5
48
48
24
24
24
72
72
24
24
7
<1
<1
88
83
87
90
79
91
89
20
89
86
89
39
45
85
86
5
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
5
6
EtOH 96%
MeOH
THF
5
7
5
8
5
9
DCM
5
10
i-PrOH
i-PrOH
10
20
1
1
a)
Reagents, reaction conditions, and ee assignment are as described in Table 1 unless otherwise noted
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Copper(II)acetate, both hydrated and anhydrous, has shown the same level of stereoselecitity,
9
2%, (Entry 1, 2). Contrary to that, complexes of copper(II)chloride and bromide, yielded
racemates in low yield (Entry 3, 4). Next, the solvent effects on enantioselectivity were examined
(Entry 5-9). All tested solvents gave results inferior to these of iso-propanol. Only THF offered
comparable enantioselectivity (90% ee), but product was isolated in 39% yield only, reflecting slow
reaction rate. (Entry 8). Finally, the impact of the amount of triethylamine on nitroaldol reaction
was evaluated. When TEA was applied in the same amount as catalyst, 10 mol%, the ee dropped
by 1%. (Entry 10). However, when the quantity of a base was increased to 20 mol%, further
reduction in stereoselectivity was observed. (Entry 11). The last two results indicate, that to
achieve a high enantioselectivity in our catalytic system, a molar quantity of a base should not
exceed that of the catalyst.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4 presents the results of the catalyst loading optimization using ligands 16a and 24a. For
both ligands, the decrease of the catalyst amount did not affected stereoselectivity significantly.
The reduction of the amount of catalyst to 5 mol% and 2.5 mol% (Entry 2, 4, 6 and 8) resulted in a
small increase of enantioselestivity, approximately by 1% ee, however, the reactions were slower.
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a
Table 4. Optimization of reaction conditions. Effect of the amount of the catalyst on the asymmetric
Henry reaction.
Cat./TEA Time Yield ee
Entry ligand
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
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[
mol%]
[h]
24
26
72
28
3
[%]
85
83
73
80
85
83
81
76
[%]
92
92
94
93
93
94
98
94
1
2
3
4
5
6
7
8
16a
16a
16a
16a
24a
24a
24a
24a
10/5
5/2.5
5/2.5
2.5/2
10/5
b
5/2.5
5/2.5
2.5/2
18
30
24
c
a)
b)
Reagents, reaction conditions, and ee assignment are as described in Table 1 unless otherwise noted.
o
c)
o
d)
Reaction was run at -20 C. Reaction was run at -40 C.
o
o
The reaction catalysed with 5 mol% of ligand 16a and 24a, was run at -20 C and -40 C
respectively. (Entry 3 and 7) Corresponding nitroalcohol was obtained with very high enantiomeric
excess, 94% and 98% ee, respectively, however both the reaction rate and the yield were
significantly lower.
Finally, we decided to assess the scope of applicability of selected ligands of type A and B in Henry
reaction with variety of aldehydes. Considering the fact that reduction of the catalyst loading
resulted in the decrease of reaction rate and a small variation of stereoselectivity (~1% ee), the
test reaction were conducted using 10 mol% of the catalyst and 5 mol % of TEA to avoid a long
reaction time in low temperature. The experimental results of reactions with both aryl and alkyl
aldehydes catalyzed with diamines 16a and 24a are collected in Table 5. As can be seen, both
ligands turned out to be versatile catalysts, offering either S- (ligand 16a) or R-configured (ligand
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1
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
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5
5
5
5
5
5
5
5
6
24a) nitroalcohols in a good to high chemical yield and with an excellent enantioselectivity up to
9
9% ee.
a,b
a,c
2
Table 5 Asymmetric Henry reaction catalyzed by Cu(OAc) complexes with ligands 16a and 24a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
d
d
d
d
Entry Time Yield Conf. Ee Aldehyde
Ee Conf. Yield Time Entry
[
day] [%]
[%]
[%]
[%]
[day]
1
2
1
3
1
2
2
2
3
4
4
4
68
64
90
86
78
72
94
63
51
56
50
S
S
S
S
S
S
S
S
S
S
S
93 benzaldehyde
99
76
96
99
R
R
R
R
R
R
R
R
R
R
R
84
75
89
88
96
75
90
65
58
78
66
1
2
1
1
1
1
1
1
3
2
1
12
13
14
15
16
17
18
19
20
21
22
2
89 2-nitrobenzaldehyde
3
92 2-bromobenzaldehyde
94 2-methoxybenzaldehyde
4
5
94 3,4-dimethoxybenzaldehyde 95
6
95 2-furaldehyde
89
98
98
98
90
7
85 1-naphthaldehyde
93 3-phenylpropionaldehyde
93 2-methylpropionaldehyde
94 Valeraldehyde
8
9
10
1
1
91 cyclohexanecarboxaldehyde 97
a
Reagents and reaction conditions are as described in Table 1 unless otherwise noted.
b
c
Reactions with ligand 16a were conducted at -20°C.
Reactions with ligand 24a were conducted at -40°C.
d
The ee’s and absolute configurations were determined by chiral HPLC analysis using OD-H, OJ-H and AD-H
12n
Chiralpack column as described in the literature.
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Based on these experimental findings and in agreement with the commonly accepted mechanism
14
of nitroaldol reaction, we proposed a reasonable transition state model for the enantioselective
Henry reaction (Figure 5). In the transition state TS-16a-Si (copper complex with ligand 16a), the Si
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
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
attack is impeded by the steric interaction of aldehyde R-substituent with piperidine ring. In TS-
1
6a-Re, the R-group faces outside, avoiding the steric hindrance and the corresponding nitroaldol
adduct is formed with the S configuration. In a case of ligand 24a with the reverse location of small
and large substituents, for the same reasons as above, Si-attack is favoured (TS-24a-Si) and the R-
configured product is formed.
Figure 5. Proposed transition state models of Henry reaction for ligands of type A and B.
3
. Conclusion
In summary, we developed a simple methodology for the preparation of novel, easily tuneable
diamine ligands that are characterized by the presence of spiro[indane-2,2'-pyrrolidine] scaffold.
The alkylation of Seebach’s oxazolidinone 6 with o-iodo benzyl bromide, followed by the Parham’s
cyclization led to formation of spiro aminoketone 8a in a high optical purity > 99% ee.
Alternatively, ketone 8a can be obtained in a one-pot reaction by the sequential addition of
organolithium reagent. The catalytic hydrogenation of N-Boc protected oxime 9b, prepared in two
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
steps from 8a, furnished diamine 10b, with cis-configuration in respect to the indane. Starting
from the mono protected diamine 10b, several ligands with different substituents at both nitrogen
atoms were obtained and applied in asymmetric Henry reaction. Based on the initial experimental
findings, further synthesis resulted in preparation of two types of ligands: type A ligands,
containing a small substituent at N-1’atom, and a large group at N-1 atom that gives
predominantly the S-configured β-nitroalcohol, and ligands type B, with the reverse location of
small and large substituents that are furnishing the R-configured product. Ligands of both types
turned out to be a versatile catalysts for Henry reaction between nitromethane and assortment of
aryl as well as alkyl aldehydes offering either S- (ligands A, up to 95% ee) or R-configured (ligands
B, up to 99% ee) nitroalcohols in a good to high chemical yield and with excellent
enantioselectivity.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Considering the efficiency of presented enantioselective synthesis of spiro-diamine ligands as well
as their ability to easily introduce substituent diversity, we expect that this methodology could be
extended to the preparation of diverse range of similar spiro-scaffolds. Initial work in this direction
is in progress in our research group.
Experimental Section
Preparation of 7a. Alkylation of oxazolidinone 6 (0.830 g, 4.54 mmol) with o-iodo benzyl bromide (1.423 g,
8
4
.79 mmol) was performed according to reported Seebach’s procedure. Product was purified by flash
chromatography on silica gel using ethyl acetate/hexane 3:97 v/v as an eluent. Yield 1.414 g (3.54 mmol,
2
3
-1 1
7
8%); oil, [α]
D
2 2 2 2 3
9.2 (c 1.0, CH Cl ); IR (CH Cl ): 2962, 2872, 1775 cm ; H-NMR (CDCl , 500 MHz): 7.83-7.81
(m, 1H), 7.52-7.49 (m, 1H), 7.26-7.21 (m, 1H), 6.91-6.86 (m, 1H), 4.22 (s, 1H), 3.25 (s, 2H), 3.11-3.04 (m, 1H),
1
3
2.80-2.74 (m, 1H), 2.14-2.08 (m, 1H), 1.94-1.87 (m, 1H), 1.80-1.67 (m, 2H), 0.72 (s, 9H); C-NMR (CDCl , 125
3
MHz): 177.4, 140.1, 139.5, 131.2, 128.6, 128.2, 105.3, 104.3, 74.3, 57.7, 45.7, 36.4, 36.2, 24.9, 24.0; MS (ES,
+
HR) m/z: (M+Na ) calcd for C17
H
2
22NO NaI: 422.0587; found: 422.0572.
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Preparation of aminoketone 8a
Procedure 1. The n-BuLi (1.6 M/hexane, 3.32 mL, 5.31 mmol) was added dropwise to the stirred solution of
a (1.414 g, 3.54 mmol) in THF (20 mL) at -78°C. Stirring was continued at this temperature for 2 h, then the
reaction mixture was poured into saturated aqueous NH Cl (20 mL), and extracted with DCM (3x40 mL).
Collected extracts were washed with water (20 mL) and brine, dried over MgSO , and evaporated under
7
4
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
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
reduced pressure. The residue was purified by flash column chromatography using ethyl acetate/MeOH,
90/10 v/v as an eluent. Yield 636 mg (3.4 mmol, 96%).
Procedure 2. The t-BuLi (1.7 M/hexane, 18.7 mmol, 11 mL) was added dropwise to the stirred solution of
oxazolidinone 6 (3.260 g, 17.81 mmol) in THF (90 mL) at -78°C. Stirring was continued at this temperature
for 0.5 h, then 2-bromobenzyl bromide (4.878 g, 19.6 mmol) in THF (10 mL) was added. The temperature
was slowly brought to -30°C and stirring was continued for 3h. The reaction mixture was cooled down to -
7
2
8°C, t-BuLi (1.7 M/hexane, 21.37 mmol, 12.6 mL) was added dropwise and solution was stirred for another
h. Further workup and purification as in procedure 1. Yield 2.053 g (10.97 mmol, 62 %).
2
3
-1 1
Oil; [α]D 18.1 (c 1.0, CH Cl ); IR (CH Cl ): 2968, 2877, 1713 cm ; H-NMR (CDCl , 500 MHz): 7.78-7.71 (d,
2
2
2
2
3
1
2
1
C
H, J=5.0 Hz), 7.63-7.56 (m, 1H), 7.44-7.33 (m, 2H), 3.37-3.27 (m, 1H), 3.19-3.14 (s, 2H), 3.14-3.07 (m, 1H),
13
.67 (br s, 1H), 2.08-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.82-1.72 (m, 1H); C-NMR (CDCl
3
, 125 MHz): 208.7,
+
51.8, 135.2, 135.0, 127.6, 126.5, 124.3, 72.1, 47.8, 43.5, 38.7, 26.3; MS (EI, HR) m/z: (M ) calcd for
12
H13NO: 187.0997; found: 187.1002.
Synthesis of N-Boc protected aminoketone 8b.
The mixture of aminoketone 8a (1.05 g, 5.61 mmol) and Boc anhydride (1.35 g, 6.17 mmol) was heated at
5
0°C for 0.5 h. Reaction mixture was cooled to rt and filtered through a pad of silica gel (ethyl
acetate/hexane, 30/70 v/v). The semisolid, obtained by removal of solvents under reduced pressure, was
crystallized from hexane.
2
3
Yield 1.55 g (5.4 mmol, 96%); colourless crystals; mp 127-128°C (hexane); [α]
D
-8.8 (c 1.0, CH
2
Cl
2
); IR
-
1
1
(CH
2
Cl
2
): 3675, 2980, 1722, 1688 cm ; Spectral data (≈1:1.8 mixture of rotamers): H-NMR (Tol-d
8
, 500
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MHz): 7.73-7.68 (m, 1H), 7.18-7.13 (m, 1H), 7.02-6.91 (m, 2H), 3.59 (d, 0.36H, J=17.0Hz), 3.56-3.48 (m, 1.28
H), 3.48-3.42 (m, 0.36H), 3.37-3.33 (m, 0.36H), 3.21 (d, 0.64H, J=17.0 Hz), 2.63-2.56 (m, 1H), 1.90-1.80 (m,
1
H), 1.68-1.60 (m, 0.36H), 1.58-1.52 (m, 0.64H), 1.48-1.39 (m, 1H), 1.37 (s, 3.24H), 1.33-1.26 (m, 1H), 1.11
13
(
s, 5.76H); C-NMR (Tol-d
8
, 125 MHz, major rotamer): 204.9, 204.1, 152.8, 150.7, 134.6, 127.7, 126.3,
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
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8
9
0
1
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0
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4
5
6
7
8
9
0
+
1
2
24.2, 79.5, 69.6, 48.3, 41.7, 39.9, 28.0, 23.6; MS (EI, HR) m/z: (M ) calcd for C17
H21NO
3
: 287.1521; found:
3
87.1526. Anal. Calcd for C17H21NO : C, 71.06; H, 7.37; N, 4.87; found: C, 71.22; H, 7.34; N, 4.88.
General procedure I for the preparation of oximes 9a and 9b.
A mixture of aminoketone 8 (4.0 mmol), hydroxylamine hydrochloride (1.39 g, 20 mmol) and pyridine (8
mL) in anhydrous ethanol (8 mL) was refluxed until the reaction was complete (TLC control). The reaction
mixture was cooled to rt, poured into saturated aqueous NaHCO
3
, (20 mL) and extracted with DCM (3x20
, and evaporated under reduced
mL). Combined extracts were washed with brine (20 mL), dried over MgSO
pressure. The residue was purified by flash column chromatography.
4
Oxime 9a.
Time to completion: 24h; eluent: DCM/MeOH/NH3/aq, 95/5/1 v/v/v; compound 9a was isolated as ≈3:1
mixture of E/Z isomers. Yield 715 mg (3.52 mmol, 88%).
1
White semisolid; H-NMR (DMSO-d , 500 MHz): 11.14 (s, 1H), 8.25 (d, 1H, J=7.8 Hz), 7.51-7.48 (m, 0.29H),
6
7
.40-7.25 (m, 3.87H), 3.18-3.12 (m, 0.29H), 3.12-3.07 (m, 1H), 3.03 (d, 1H, J=16.5 Hz), 2.97 (d, 1H, J=16.5
Hz), 2.89-2.83 (m, 1H), 2.83-2.80 (m, 0.29H), 2.26 (m, 0.29H), 1.93-1.74 (m, 4.58H), 1.71-1.68 (m, 0.29H);
1
3
6
C-NMR (DMSO-d , 125 MHz), major isomer: 161.0, 145.0, 132.7, 130.3, 128.4, 126.5, 125.2, 69.5, 45.8,
44.9, 38.2, 25.4, minor isomer: 161.4, 144.0, 136.0, 130.1, 127.0, 125.5, 120.5, 70.3, 46.2, 46.0, 35.7, 25.1;
+
MS (ES, HR) m/z: (M+H ) calcd for C H N O: 203.1184; found: 203.1184.
1
2
15
2
Reduction of oxime 9a.
2
Pearlman’s catalyst (Pd(OH) /C, 20% wt loading, 100 mg) and acetic acid (2 mL) were added to the solution
of oxime 9a (600 mg, 2.97 mmol) in methanol (30 mL) and the mixture was stirred for 24h at rt under
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hydrogen atmosphere (balloon). The solution was filtered through Celite and concentrated under reduced
pressure. The residue was dissolved in DCM (10 mL), washed with aqueous NaOH (10%, 10 mL), dried over
2 4
Na SO , filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on
silica gel (DCM/MeOH/NH3/aq, 93/7/1 v/v/v) to give diamine 10a and 11a.
10
11
12
13
14
15
16
17
18
19
20
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45
46
47
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49
50
51
52
53
54
55
56
57
58
59
60
2
3
Cis-diamine 10a: Yield 20 mg ( 0.106 mmol, 4%); oil; [α]
D
-38.9 (c 1.0, CH
2 2 2 2
Cl ); IR (CH Cl ): 3601, 3369,
-
1 1
2
962, 1606 cm ; H-NMR (CDCl , 500 MHz): 7.33-7.30 (m, 1H), 7.22-7.15 (m, 3H), 3.98 (s, 1H), 3.12-3.06 (m,
3
1
3
1H), 3.07 (d, 1H, J=15.5 Hz), 3.04-2.97 (m, 1H), 2.84 (d, 1H, J=15.5 Hz), 2.17 (br s, 3H), 1.90-1.75 (m, 4H); C-
NMR (CDCl , 125 MHz): 145.9, 140.9, 127.4, 126.7, 124.9, 124.1, 73.3, 62.5, 45.9, 43.6, 35.7, 25.4; MS (EI,
3
+
HR) m/z: (M ) calcd for C12
H
16
N
2
: 188.1313; found: 188.1321.
23
Trans-diamine 11a: Yield 410 mg (2.18 mmol, 73%); oil; [α]
D
-7.2 (c 1.0, CH
, 500 MHz): 7.30-7.27 (m, 1H), 7.23-7.12 (m, 3H), 4.22 (s, 1H), 3.15-
.09 (m, 1H), 3.09-3.03 (m, 1H), 2.98 (d, 1H, J=15.0 Hz), 2.81 (d, 1H, J=15.0 Hz), 2.02 (br s, 3H), 1.92-1.80 (m,
2 2 2 2
Cl ); IR (CH Cl ): 3601, 3389,
-
1 1
2
3
3
964, 2875, 1606 cm ; H-NMR (CDCl
3
1
3
H), 1.45-1.39 (m, 1H); C-NMR (CDCl , 125 MHz): 145.6, 140.3, 127.3, 126.7, 124.7, 123.1, 75.7, 63.1, 46.0,
3
+
44.0, 29.9, 24.9; MS (EI, HR) m/z: (M ) calcd for C12
H
16
N
2
: 188.1313; found: 188.1308.
Preparation of compound 12.
The diisopropylethylamine (20 µl, 0.117 mmol) and phosgene (31 µl, 20% solution in toluene) were added
to the solution of amine 10a (11 mg, 0.0585 mmol) in DCM (1 mL) at -20°C. The solution was brought to rt
and stirring was continued until disappearance of 10a, (TLC control,
into aqueous NaOH (10%, 5 mL) and extracted with DCM (2x10 mL). The combined extracts were washed
with brine, dried over MgSO , and evaporated under reduced pressure. The residue was purified by flash
column chromatography using ethyl acetate/hexane, 80/20 v/v as an eluent. Yield 5 mg (0.023 mmol, 40%);
~
3h). The reaction mixture was poured
4
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-1 1
oil; [α]
D
2 2 2 2 3
-162.1 (c 1.0, CH Cl ); IR (CH Cl ): 1702 cm ; H-NMR (CDCl , 600 MHz): 7.29-7.18 (m, 4H), 6.69 (br
s, 1H), 4.88 (s, 1H), 3.73-3.66 (m, 1H), 3.22 (d, 1H, J=16.4 Hz), 3.17-3.12 (m, 1H), 2.98 (d, 1H, J=16.4 Hz),
1
3
2
.14-2.05 (m, 1H), 2.05-1.89 (m, 3H); C-NMR (CDCl
3
, 150 MHz): 164.6, 142.1, 140.3, 128.5, 127.4, 125.2,
+
124.6, 76.3, 63.0, 43.9, 43.6, 34.3, 25.2; MS (EI, HR) m/z: (M ) calcd dof C13
H
14
N
2
O: 214.1106; found:
2
14.1102.
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Preparation of diamine 10b.
Oxime 9b was obtained from aminoketone 8b (1.753 g, 6.11 mmol) followed general procedure I.
Time to completion: 72h; eluent DCM/MeOH/NH3/aq, 98.5/1.5/0.5 v/v/v; semisolid; yield 1.642 g (5.44
mmol, 89%). The crude oxime 9b was hydrogenated using the same procedure as used for oxime 9a.
Purification by flash chromatography on silica gel (MTBE/MeOH/NH3/aq, 98.5/1.5/0.5 v/v/v) followed by
crystallization (from MTBE) of solid obtained by solvent removal, gave enantiomerically pure amine 10b.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
Yield 1.531 g (4.73 mmol, 87%); colourless crystals; mp 104-105°C (MTBE); [α]
D
-4.3 (c 1.0, CH
2 2
Cl ); IR
-
1 1
(
CH Cl ): 3387, 2978, 1680 cm ; H-NMR (Tol-d , 70°C, 600 MHz): 7.31 (d, 1H, J=6.0 Hz), 7.11-7.04 (m, 2H),
2
2
8
7
3
1
.00-6.96 (m, 1H), 3.77 (s, 1H), 3.48-3.40 (m, 2H), 2.64 (d, 1H, J=16.6 Hz), 1.70-1.60 (m, 2H), 1.58-1.49 (m,
13
º
H), 1.45-1.38 (m, 1H), 1.23 (s, 9H); C-NMR (Tol-d , 70 C, 150 MHz): 155.0, 146.5, 141.3, 127.7, 126.7,
8
+
24.2, 78.9, 71.9, 68.0, 49.4, 43.9, 28.6, 28.4, 22.3; MS (EI, HR) m/z: (M ) calcd for C17
H
24
N
2
O
2
: 288.1838;
24 2 2
found: 288.1830. Anal. Calcd for C17H N O : C, 70.80; H, 8.39; N, 9.71; found: C, 70.88; H, 8.37; N, 9.64.
Preparation of ligands 13-15.
General procedure II for N-Boc deprotection.
The N-Boc protected amine (1 mmol) was dissolved in TFA (4 mL) at rt and stirred until disappearance of
the starting material, typically 0.5-1 h (TLC control). The solvent was evaporated in vacuo and residue was
dissolved in DCM (20 mL), washed with aqueous NaOH (10%, 2x 5mL), dried and concentrated in vacuo.
Crude product was directly used in the next step or was purified by flash chromatography.
General procedure III for reductive amination.
To the solution of amine (1 mmol) in MeOH (10 mL) either the monoaldehyde (3 equiv.) or dialdehyde (1.5
equiv.) were added at rt, followed by NaBH CN (3 equiv.). The pH of the solution was adjusted to 6.0 with
3
acetic acid, and the resulted mixture was stirred until the reaction was complete (TLC control). The reaction
mixture was concentrated in vacuo, the residue was dissolved in DCM (20 mL), washed with aqueous NaOH
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(10%, 2x 10 mL), dried and concentrated. Crude product was directly used in the next step or was purified
by flash chromatography.
General procedure IV for amine alkylation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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29
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59
60
2 3
Solid Na CO (744 mg, 7.00 mmol), NaI (375 mg, 2.5 mmol) and alkyl halide were added to the solution of
amine (1 mmol) in MeCN (10 mL). The resulted mixture was stirred at selected temperature until reaction
was complete (TLC control). The reaction mixture was cooled to rt, poured into water (20 mL) and
4
extracted with ethyl acetate (2x10 mL). Combined extracts were washed with brine, dried over MgSO , and
evaporated under reduced pressure. Crude product was directly used in the next step or was purified by
flash chromatography.
Ligand 13a.
Amine 10b (202 mg, 0.70 mmol) was submitted to methylation with formaldehyde using the general
procedure III. Next, Boc group was removed from crude product following the general procedure II.
Purification by flash chromatography on silica gel (MTBE/MeOH/NH3/aq, 90/10/1 v/v/v) gave diamine 13a.
Yield: 124 mg (0.574 mmol, 82%).
23
-1 1
Oil; [α]
D
13.9 (c 0.960, CH
2 2 2 2 3
Cl ); IR (CH Cl ): 3277, 2943, 2866, 1605, 1458 cm ; H-NMR (CDCl , 600 MHz):
7
2
.28-7.18 (m, 4H), 3.52 (s, 1H), 3.44 (br s, 1H), 3.19 (d, 1H, J=16.2 Hz), 3.13-3.08 (m, 1H), 3.07-3.02 (m, 1H),
1
3
3
.87 (d, 1H, J=16.2 Hz), 2.21 (s, 6H), 1.93-1.85 (m, 1H), 1.78-1.66 (m, 3H); C-NMR (CDCl , 150 MHz): 142.9,
139.1, 127.9, 126.3, 126.0, 124.9, 76.1, 69.8, 47.3, 47.1, 42.4, 41.7, 25.7; MS (EI, HR) m/z: (M+) calcd for
C H N : 216.1626; found: 216.1634.
1
4
20
2
Ligand 13b.
Following the general procedure II Boc group was removed from diamine 10b (160 mg, 0.555 mmol). The
crude product was submitted to methylation with formaldehyde using the general procedure III.
Purification by flash chromatography on silica gel (MTBE/MeOH/NH3/aq, 93/7/0.5 v/v/v) gave diamine 13b.
Yield: 99.7 mg (0.433 mmol, 78%).
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-1 1
Oil; [α]D 29.5 (c 1.0, CH Cl ); IR (CH Cl ): 2935, 1477, 1459 cm ; H-NMR (CDCl
3
, 500 MHz): 7.28-7.24 (m,
2
2
2
2
1H), 7.23-7.20 (m, 2H), 7.20-7.15 (m, 1H), 3.65 (s, 1H), 3.38 (d, 1H, J=15.5 Hz), 3.25-3.18 (m, 1H), 2.81-2.74
1
3
(
m, 1H), 2.54 (d, 1H, J=15.5 Hz), 2.52 (s, 3H), 2.28 (s, 6H), 1.86-1.76 (m, 3H), 1.68-1.59 (m, 1H); C-NMR
(
CDCl , 125 MHz): 142.2 140.2, 127.6, 126.2, 125.9, 124.9, 76.3, 74.0, 56.4, 43.1, 39.8, 38.4, 38.3, 29.7, 21.4;
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
22 2
MS (EI, HR) m/z: (M ) calcd for C15H N : 230.1783; found: 230.1792.
Ligand 13c.
Amine 13a (43 mg, 0.20 mmol) was submitted to reductive amination with benzaldehyde using the general
procedure III. Purification by flash chromatography on silica gel (CH Cl /MeOH/NH3/aq, 98/2/0.5 v/v/v)
2
2
gave ligand 13c. Yield: 36 mg (0.118 mmol, 59%).
2
3
-1
1
Oil; [α]
D
18.6 (c 0.735, CH
2
Cl
2
); IR (CH
2
Cl
2
): 2961, 2931, 1478, 1458 cm ; H-NMR (CDCl
3
, 500 MHz): 7.44-
7.40 (m, 2H), 7.33-7.27 (m, 3H), 7.25-7.22 (m, 3H), 7.22-7.16 (m, 1H), 4.20 (d, 1H, J=13.3 Hz), 3.73 (s, 1H),
3
2
1
.68 (d, 1H, J=13.3 Hz), 3.43 (d, 1H, J=15.4 Hz), 3.07-3.00 (m, 1H), 2.70-2.66 (m, 1H), 2.63 (d, 1H, J=15.4 Hz),
13
3
.37 (s, 6H), 1.88-1.76 (m, 3H), 1.69-1.62 (m, 1H); C-NMR (CDCl , 125 MHz): 142.4, 141.4, 138.9, 128.5,
28.1, 127.5, 126.4, 126.4, 125.8, 124.8, 76.0, 74.5, 55.4, 52.6, 43.5, 40.0, 39.3, 21.3; MS (EI, HR) m/z: (M+)
: 306.2096; found: 306.2106.
26 2
calcd for C21H N
Ligand 14a.
Amine 10b (300 mg, 1.04 mmol) was alkylated with 1,4-dibromobutane (150 µl, 1.30 mmol) using the
general procedure IV. The reaction mixture was heated at reflux for 16h. Next, Boc group was removed
from crude product following the general procedure II. Purification by flash chromatography on silica gel
(
MTBE/MeOH/NH3/aq, 90/10/1 v/v/v) gave ligand 14a. Yield: 169 mg (0.70 mmol, 67%).
2
3
-1 1
Oil; [α]
D
2 2 2 2 3
96.7 (c 1.0, CH Cl ); IR (CH Cl ): 3278, 2961 cm ; H-NMR (CDCl , 500 MHz): 7.26-7.15 (m, 4H),
3
.78 (s, 1H), 3.52 (br s, 1H), 3.18 (d, 1H, J=16.1 Hz), 3.13-3.03 (m, 2H), 2.85 (d, 1H, J=16.1 Hz), 2.74-2.67 (m,
1
3
2H), 2.37-2.31 (m, 2H), 1.93-1.85 (m, 1H), 1.81-1.59 (m, 7H); C-NMR (CDCl , 125 MHz): 143.2, 139.5,
3
+
127.8, 126.4, 126.0, 124.7, 71.1, 70.3, 49.2, 47.0, 46.8, 40.8, 25.7, 23.3; MS (EI, HR) m/z: (M ) calcd for
C H N : 242.1783; found: 242.1781.
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Ligand 14b.
Amine 14a (68 mg, 0.28 mmol) was submitted to methylation with formaldehyde using the general
procedure III. Purification by flash chromatography on silica gel (MTBE/MeOH/NH3/aq, 90/10/1 v/v/v) gave
diamine 14b. Yield: 64 mg (0.25 mmol, 89%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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50
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58
59
60
2
3
-1 1
Oil; [α]D 67.7 (c 1.0, CH Cl ); IR (CH Cl ): 2966, 2788, 1473, 1459 cm ; H-NMR (Tol-d , 80°C, 500 MHz):
2
2
2
2
8
7
3
.14-6.97 (m, 4H), 3.62 (s, 1H), 3.34 (d, 1H, J=14.9 Hz), 3.04-2.98 (m, 1H), 2.90-2.84 (m, 2H), 2.58-2.52 (m,
H), 2.44 (s, 3H), 2.22 (d, 1H, J=14.9 Hz), 1.79-1.67 (m, 2H), 1.61-1.50 (m, 4H), 1.48-1.42 (m, 1H), 1.36-1.27
1
3
(
m, 1H); C-NMR (Tol-d
8
, 80°C, 125 MHz): 142.6, 126.9, 126.0, 125.2, 124.5, 75.2, 74.0, 56.3, 51.7, 40.0,
+
3
7.3, 36.9, 23.7, 22.1; MS (EI, HR) m/z: (M ) calcd for C17
H
24
N
2
: 256.1939; found: 256.1933.
Ligand 14c.
Amine 14a (80 mg, 0.33 mmol) was submitted to reductive amination with benzaldehyde using the general
procedure III. Purification by flash chromatography on silica gel (gradient CH Cl /MeOH, 97/3 to
2
2
CH
2
Cl
2
/MeOH/NH3/aq, 95/5/1 v/v/v) gave ligand 14c. Yield: 82 mg (0.248 mmol, 75%).
2
3
-1 1
Oil; [α]
D
2 2 2 2 8
37.7 (c 1.0, CH Cl ); IR (CH Cl ): 2964, 2929, 1453 cm ; H-NMR (Tol-d , 80°C, 500 MHz): 7.41-7.37
(
m, 2H), 7.21-7.17 (m, 2H), 7.15-7.11 (m, 1H), 7.09-6.96 (m, 4H), 4.33 (d, 1H, J=13.6 Hz), 3.78 (s, 1H), 3.69
(
d, 1H, J=13.6 Hz), 3.35 (d, 1H, J=15.1 Hz), 3.02-2.97 (m, 1H), 2.77-2.71 (m, 2H), 2.60-2.52 (m, 3H), 2.40 (d,
1
3
1
1
8
H, J=15.1 Hz), 1.77-1.72 (m, 1H), 1.70-1.63 (m, 1H), 1.60-1.47 (m, 6H); C-NMR (Tol-d , 80°C, 125 MHz):
42.3, 142.1, 141.9, 128.0, 127.8, 127.2, 126.0, 126.0, 125.5, 124.6, 74.1, 74.0, 55.1, 52.5, 51.6, 40.3, 38.6,
+
23.6, 21.5; MS (EI, HR) m/z: (M ) calcd for C23
H
28
N
2
: 332.2252; found: 332.2259.
Ligand 15a.
Amine 10b (143 mg, 0.496 mmol) was submitted to reductive amination with benzene-1,2-dicarbaldehyde
using the general procedure III. Next, Boc group was removed from crude product following the general
procedure II. Purification by flash chromatography on silica gel (CH
diamine 15a. Yield: 64 mg (0.223 mmol, 45%).
2 2
Cl /MeOH/NH3/aq, 95/5/0.5 v/v/v) gave
2
3
-1 1
Oil; [α]
D
2 2 2 2 3
174.8 (c 1.0, CH Cl ); IR (CH Cl ): 3286, 2958, 2942, 1678 cm ; H-NMR (CDCl , 500 MHz): 7.30-
7.27 (m, 1H), 7.26-7.20 (m, 2H), 7.17-7.11 (m, 5H), 4.18 (d, 2H, J=10.5 Hz), 3.96 (s, 1H), 3.85 (d, 2H, J=10.5
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Hz), 3.22 (d, 1H, J=16.1 Hz), 3.13-3.01 (m, 2H), 2.91 (d, 1H, J=16.1 Hz), 1.96-1.88 (m, 1H), 1.85-1.77 (m, 2H),
1
3
1.75-1.68 (m, 1H); C-NMR (CDCl
3
, 125 MHz): 143.0, 140.0, 139.8, 128.0, 126.9, 126.6, 126.6, 124.9, 122.3,
+
7
2
1.3, 70.5, 55.1, 47.0, 46.7, 40.6, 25.7; MS (ES, HR) m/z: (M+H ) calcd for C20
H
23
N
2
: 291.1856; found:
91.1844.
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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0
Ligand 15b.
Amine 15a (35 mg, 0.12 mmol) was submitted to methylation with formaldehyde using the general
procedure III. Purification by flash chromatography on silica gel (CH Cl /MeOH/NH3/aq, 95/5/0.5 v/v/v)
2
2
gave diamine 15b. Yield: 20 mg (0.065 mmol, 54%).
2
3
1
Oil; [α]
D
2 2 8
72.3 (c 1.0, CH Cl ); H-NMR (Tol-d , 80°C, 500 MHz): 7.14-6.99 (m, 8H), 4.34 (d, 2H, J=11.1 Hz),
4.11 (d, 2H, J=11.1 Hz), 3.99 (s, 1H), 3.28 (d, 1H, J=15.1 Hz), 3.08-3.01 (m, 1H), 2.56-2.49 (m, 1H), 2.32 (s,
1
3
3
1
2
H), 2.28 (d, 1H, J=15.1 Hz), 1.94-1.86 (m, 1H), 1.79-1.70 (m, 1H), 1.58-1.47 (m, 2H); C-NMR (Tol-d , 80°C,
8
25 MHz): 142.5, 141.1, 129.2, 128.3, 126.7, 126.3, 125.5, 122.4, 75.2, 74.6, 57.7, 56.8, 39.8, 37.7, 37.5,
+
2.3; MS (ES, HR) m/z: (M+H ) calcd for C21
H
25
N
2
: 305.2012; found: 305.2004.
Ligand 16a.
Amine 10b (432 mg, 1.5 mmol) was alkylated with 1,5-dibromopentane (246 µl, 1.8 mmol) using the
general procedure IV. The reaction mixture was heated at reflux for 24h. Next, Boc group was removed
from crude product following the general procedure II. Purification by flash chromatography on silica gel
(MTBE/MeOH/NH3/aq, 90/10/1 v/v/v) gave ligand 16a. Yield: 330 mg (1.29 mmol, 86%).
2
3
-1 1
Semisolid; [α]
D
2 2 2 2 3
55.7 (c 0.545, CH Cl ); IR (CH Cl ): 3268, 2937, 1605 cm ; H-NMR (CDCl , 600 MHz): 7.29-
7
.27 (m, 1H), 7.25-7.22 (m, 1H), 7.21-7.17 (m, 2H), 3.47 (s, 1H), 3.27 (d, 1H, J=16.5 Hz), 3.15-3.10 (m, 2H),
2.94 (d, 1H, J=16.5 Hz), 2.60-2.53 (m, 2H), 2.24 (br s, 2H), 1.96-1.89 (m, 1H), 1.80-1.72 (m, 3H), 1.61-1.47
1
3
(m, 4H), 1.38-1.30 (m, 2H); C-NMR (CDCl
3
, 150 MHz): 142.5, 139.5, 127.9, 126.3, 126.1, 125.0, 77.3, 69.6,
+
4
7.2, 46.9, 41.5, 26.7, 25.5, 24.1; MS (EI, HR) m/z: (M ) calcd for C H N : 256.1940; found: 256.1944.
1
7
24
2
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Ligand 16b.
Amine 10b (86 mg, 0.30 mmol) was alkylated with bis(2-chloroethyl) ether (42 µl, 0.36 mmol) using
modified general procedure IV. The reaction mixture in DMF solution was heated at 110°C for 16h. Next,
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11
12
13
14
15
16
17
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46
47
48
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53
54
55
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58
59
60
Boc group was removed from crude product following the general procedure II. Purification by flash
chromatography on silica gel (MTBE/MeOH/NH3/aq, 90/10/1 v/v/v) gave ligand 16b. Yield: 51 mg (0.198
mmol, 66%).
2
3
-1 1
Oil; [α]D 61.9 (c 0.945, CH Cl ); IR (CH Cl ): 3278, 2962, 2858 cm ; H-NMR (C D , 600 MHz): 7.09-7.03 (m,
2
2
2
2
6 6
4H), 3.52-3.47 (m, 2H), 3.44-3.39 (m, 2H), 3.22 (s, 1H), 3.03 (d, 1H, J=16.3 Hz), 2.98-2.93 (m, 1H), 2.91-2.86
(m, 1H), 2.73 (d, 1H, J=16.3 Hz), 2.52-2.46 (m, 2H), 2.10-2.04 (m, 2H), 1.68-1.59 (m, 1H), 1.53-1.43 (m, 3H);
1
3
C-NMR (C
6
D
6
, 150 MHz): 143.0, 139.9, 127.8, 126.4, 126.0, 124.9, 77.1, 70.0, 67.1, 50.6, 48.3, 47.0, 41.9,
+
2
5.8; MS (EI, HR) m/z: (M ) calcd for C16
H
22
N
2
O: 258.1732; found: 258.1721.
Ligand 16c.
Amine 10b (58 mg, 0.20 mmol) was alkylated with benzyl chloride (54 µl, 0.45 mmol) using the general
procedure IV. The reaction mixture was stirred at 50°C for 3h. Next, Boc group was removed from crude
product following the general procedure II. Purification by flash chromatography on silica gel
(MTBE/MeOH/NH3/aq, 97/3/0.5 v/v/v) gave ligand 16c. Yield: 68 mg (0.184 mmol, 92%).
2
3
-1 1
Oil; [α]
H), 7.35-7.30 (m, 3H), 7.18-6.98 (m, 10H), 3.80 (d, 2H, J=13.2 Hz), 3.78 (s, 1H), 3.34-3.25 (br d, 2H, J=13.2
Hz), 3.18 (d, 1H, J=16.3 Hz), 2.99-2.91 (m, 2H), 2.73 (d, 1H, J=16.3 Hz), 1.50-1.43 (m, 1H), 1.42-1.27 (m, 3H),
D
2 2 2 2 6 6
136.8 (c 1.68, CH Cl ); IR (CH Cl ): 3279, 2957, 2931 cm ; H-NMR (C D , 600 MHz): 7.39-7.36 (m,
1
1
3
1
.14-1.05 (m, 1H); C-NMR (C D , 150 MHz): 143.2, 141.3, 140.2, 129.1, 128.8, 128.2, 127.8, 126.9, 126.1,
6 6
+
29 2
126.0, 125.1, 125.0, 70.4, 70.2, 55.5, 48.3, 47.3, 42.0, 25.8; MS (EI, HR) m/z: (M+H ) calcd for C26H N :
369.2325; found: 369.2326.
Ligand 16d.
1
5
Amine 10b (86 mg, 0.30 mmol) was alkylated with 1,8-bis(bromomethyl)naphthalene (113 mg, 0.36
mmol) using the general procedure IV. The reaction mixture was stirred at rt for 4h. Next, Boc group was
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