Synthesis of chiral 1,3-diamines derived from cis-2- benzamidocyclohexanecarboxylic acid and their application in the Cu-catalyzed enantioselective Henry reaction

Article abstract of DOI:10.1002/chem.201102136

In this study, 13 different chiral 1,3-diamines were synthesized from (-)-cis-2-benzamidocyclohexanecarboxylic acid. They were successfully applied as ligands in the Cu-catalyzed asymmetric Henry reaction between benzaldehyde and nitromethane. It was conf

Full text of DOI:10.1002/chem.201102136

DOI: 10.1002/chem.201102136
Synthesis of Chiral 1,3-Diamines Derived from cis-2-
BenzamidoACTHUNGTRENcNNGU ycloACHTUNTRGEGhNNUN exaneCAHTNUGTRENcGUNN arboxylic Acid and Their Application in the
Cu-Catalyzed Enantioselective Henry Reaction
Koichi Kodama,* Kazuyuki Sugawara, and Takuji Hirose*[a]
Abstract: In this study, 13 different
A time-course study revealed a de-
crease in product enantioselectivity
caused by spontaneous retro-Henry re-
action, which was suppressed by con-
ducting the reaction at 08C. This versa-
tile reaction afforded various b-nitroal-
chiral 1,3-diamines were synthesized
from (À)-cis-2-benzamidocyclohexane-
carboxylic acid. They were successfully
applied as ligands in the Cu-catalyzed
asymmetric Henry reaction between
benzaldehyde and nitromethane. It was
confirmed that the enantioselectivity of
the product could be controlled by the
substituents on the two amino groups.
cohols in excellent yields and enantio-
selectivities (up to 98% yield, 91%
enantiomeric excess) under the opti-
mized reaction conditions. The chiral
induction mechanism was explained on
the basis of a previously proposed tran-
sition-state model.
Keywords: asymmetric synthesis ·
chirality · copper · diamines · Henry
reaction
Introduction
made chiral catalyst, that is, no naturally occurring enantio-
pure compound is used in the synthesis of the chiral cata-
lysts.
Due to the high demand and preference for the use of enan-
tiopure compounds in the fields of pharmaceuticals, per-
fumes, food additives, etc., there has been a great interest in
catalytic asymmetric synthesis as a tool for their efficient
preparation. Although large numbers of chiral ligands and
organocatalysts have been synthesized and applied for a va-
riety of asymmetric reactions, most of them are derivatives
and analogues of the “privileged chiral catalysts”.[1] To fur-
ther expand the potential of asymmetric synthesis, we aimed
to develop novel chiral catalysts without privileged struc-
tures in a readily accessible manner.
Since the report revealing the preparation of enantiopure
1 by preferential crystallization, compound 1 and its deriva-
tives have been applied as resolving agents,[3] for example,
in the synthesis of b-peptides.[4] However, to the best of our
knowledge, few reports about their application towards
asymmetric synthesis have been published.[5] For example,
Saigo reported the only example of their application to a
catalytic asymmetric reaction and the enantiomeric excess
(ee) values achieved in this reaction were very low
AHCTUNGTRENNUNG
(<10% ee).[6] These facts also motivated us to explore reac-
We focused on cis-2-benzamidocyclohexanecarboxylic
acid (1) as a starting material for the synthesis of chiral cata-
lysts. Compound 1 is a very attractive chiral compound be-
cause, not only can it be readily synthesized from inexpen-
sive starting materials, but it also has functional groups that
can be easily transformed (i.e., hydroxy and amino groups).
In addition, both enantiomers of 1 can be prepared by pref-
erential resolution and, therefore, require no resolving agent
as an external chiral source.[2] Thus, compound 1 can be
easily and economically derivatized as a completely man-
tions in which derivatives of 1 can be applied as chiral cata-
lysts.
Recently, our group reported the application of 1,3-ami-
noalcohols and 1,3-aminosulfonamide chiral ligands derived
from (À)-1 to the catalytic enantioselective addition of orga-
nozinc reagents to aldehydes.[7a–c] Also, chiral ionic liquids
and 1,3-aminothioureas derived from (+)-1 have been ap-
plied in asymmetric Michael addition reactions between al-
dehydes and b-nitroolefins.[7d–e] As an extension of our work,
we designed and synthesized an array of enantiopure 1,3-di-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Dr. K. Kodama, K. Sugawara, Prof. T. Hirose
Department of Applied Chemistry
Graduate School of Science and Engineering
Saitama University
Cu-catalyzed enantioselective Henry reaction.
The Henry reaction entails addition of a nitroalkane to
the carbonyl group of an aldehyde or a ketone.[8] Since the
first asymmetric version of this reaction was reported by
Shibasaki,[9] various chiral metal-containing catalysts and or-
ganocatalysts have been developed. In particular, it has
been determined that Cu complexes with chiral aza-contain-
255 Shimo-Okubo, Sakura-ku
Saitama 338-8570 (Japan)
Fax : (+81)48-858-9548
E-mail: kodama@mail.saitama-u.ac.jp
hirose@apc.saitama-u.ac.jp
ing ligands (e.g. aminoalcohols, Schiff bases, diACTHNUTRGENUGaN mines) are
highly efficient catalysts for the asymmetric Henry reac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102136.
13584
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Chem. Eur. J. 2011, 17, 13584 – 13592

FULL PAPER
tion.[10] Chiral b-nitroalcohols, the products of this asymmet-
ric transformation, are very important intermediates or
building blocks in organic synthesis because they can be
readily converted into b-aminoalcohols by reduction of the
nitro group, a-hydroxycarboxylic acids by the Nef reaction,
and so on.[11] Due to the practical importance of this reac-
tion, it is a worthy challenge to develop an efficient and
readily available catalyst for the asymmetric Henry reaction.
Herein, we report the synthesis of novel chiral 1,3-di-
form a mixed anhydride, followed by addition of the appro-
priate amine (or aqueous amine solution) furnished di-
A
ACHTUNGTRENaNGNU mides with lith-
AHCTUNGTRENNUNG
verted to 4d by hydrogenolysis of the N-benzyl group, cata-
lyzed by Pd/C. The reductive amination of 4d with a variety
of aromatic aldehydes afforded diACHTUNTRGNEUNGamines 4e–i. Aminoamide
6 was formed by amidation of 4a with benzoyl chloride,
which was then reduced to yield 4j.
amines from (À)-1 by simple chemical transformations and
their successful application as chiral ligands in the Cu-cata-
lyzed enantioselective Henry reaction.
Investigation of chiral 1,3-diamine ligands in the Cu-cata-
lyzed enantioselective Henry reaction: With the enantiopure
1,3-diACHTNUTRGNEaUNG mine ligands 2, 3a, 3b, and 4a–j in hand, we exam-
Results and Discussion
ined their asymmetric induction abilities in the Cu-catalyzed
enantioselective Henry reaction between benzaldehyde (7a)
Synthesis of chiral 1,3-diamine ligands derived from (À)-1:
and nitromethane (8) in the presence of CuACTHNGUTERNNU(G OAc)2·H2O in
We designed 1,3-di
amines with two different amino groups:
99% EtOH.[12]
a cyclohexylmethylamino (primC-amino) group and a cyclo-
hexylamino (secC-amino) group. The synthetic routes to
The results are summarized in Table 1. When di
ACHTUNGTRNEaNUNG mine 4a
was used as a chiral ligand, 9a was obtained with a moder-
three types of 1,3-diACHTUNGTRENNUNG
amines, namely, 2 (primary primC-amine),
3a and 3b (secondary primC-amines), and 4a–j (tertiary primC-
Table 1. Investigation of 1,3-di
tive Henry reaction.
ACHTUNGTRENUNaNG mine ligands in the catalytic enantioselec-
amines), are shown in Scheme 1. All of the enantiopure 1,3-
1,3-Diamine ligand ([mol%])
Yield
[%][a]
ee
R1
R2
R3
R4
[%][b,c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2 (12)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bn
H
Bn
Bn
Bn
Bn
Bn
Bn
H
65
87
>99
83
rac.[d]
5
3a (12)
3b (12)
4a (12)
4b (12)
4c (12)
4d (12)
4e (12)
4 f (12)
4g (12)
4h (12)
4i (12)
4j (12)
4h (10)
Me
Bn
Me
Et
À
rac.[d]
55
Me
Et
À
85
30
24
19
55
60
53
63
54
(CH2)4
>99
>99
82
77
77
73
90
51
66
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-ClC6H4CH2
4-MeOC6H4CH2
4-PhC6H4CH2
1-naphthy CH2
2-naphthyl CH2
À
À
Bn
11
69
À
1-naphthyl CH2
Scheme 1. Synthetic routes to the chiral 1,3-diACTHNUTRGNEaNUG mine ligands 2–4. Re-
[a] Yields based on 7a. [b] Determined by chiral HPLC analysis. [c] Ab-
solute configurations were determined by comparison of the HPLC elu-
tion order with the literature data. [d] Less than 5% ee.
agents and conditions: a) ClCO2Et, triethylamine (TEA), dry THF or dry
CH2Cl2, 08C to RT; b) add R1R2NH, RT; c) LiAlH4, dry THF or dry 1,4-
dioxane, 08C to reflux temperature; d) H2 (1 atm), cat. Pd/C, EtOH,
708C; e) 7, 3 ꢁ molecular sieves, dry CH2Cl2, RT or MeOH, reflux tem-
perature; f) NaBH4, EtOH or MeOH, RT; g) PhCOCl, TEA, dry THF,
08C to RT.
ate ee (Table 1, entry 4). In contrast, the product was ob-
tained with negligible selectivity when ligands 2, 3a, or 3b
were used (Table 1, entries 1–3). Considering the relation-
ship between the structures of these ligands and ee values of
the obtained Henry adducts, it appears that a tertiary primC-
amino group in the chiral ligand results in improved enan-
tioselectivity. Additionally, the use of 4d and 4j as chiral li-
gands afforded products with low ee values. Moreover, in
diACHTUNGTRENNUNGamines were synthesized by simple methods in moderate
to high yields. The synthesis and characterization of 2, 4a–d,
5a, and 5d–f were reported in a previous paper.[7c] Enantio-
pure (À)-1 was prepared according to the literature proce-
dure.[2] The reaction of (À)-1 and ethyl chloroformate to
Chem. Eur. J. 2011, 17, 13584 – 13592
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13585

T. Hirose, K. Kodama, and K. Sugawara
the case of 4j, the yield of the product also decreased
(Table 1, entries 7 and 13). Comparing these results with
that reported in Table 1, entry 4, from the perspective of the
chiral ligand structures and resultant enantioselectivities, it
is evident that the secC-amino group in the chiral ligands
should be a secondary amino group to further increase the
enantioselectivity of the reaction. The details of the relation-
ships between the structures of the chiral ligands and the
enantioselectivities are discussed later in terms the transi-
tion-state model (see below, Figure 1). A subsequent investi-
gation of the substituents on the tertiary primC-amino group
(Table 1, entries 4–6) and secondary secC-amino group
reaction within 12 h before the retro-Henry reaction begins.
However, at 508C, the retro-Henry reaction was notably ac-
celerated and the enantioselectivity decreased to 71% ee
after only 1 h (Table 2, entry 2). Furthermore, the yield of
the adduct also decreased as the reaction proceeded. This is
because of the enhanced dehydration reaction of adduct 9a
at a higher temperature to afford b-nitrostyrene, which was
1
confirmed by H NMR spectroscopic analysis. Therefore, we
conducted the reaction at 08C to prevent the retro-Henry
reaction; it was found that the decrease in the ee of the
adduct was suppressed until the reaction was finished and
the selectivity was improved, although the reaction rate was
drastically reduced (Table 2, entry 3).
(Table 1, entries 8–13) revealed that 1,3-diACTHNURTGNEUaGN mine 4h was the
most effective chiral ligand for the enantioselective Cu-cata-
lyzed Henry reaction (Table 1, entry 11). Reducing the load-
ing amount of 4h from 12 to 10 mol% improved the ee of
the Henry adduct (Table 1, entry 14). This result is probably
due to the suppression of a non-enantioselective reaction
pathway catalyzed by an excess amount of free diACTHNUTRGNEUGaN mine 4h.
From these results, it was demonstrated that 4h, which fea-
tures (N,N-dimethylamino)methyl and N’-(1-naphthylmeth-
Optimization of the reaction conditions: To improve the re-
action rate without promoting the retro-Henry reaction, fur-
ther optimization of the reaction conditions was carried out.
First, the effects of an additional base were examined be-
cause the deprotonation of nitromethane to form the corre-
sponding nitronate is a rate-determining step in the Henry
reaction.[10] Triethylamine (TEA) was selected as a basic ad-
ditive; the effect of loading amount was investigated and the
results are summarized in Table 3. The addition of increas-
ing amounts of TEA was found to drastically enhance the
reaction, however, more than 5 mol% of TEA resulted in
lower enantioselectivities (Table 3, entries 4–7) and an equi-
molar amount of TEA afforded the product with only
59% ee (Table 3, entry 7). This result is probably due to en-
hancement of the non-enantioselective reaction pathway
mentioned above. The best result was obtained by the addi-
tion of TEA (2 mol%) as an external base (Table 3,
entry 2).
Several organic bases were examined as additives and the
results are shown in Table 4. Notably, weaker bases afforded
the product in slightly higher enantioselectivities (Table 4,
entries 5–7). Considering the pKa value of nitromethane
(10.2) and the pKaH values of the corresponding conjugate
acids, the bases with pKaH values smaller than 10.2 afforded
higher selectivities. This is because the weaker bases selec-
tively deprotonate Cu-coordinated nitromethane,
ACHTUNGTRENNUNGyl)amino groups at the 1,2-cis positions of the cyclohexane
ring, is the optimal chiral ligand for this reaction.
Verification and control of the retro-Henry reaction in the
catalytic enantioselective Henry reaction: Although it was
determined that 1,3-diACTHNUGRTENUNGamine 4h is the optimal chiral ligand
for the enantioselective Henry reaction, the enantioselectivi-
ty was still not very high. According to Nagasawa, the ee of
the Henry adduct can gradually decrease as a result of a
retro-Henry reaction.[13] To investigate the influence of the
retro-Henry reaction under the above reaction conditions,
time-course studies of the reaction were carried out at room
temperature. The ee values of the Henry adduct remained
constant until 12 h, however, they gradually decreased as
the reaction continued (Table 2, entry 1). This result indi-
cates that the retro-Henry reaction did proceed at RT and
lowered the enantioselectivity of the reaction. Based on this
result, we conducted the reaction at 508C to culminate the
which is more acidic than free nitromethane, and
Table 2. Verification and control of the retro-Henry reaction in the catalytic enantio-
selective Henry reaction (time-course studies at several reaction temperatures).
suppression of the unselective reaction pathway re-
sults. The exceptionally lower yield of 9a after the
addition of pyridine is probably due to the higher
coordination affinity of the latter for the copper ion
(Table 4, entry 7). Judging from these results and
the properties of the bases, DABCO was selected
as the best external base to give 9a in high yield
and selectivity (Table 4, entry 5).
Finally, the solvent and the amount of the cata-
lyst were optimized, as shown in Table 5. The ee
values of the product 9a were almost unchanged in
the five solvents examined (Table 5, entries 1–5),
however, ethanol resulted in a higher yield than
any of the other solvents (Table 5, entry 1). This is
T
Yield [%][a] (ee [%])[b,c]
[8C]
1 h
3 h
6 h
12 h
24 h
48 h
72 h
–
96 h
–
1
2
3
RT
50
0
20
(84)
47
(71)
4
40
(85)
70
(50)
5
54
(84)
60
(42)
11
65
(83)
54
(42)
25
67
(76)
36
(40)
40
70
(71)
27
(23)
52
–
–
83
99
(83)
(89)
(89)
(90)
(88)
(90)
(90)
(90)
[a] Yields based on 7a. [b] Determined by chiral HPLC analysis. [c] Absolute configu-
rations were determined by comparison of the HPLC elution order with the literature
data.
probably because the lower solubility of Cu
ACHTUNGTRENNUNG(OAc)2
in the other solvents decreased the amount of avail-
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Synthesis of Chiral 1,3-Diamines
FULL PAPER
Table 3. Effect of TEA as an external base on the catalytic enantioselec-
tive Henry reaction.
Table 5. Investigation of solvents and loading amount of pre-catalysts in
the catalytic enantioselective Henry reaction.
TEA [mol%]
Yield [%][a]
ee [%][b,c]
Solvent Cu
(OAc)2·H2O/4h/DABCO
Yield
[%][a]
ee
[mol%]
[%][b,c]
1[d]
2
3
4
5
0
2
5
10
20
50
100
40
86
94
91
90
89
84
88
88
85
82
76
67
59
1
2
3
4
5
6
7
8
9
EtOH 10:10:2
MeOH 10:10:2
89
72
56
21
17
59
65
87
92
90
88
87
87
86
90
90
90
90
THF
10:10:2
toluene 10:10:2
CH2Cl2 10:10:2
EtOH 5:5:1
EtOH 5:5:2
EtOH 20:20:2
EtOH 20:20:4
6
7
[a] Yields based on 7a. [b] Determined by chiral HPLC analysis. [c] Ab-
solute configurations were determined by comparison of the HPLC elu-
tion order with the literature data. [d] The result reported in Table 2,
entry 3 at 24 h.
[a] Yields based on 7a. [b] Determined by chiral HPLC analysis. [c] Ab-
solute configurations were determined by comparison of the HPLC elu-
tion order with the literature data.
Table 4. Investigation of external bases in the catalytic enantioselective
Henry reaction.
exposing 9a with a known enantiopurity (88% ee) to various
conditions for 24 h (Table 6). Enantioenriched 9a was dis-
solved in ethanol and the enantiopurity of recovered 9a was
unchanged, which revealed that no spontaneous retro-Henry
reaction proceeded, even at room temperature (Table 6,
entry 1). In the presence of CuACHTNUTRGNEUNG(OAc)2·H2O (10 mol%) or
4h (10 mol%), the enantiopurity of recovered 9a remained
high, however, it was notably decreased in the presence of
[a]
External base
pKaH
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
DBU
12.5
12.3
11.4
10.8
8.8[f]
7.4
94
92
91
86
89
88
53
84
87
86
88
90
90
90
proton Sponge[e]
DIPEA
TEA
both Cu
sults suggest that the retro-Henry reaction proceeded
through interaction of 9a with the Cu–diamine complex.
ACHTUNGTRNEN(UNG OAc)2·H2O and 4h (Table 6, entries 2–4). These re-
DABCO
NMM
pyridine
AHCTUNGTRENNUNG
The further addition of 8 (9 equiv) improved the enantiopur-
ity of recovered 9a to some extent (Table 6, entry 5). It is
5.2
[a] The pKa value of the conjugate acid of the external base. [b] Yield
based on 7a. [c] Determined by chiral HPLC analysis. [d] Absolute con-
figurations were determined by comparison of the HPLC elution order
with the literature data. [e] 1,8-bis(dimethylamino)naphthalene. [f] The
pKa value of the monoprotonated species. DBU=1,8-diazabicyclo-
Table 6. Verification of the suppression of the retro-Henry reaction under
the optimized reaction conditions.[a]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
able active 4h–[CuACHTUNGTRENNUNG(OAc)2] complex. Next, the catalyst load-
ing was investigated with ethanol as the solvent. When the
amount of catalyst was decreased to 5 mol%, the yield of
9a decreased but the selectivity remained high (Table 5, en-
tries 6 and 7). On the other hand, increasing the amount of
catalyst to 20 mol% afforded similar results to the initial
conditions (Table 5, entries 8 and 9). In summary, from
these investigations the optimized reaction conditions are:
Cu
A
G
DABCO
A
8
T
ee of
ee of
E
9a
9a
[%][b,c]
[%][b,c]
1
2
3
4
5
6
7
–
10
–
10
10
10
10
–
–
–
–
–
–
–
–
2
–
–
–
–
9
9
9
RT 88
RT 88
RT 88
RT 88
RT 88
87
88
85
73
80
87
87
10
10
10
10
10
CuACHTUNGTRENNUNG(OAc)2·H2O (10 mol%), 4h (10 mol%), DABCO
(2 mol%), EtOH, 08C.
0
0
88
88
Proof of suppression of the retro-Henry reaction under the
optimized conditions: To further confirm suppression of the
retro-Henry reaction under the optimized conditions, the
change in the enantiopurity of product 9a was examined by
[a] All reactions were performed on a 0.1 mmol scale in EtOH (0.3 mL).
[b] Determined by chiral HPLC analysis. [c] Absolute configurations were
determined by comparison of the HPLC elution order with the literature
data.
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13587

T. Hirose, K. Kodama, and K. Sugawara
plausible that coordination of an excess amount of CH3NO2
to the Cu–diamine complex prevents the interaction be-
tween 9a and the Cu–diamine complex. Lowering the tem-
perature to 08C resulted in no change in the enantiopurity
of recovered 9a (Table 6, entry 6) and the inclusion of
DABCO (2 mol%), which corresponds to the optimized
conditions, afforded the same result (Table 6, entry 7).
These experiments clearly show that racemization of 9a
through the retro-Henry reaction was successfully sup-
pressed under the optimized conditions.
methyl group was from the formyl group, the lower the
chemical yield (i.e. p-tolualdehyde gave the lowest yield). In
addition, a bulkier phenyl group at the para position of ben-
zaldehyde lowered the yield further (Table 7, entry 10). All
of the aldehydes showed comparable selectivities. The rela-
tionship between the yield and the position of the substitu-
ent is discussed later (see Scheme 4 and Figure 1 below).
The reaction proceeded in a highly enantioselective fashion
for other aromatic aldehydes (Table 7, entries 11–14) and an
a,b-unsaturated aldehyde (Table 7, entry 15). Under the
same conditions, the reactions of aliphatic aldehydes 7p–t
afforded 9p–t in low yields (Table 7, entries 16–20). Such a
drastic decrease in yield for the aliphatic aldehydes with an
sp3-hybridized a-carbon atom indicates that this reaction is
very sensitive to the steric demand around the carbonyl
carbon atom. The products from reaction of the a-branched
aliphatic aldehydes, 9p and 9q, showed ee values as high as
those of the aromatic analogues (Table 7, entries 16 and 17).
On the other hand, the selectivities decreased for b-
branched, g-branched, and linear aliphatic substituents
(Table 7, entries 18–20). Doubling the reaction time (48 h)
for substrate 7s gave 9s in approximately double the yield
(Table 7, entry 19) and no products other than 9s were de-
tected by analytical TLC during the reaction, which indi-
cates that the low yields for the aliphatic aldehydes were
not caused by undesirable side reactions but rather by their
slower reaction rates. It was also revealed that, in all cases,
the nucleophilic addition proceeded from the Si face of the
aldehydes.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Scope and limitation of the substrates: A variety of aromatic
and aliphatic aldehydes were tested as substrates under the
optimized conditions to demonstrate the reaction versatility.
The results are summarized in Table 7. The reactions of ben-
Table 7. Scope of aldehydes in the catalytic enantioselective Henry reac-
tion.
R
Aldehyde Product Yield
[%][a]
ee
Config-
[%][b]
uration[c]
1
2
3
4
5
6
7
8
Ph
7a
7b
9a
9b
9c
9d
9e
9 f
9g
9h
9i
89
61
60
90
97
94
67
76
85
55
74
98
63
81
71
26
12
32
90
91
88
88
87
83
91
88
87
86
89
88
84
85
84
86
85
71
R
R
R
R
R
R
R
R
R
R
R
R
S[d]
S[d]
R
R
R
R
R
R
4-MeOC6H4
3,4-(MeO)2C6H3 7c
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-PhC6H4
1-naphthyl
2-naphthyl
2-thienyl
2-furyl
(E)-PhCH=CH 7o
Cy
iPr
iBu
7d
7e
7 f
7g
7h
7i
7j
7k
7l
Catalytic diastereo- and enantioselective Henry reaction be-
tween nitroethane and benzaldehyde: The successful results
obtained for the catalytic enantioselective Henry reaction
promoted us to carry out a diastereo- and enantioselective
Henry reaction between 7a and nitroethane (10) under the
optimized conditions (Scheme 2).[14]
9
10
11
12
13
14
15
16
17
18
9j
9k
9l
7m
7n
9m
9n
9o
9p
9q
9r
9s
9t
7p
7q
7r
7s
7t
19[e] PhCH2CH2
20
18 (33) 79 (80)
36 73
Et
[a] Yields based on 7. [b] Determined by chiral HPLC analysis. [c] Abso-
lute configurations were determined by comparison of the HPLC elution
order with the literature data. [d] Formal inversion of the stereodescrip-
tor due to the Cahn–Ingold–Prelog notation. [e] The values in parenthe-
ses are the results after 48 h.
Scheme 2. Catalytic diastereo- and enantioselective Henry reaction be-
tween benzaldehyde and nitroethane. Reaction conditions: 4h
(10 mol%), Cu
24 h.
ACHTUNGTRNEN(UNG OAc)2·H2O (10 mol%), DABCO (2 mol%), EtOH, 08C,
zaldehydes substituted with electron-donating groups afford-
ed the Henry adducts 9b, 9c, and 9g in lower yields than 9a
(Table 7, entries 2, 3, and 7). Conversely, electron-withdraw-
ing substituents made the yield higher (Table 7, entries 4–6).
Although the electronic properties of the substituents on
the aromatic ring affected the yield, they had little influence
on the enantioselectivity. Next, the steric effect of the alde-
hydes was investigated with positional isomers of tolualde-
hyde (Table 7, entries 7–9). It was found that the further the
The reaction gave the products 11 with moderate diaste-
reoselectivity (anti/syn=71:29) and high enantioselectivities
(91 and 89% ee for the anti- and syn-isomers, respectively).
The enantioselectivities were similar to the enantioselective
reaction of 7a with 8 to give (R)-9a (Table 7, entry 1) and
the absolute configurations of the products were (1R,2S)-
anti-11 and (1R,2R)-syn-11; the 1R centers were commonly
13588
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Chem. Eur. J. 2011, 17, 13584 – 13592

Synthesis of Chiral 1,3-Diamines
FULL PAPER
produced by nucleophilic addition from the Si face of the
carbonyl group of benzaldehyde. This result indicates that
both reactions proceed through a similar transition state.
The lower yield of 11 relative to 9a can probably be attrib-
uted to the steric hindrance of 10 because its acidity is
higher than that of 8 (pKa =8.6 and 10.2, respectively).
Catalytic cycle and the mechanism of the Henry reaction:
Based on the above results and Jorgensenꢃs report,[15] we
proposed a catalytic cycle for this asymmetric Henry reac-
tion (Scheme 3). First, complex A was formed from Cu-
ACHTUNGTRENNUNG(OAc)2 and 4h, followed by coordination of the nitroalkane
and aldehyde to generate complex B. Deprotonation of the
nitroalkane was promoted by DABCO and stereoselective
bond formation was achieved through transition state C to
give complex D. Finally, release of the adduct from complex
D and coordination of another nitroalkane and aldehyde
molecule regenerated complex B to complete the catalytic
cycle.
Figure 1. a) Proposed transition state for the catalytic asymmetric Henry
reaction with 4h as the diACTHNUGRTNEUNGamine ligand. b) Schematic representation of
the transition state. Nitronate and acetate are omitted for clarity.
less-crowded space II, whereas
the corresponding nitroalkane
approaches from the unoccu-
pied upper side of the complex
to permit nucleophilic attack
from the Si face of the alde-
hyde. For the diastereoselective
reaction, the anti isomer was
obtained as the major product.
This is probably because the
terminal methyl group of coor-
dinated 10 was oriented toward
the vacant space II to avoid
steric interactions. The moder-
ate diastereoselectivity is prob-
ably attributed to the less con-
trol of the orientation of an ap-
proaching molecule of 10 be-
Scheme 3. Proposed catalytic cycle for the Cu-catalyzed asymmetric Henry reaction.
cause the methyl group is
remote from the ligand and less
sensitive to steric effects than
To clarify the mechanism of the enantioselective Henry
reaction, a detailed analysis of transition state C was carried
out, based on the generally accepted model proposed by
Evans (Figure 1a).[16] The octahedral CuII complex gives
four strong coordination sites at the equatorial positions and
two weak coordination sites at the apical positions, by Jahn–
Teller distortion. The two highly coordinative nitrogen
atoms of 4h occupy two neighboring strong coordination
sites. Both the aldehyde and nitroalkane reactants are effi-
ciently activated by coordination to the equatorial and
apical positions of the Cu complex, respectively. To explain
the observed enantioselectivity, a schematic illustration of
the transition state is represented in Figure 1b. The substitu-
ents on the two amino groups of 4h sterically shield three
sections around the reaction site (I, III, and IV) to leave
only one space (II). The aldehyde molecule coordinates to
the copper ion with the bulky R group oriented towards the
7a, which results in moderate recognition between the ter-
minal methyl group and hydrogen atom in coordinated 10.
This model also explains the relationship between the
structure of 1,3-di
ACHTUNGTRENUNaNG mines and their chiral induction ability.
The 1,3-di
AHCTUNGTRENNUNG
groups (2, 3a, and 3b) shield spaces I and IV less effectively,
which reduces the control over the orientation of the alde-
hyde. The primary secC-amino group (4d) shields spaces II
and III less effectively, whereas the tertiary secC-amino
group (4j) shields both spaces II and III. In either case, it is
difficult to control the direction of nitroalkane addition,
which, in turn, results in lower enantioselectivities.
Finally, the difference in the product yields for the three
positional isomers of tolualdehyde is discussed (Table 7, en-
tries 7–9). As shown in Figure 1b, an aromatic aldehyde is
positioned in space II to avoid steric repulsion between its
aromatic ring and the Cu–diACTHNURGTNEaUNG mine complex. The tilted alde-
Chem. Eur. J. 2011, 17, 13584 – 13592
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13589

T. Hirose, K. Kodama, and K. Sugawara
Chemical shifts (d) of 1H NMR spectra are given in parts per million
(ppm) relative to tetramethylsilane (TMS) as an internal standard (d=
0 ppm) in CDCl3 solution and those of the 13C NMR spectra are given in
ppm relative to the residual solvent peak (d=77.16 ppm) in CDCl3 solu-
tion. Multiplicity is described as follows: s=singlet, d=doublet, t=trip-
let, q=quartet, m=multiplet, br=broad, app.=apparent. The coupling
constants (J) are given in hertz (Hz). IR spectra are reported in recipro-
cal centimeters (cmÀ1). Mass spectra were recorded by using electrospray
ionization mass spectrometry (ESI MS). Determination of the ee was
conducted by means of chiral HPLC. Optical rotations were measured
with a polarimeter. Melting points are uncorrected.
hyde viewed from the upper side of Figure 1b is represented
in Scheme 4. Considering the rotation of the aromatic ring
À
around the C C bond, the steric hindrance of the substitut-
All commercially available substrates were used in reactions as received
unless noted. Dry CH2Cl2 was prepared by distillation from CaH2, and
stored over 4 ꢁ molecular sieves under N2 atmosphere. Dry THF was
freshly distilled from sodium and benzophenone (as a moisture indicator)
under N2 atmosphere. All liquid aldehydes were freshly distilled under
reduced pressure and solid aldehydes were purified by silica gel column
chromatography before use. (À)-cis-2-benzamidocyclohexanecarboxylic
acid ((À)-1) was prepared according to the literature procedure.[2]
Analytical TLC was performed on precoated aluminum-backed silica gel
60 F254 plates and visualized by UV lamp (254 nm) and staining with
phosphomolybdic acid or ninhydrin. Silica gel (B-5F, 45 mm) was used for
preparative TLC (PTLC) and silica gel (Silica gel 60N, spherical, neutral,
100–210 mm) was used for column chromatography. The synthesis and
characterization of compounds 2, 4a–d, 5a, and 5d–f have been reported
in our previous paper.[7c]
Scheme 4. Relationship between the position of the benzaldehyde sub-
stituent and yield of the Henry adduct. The aldehydes are viewed from
the upper side of space II in Figure 1b.
ed methyl group towards the approaching nitroalkane in-
creases in the order ortho<meta<para. That is, the 4-
methyl group always protrudes to the upper side of space II
and, on the other hand, the 2-methyl group gives little steric
hindrance regardless of the bond rotation. It appears that
the 3-methyl group prevents the approach of the nitroalkane
from the upper side, dependant on the rotation angle of the
aromatic group. It is expected that 4-biphenylcarbaldehyde
(7j) affords the largest steric demand. The decrease of the
product yield reflects this steric effect, which prevents coor-
dination of the nitroalkane to the metal ion.
Typical procedure A, for the synthesis of diamides 5a–f: At 08C, ethyl
chloroformate (96.5 mL, 1.02 mmol) was added dropwise to a solution of
(À)-1 (251 mg, 1.01 mmol) and TEA (145 mL, 1.04 mmol) in dry CH2Cl2
(10 mL). After the addition was complete, the reaction mixture was al-
lowed to warm to RT and stirred for 30 min. A 25% aqueous NH3 solu-
tion (5.00 mL, 66.8 mmol) was added to the reaction mixture under vigo-
rous stirring and stirring was continued for 15 h at RT. The reaction mix-
ture was neutralized by addition of 6m aqueous HCl solution and the sol-
vents were removed under reduced pressure. The residue was diluted
with EtOAc (20 mL) and the organic solution was washed with 1m aque-
ous HCl solution (2ꢄ10 mL) and 1m aqueous NaOH solution (2ꢄ
10 mL), then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was dried in vacuo to give di-
Conclusion
We have developed structurally related enantiopure 1,3-di-
amines derived from (À)-cis-2-benzamidocyclohexanecar-
boxylic acid (1), and applied them as ligands for the catalyt-
ic enantioselective Henry reaction. It was found that the
product enantioselectivity was controlled by the substituents
on the two amino groups of the ligands. A gradual decrease
in enantioselectivity caused by the retro-Henry reaction was
successfully suppressed by conducting the reaction at 08C.
Further optimization of the reaction conditions (external
bases, solvents, and loading amounts of the precatalysts) im-
proved the results and enantiomeric b-nitroalcohols were
provided in high yields and enantioselectivities (up to 98%
yield and 91% ee). It has been proven that high chiral in-
AHCTUNGTREGaNNUN mide 5a (242 mg, 0.984 mmol, 97%) as a white powder. Diamide 5a
was used directly in the next reaction without further purification.
Compound 5b: Diamide 5b (233 mg, 0.895 mmol, 90%) was obtained as
a white powder by typical procedure A; (À)-1 (247 mg, 1.00 mmol), TEA
(140 mL, 1.01 mmol), ethyl chloroformate (95.0 mL, 1.00 mmol), 40%
aqueous MeNH2 solution (2.00 mL, 23.2 mmol). An analytical sample
was prepared by silica gel PTLC (EtOAc/hexane=1:1). M.p. 101–1028C;
[a]2D3 =À14.0 (c=0.72, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.80–
7.78 (m, 2H), 7.62 (br d, J=6.8 Hz, 1H), 7.50–7.46 (m, 1H), 7.44–7.40
(m, 1H), 6.20–6.00 (br, 1H), 4.26 (ddd, J1 =11.6 Hz, J2 =J3 =4.8 Hz, 1H),
2.78 (d, J=4.8 Hz, 3H), 2.70 (ddd, J1 =J2 =J3 =4.8 Hz, 1H), 2.16–2.10 (m,
1H), 1.95–1.90 (m, 1H), 1.80–1.74 (m, 1H), 1.69–1.67 (m, 2H), 1.55–
1.47 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=174.8, 166.9, 134.9,
131.4, 128.6, 127.1, 49.0, 44.7, 29.5, 27.6, 26.3, 23.4, 22.8 ppm; IR (KBr):
n˜max =3344, 3299, 2943, 2928, 2846, 1639, 1578, 1542, 1488, 1419, 1324,
duction was achieved by the enantiopure diACTHUNRTGNEUNGamine ligand 4h
(derived from 1) which is available without any external
chiral source. The successful control of enantioselectivity by
changing the substituents on the two amino groups will
enable us to design other 1,3-functionalized chiral ligands
derived from 1. Their development and application to vari-
ous catalytic asymmetric reactions are currently under inves-
tigation.
1303, 1264, 1162, 691, 599 cmÀ1
;
HRMS (ESI+): m/z calcd for
C15H20N2O2Na: 283.1417 [C15H20N2O2+Na]+; found: 283.1424.
Compound 5c: Diamide 5c (150 mg, 0.445 mmol, 87%) was obtained as
a white powder by typical procedure A; (À)-1 (127 mg, 0.513 mmol),
TEA (71.5 mL, 0.514 mmol), ethyl chloroformate (49.0 mL, 0.517 mmol),
BnNH2 (56.0 mL, 0.514 mmol), dry THF. An analytical sample was pre-
pared by silica gel PTLC (EtOAc/hexane=1:1). M.p. 140–1418C; [a]D18
=
+8.8 (c=0.50, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.76 (d, J=
7.2 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.46–7.40 (m, 3H), 6.40–6.20 (br,
1H), 4.47–4.37 (m, 2H), 4.34–4.28 (m, 1H), 2.78 (ddd, J1 =J2 =J3 =
4.8 Hz, 1H), 2.21–2.15 (m, 1H), 1.97–1.93 (m, 1H), 1.84–1.80 (m, 1H),
1.79–1.69 (m, 2H), 1.60–1.49 ppm (m, 3H); 13C NMR (100 MHz, CDCl3):
d=174.1, 166.9, 138.2, 134.8, 131.5, 128.8, 128.6, 127.7, 127.6, 127.1, 49.0,
44.8, 43.5, 29.4, 27.6, 23.5, 22.6 ppm; IR (KBr): n˜max =3287, 2931, 1630,
Experimental Section
General and materials: All 1H and 13C NMR (with complete proton de-
coupling) spectra were recorded on a 400 or 500 MHz spectrometer.
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Chem. Eur. J. 2011, 17, 13584 – 13592

Synthesis of Chiral 1,3-Diamines
FULL PAPER
1545, 1415, 1291, 729, 695 cmÀ1
;
HRMS (ESI+): m/z calcd for
Method b (4g): p-Phenylbenzaldehyde (68.2 mg, 0.374 mmol) was added
to a solution of 4d (51.2 mg, 0.328 mmol) in MeOH (5 mL) and the reac-
tion mixture was heated at reflux for 5 h. After completion of the reac-
tion, the mixture was cooled to RT, then NaBH4 (38.2 mg, 1.01 mmol)
was added and the mixture was stirred for 24 h. Workup and purification
C21H24N2O2Na: 359.1730 [C21H24N2O2+Na]+; found: 359.1738.
Typical procedure B, for the synthesis of diamines 2, 3a, 3b, and 4a–c:
At 08C under N2 atmosphere, a solution of 5a (235 mg, 0.956 mmol) in
dry THF (5 mL) was added dropwise to a suspension of LiAlH4 (181 mg,
4.78 mmol) in dry THF (5 mL). After the addition was complete, the re-
action mixture was heated at reflux for 96 h. The reaction was quenched
at 08C by addition of ion-exchanged water (180 mL), 15% aqueous
NaOH solution (180 mL), and a second portion of ion-exchanged water
(540 mL). The cloudy reaction mixture was filtered through Celite, the fil-
trate was concentrated under reduced pressure, and the residue was dis-
solved in 1m aqueous HCl solution (20 mL). The aqueous solution was
washed with EtOAc (2ꢄ10 mL) and basified (pH>11) by addition of 6m
aqueous NaOH solution. The resulting cloudy aqueous solution was ex-
tracted with CHCl3 (3ꢄ10 mL) and the organic layer was dried over an-
hydrous Na2SO4. The solvent was removed under reduced pressure and
the residue was purified by silica gel PTLC (MeOH/CHCl3 =1:10) to
were performed as described in method a to afford diACHTUNTRGNEUaGN mine 4g (51.8 mg,
0.161 mmol, 49%) as a pale yellow oil. [a]2D3 =+11.9 (c=0.49, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.59 (d, J=7.6 Hz, 2H), 7.55 (d, J=
8.0 Hz, 2H), 7.44–7.40 (m, 4H), 7.32 (t, J=7.2 Hz, 1H), 3.87 (d, J=
13.2 Hz, 1H), 3.76 (d, J=13.2 Hz, 1H), 2.85 (ddd, J1 =6.4 Hz, J2 =J3 =
3.2 Hz, 1H), 2.36 (dd, J=12.2, 6.4 Hz, 1H), 2.26–2.21 (m, 7H), 1.84–1.82
(m, 1H), 1.76–1.72 (m, 1H), 1.62–1.50 (m, 3H), 1.48–1.36 ppm (m, 5H);
13C NMR (100 MHz, CDCl3): d=141.2, 140.5, 140.5, 139.8, 128.8, 128.7,
127.2, 127.2, 60.9, 55.7, 51.3, 46.3, 37.7, 29.0, 26.8, 24.1, 22.4 ppm; IR
(neat): n˜max =3028, 2927, 2853, 2815, 2763, 1488, 1457, 1032, 849, 761, 737,
698 cmÀ1
;
HRMS (ESI+): m/z calcd for C22H31N2: 323.2482
[C22H30N2+H]+; found: 323.2485.
Compound 4 f: Diamine 4 f (103 mg, 0.372 mmol, 74%) was obtained as
afford diACHTUNGTRENNUNGamine 2 (160 mg, 0.733 mmol, 77%) as a white powder.
a
pale yellow oil by typical procedure C, method a; 4d (78.9 mg,
Compound 3a: Diamine 3a (88.9 mg, 0.383 mmol, 44%) was obtained as
a pale yellow oil by typical procedure B; 5b (226 mg, 0.868 mmol),
LiAlH4 (166 mg, 4.18 mmol). [a]2D1 =+33.8 (c=0.40, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.33–7.27 (m, 4H), 7.23–7.20 (m, 1H), 3.82 (d, J=
13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 2.77 (ddd, J1 =6.5 Hz, J2 =J3 =
3.5 Hz, 1H), 2.71 (dd, J=12.0, 7.5 Hz, 1H), 2.42 (dd, J=12.0, 6.5 Hz,
1H), 2.36 (s, 3H), 1.83–1.72 (m, 2H), 1.61–1.52 (m, 2H), 1.49–1.27 ppm
(m, 7H); 13C NMR (125 MHz, CDCl3): d=141.2, 128.2, 128.0, 126.7, 55.1,
53.3, 51.2, 39.6, 36.8, 28.5, 26.7, 24.0, 22.1 ppm; IR (neat): n˜max =3302,
2926, 2852, 2791, 1495, 1453, 741, 699 cmÀ1; HRMS (ESI+): m/z calcd for
C15H25N2: 233.2012 [C15H24N2+H]+; found: 233.2015.
0.505 mmol), p-methoxybenzaldehyde (134 mg, 0.986 mmol), NaBH4
(170 mg, 4.49 mmol). [a]D22 =+8.4 (c=0.38, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.27 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 3.79 (s,
3H), 3.76 (d, J=12.8 Hz, 1H), 3.65 (d, J=12.8 Hz, 1H), 2.81 (ddd, J1 =
6.4 Hz, J2 =J3 =3.2 Hz, 1H), 2.33 (dd, J=12.2, 6.6 Hz, 1H), 2.24–2.20 (m,
7H), 1.85–1.77 (m, 1H), 1.72–1.65 (m, 1H), 1.61–1.45 (m, 3H), 1.45–
1.26 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=158.6, 133.4, 129.3,
113.8, 60.8, 55.6, 55.4, 51.0, 46.3, 37.5, 29.0, 26.8, 24.0, 22.4 ppm; IR
(neat): n˜max =2930, 2854, 2764, 1612, 1513, 1458, 1301, 1248, 1180, 1038,
823, 524 cmÀ1
;
HRMS (ESI+): m/z calcd for C17H29N2O: 277.2274
[C17H28N2O+H]+; found: 277.2275.
Compound 3b: Diamine 3b (87.7 mg, 0.284 mmol, 64%) was obtained as
a white solid by typical procedure B; 5c (149 mg, 0.442 mmol), LiAlH4
(85.1 mg, 2.24 mmol), dry 1,4-dioxane. M.p. 64–658C; [a]1D8 =+12.7 (c=
0.50, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.31–7.20 (m, 10H), 3.82
(d, J=13.5 Hz, 1H), 3.76 (d, J=13.5 Hz, 1H), 3.73 (d, J=13.0 Hz, 1H),
3.69 (d, J=13.0 Hz, 1H), 2.84–2.79 (m, 2H), 2.52 (dd, J=11.5, 6.0 Hz,
1H), 1.85–1.81 (m, 1H), 1.78–1.73 (m, 1H), 1.60–1.45 (m, 5H), 1.42–
1.26 ppm (m, 4H); 13C NMR (125 MHz, CDCl3): d=141.3, 140.9, 128.4,
128.3, 128.2, 126.9, 55.4, 54.5, 51.5, 50.9, 39.9, 28.7, 27.0, 24.2, 22.2 ppm;
IR (KBr): n˜max =3270, 2925, 2884, 2852, 1496, 1451, 1145, 1115, 1091, 746,
Compound 4h: Diamine 4h (66.2 mg, 0.223 mmol, 70%) was obtained as
a
pale yellow oil by typical procedure C, method b; 4d (49.8 mg,
0.319 mmol), 1-naphthaldehyde (55.2 mg, 0.353 mmol), NaBH4 (38.2 mg,
1.01 mmol). [a]2D3 =+17.2 (c=1.06, CHCl3); 1H NMR (400 MHz, CDCl3):
d=8.22 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz,
1H), 7.52–7.38 (m, 4H), 4.25 (d, J=12.8 Hz, 1H), 4.12 (d, J=12.8 Hz,
1H), 2.96 (ddd, J1 =6.0 Hz, J2 =J3 =3.2 Hz, 1H), 2.33 (dd, J=12.2,
7.0 Hz, 1H), 2.17 (s, 6H), 2.13 (dd, J=12.4, 7.6 Hz, 1H), 1.83–1.81 (m,
2H), 1.64–1.55 (m, 3H), 1.50–1.31 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3): d=137.0, 133.9, 132.2, 128.6, 127.7, 126.2, 125.9, 125.6, 125.5,
124.4, 61.1, 56.2, 50.0, 46.3, 38.1, 29.1, 26.7, 24.4, 22.2 ppm; IR (neat):
n˜max =3045, 2927, 2853, 2815, 2763, 1457, 794, 777 cmÀ1; HRMS (ESI+):
m/z calcd for C20H29N2: 297.2325 [C20H28N2+H]+; found: 297.2323.
699 cmÀ1
;
HRMS (ESI+): m/z calcd for C21H29N2: 309.2325
[C21H28N2+H]+; found: 309.2328.
Typical procedure C for the synthesis of diamines 4e–i
Method a (4e): p-Chlorobenzaldehyde (79.4 mg, 0.565 mmol) was added
to a mixture of 4d (79.5 mg, 0.509 mmol) and 3 ꢁ molecular sieves
(50 mg) in dry CH2Cl2 (5 mL) and the mixture was stirred for 24 h at RT.
After completion of the reaction, the molecular sieves were removed by
filtration and the filtrate was concentrated under reduced pressure. The
residue was dissolved in EtOH (5 mL), then NaBH4 (53.6 mg, 1.42 mmol)
was added to the solution under stirring. After stirring for 24 h, the reac-
tion was quenched by addition of 1m aqueous HCl solution (1 mL) and
the solvents were removed under reduced pressure. The residue was dis-
solved in 1m aqueous HCl solution (10 mL) and the aqueous solution
was washed with EtOAc (2ꢄ10 mL) and basified (pH>11) by addition
of 6m aqueous NaOH solution. The resulting cloudy aqueous solution
was extracted with CHCl3 (3ꢄ10 mL) and the combined organic layers
were dried over anhydrous Na2SO4. The solvent was removed under re-
duced pressure and the residue was purified by silica gel PTLC (MeOH/
Compound 4i: Diamine 4i (58.6 mg, 0.198 mmol, 62%) was obtained as
a
pale yellow oil by typical procedure C, method b; 4d (49.8 mg,
0.319 mmol), 2-naphthaldehyde (54.7 mg, 0.350 mmol), NaBH4 (38.2 mg,
1.01 mmol). [a]2D3 =+13.7 (c=0.73, CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.81–7.78 (m, 4H), 7.49 (d, J=8.4 Hz, 1H), 7.46–7.40 (m, 2H), 3.98
(d, J=13.4 Hz, 1H), 3.87 (d, J=13.4 Hz, 1H), 2.85 (ddd, J1 =6.0 Hz, J2 =
J3 =3.0 Hz, 1H), 2.36 (dd, J=12.2, 6.6 Hz, 1H), 2.26–2.21 (m, 7H), 1.84–
1.82 (m, 1H), 1.75–1.71 (m, 1H), 1.62–1.48 (m, 3H), 1.45–1.30 ppm (m,
4H); 13C NMR (100 MHz, CDCl3): d=138.8, 133.5, 132.7, 127.9, 127.7,
127.7, 126.9, 126.4, 126.0, 125.5, 60.9, 55.5, 51.6, 46.3, 37.5, 28.9, 26.8, 24.1,
22.3 ppm; IR (neat): n˜max =3053, 2928, 2854, 2816, 2765, 1458, 1032, 853,
818, 753 cmÀ1
;
HRMS (ESI+): m/z calcd for C20H29N2: 297.2325
[C20H28N2+H]+; found: 297.2328.
Compound 6: At 08C, benzoyl chloride (105 mL, 0.908 mmol) was added
to a solution of 4a (199 mg, 0.806 mmol) and TEA (125 mL, 0.898 mmol)
in dry THF (5 mL). The reaction mixture was allowed to warm to RT
and stirred for 2 h. The reaction was quenched by addition of ion-ex-
changed water (1 mL) and the solvents were removed under reduced
pressure. The residue was dissolved in EtOAc (20 mL) and the organic
solution was washed with 1m aqueous NaOH solution (2ꢄ10 mL) and
1m aqueous HCl solution (2ꢄ10 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue
was purified by silica gel PTLC (EtOAc) to give aminoamide 6 (283 mg,
0.806 mmol, >99%) as a colorless viscous liquid. [a]2D3 =À137.7 (c=0.42,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.60–7.00 (m, 10H), 4.80–4.55
CHCl3 =1:10) to furnish diACTHUNRGTNEaNUG mine 4e (76.6 mg, 0.273 mmol, 54%) as a
pale yellow oil. [a]2D2 =+16.3 (c=0.39, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.31 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 3.81 (d, J=
13.4 Hz, 1H), 3.69 (d, J=13.4 Hz, 1H), 2.82 (ddd, J1 =6.0 Hz, J2 =J3 =
3.2 Hz, 1H), 2.38 (dd, J=12.4, 7.2 Hz, 1H), 2.21–2.17 (m, 7H), 1.85–1.80
(m, 1H), 1.73–1.65 (m, 1H), 1.60–1.52 (m, 2H), 1.48–1.26 ppm (m, 5H);
13C NMR (100 MHz, CDCl3): d=139.6, 132.5, 129.6, 128.5, 61.0, 55.6,
50.7, 46.2, 37.4, 28.8, 26.9, 24.0, 22.3 ppm; IR (neat): n˜max =2929, 2854,
2816, 2765, 1491, 1458, 1091, 1032, 1015, 848, 813 cmÀ1; HRMS (ESI+):
m/z calcd for C16H26ClN2: 281.1779 [C16H25ClN2+H]+; found: 281.1779.
Chem. Eur. J. 2011, 17, 13584 – 13592
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13591

T. Hirose, K. Kodama, and K. Sugawara
(m, 1H), 4.50–4.21 (m, 1H), 2.65–2.60 (m, 1H), 2.55–2.05 (m, 8H), 2.01–
1.80 (m, 1H), 1.80–1.65 (m, 2H), 1.57–1.55 (m, 2H), 1.51–1.40 (m, 1H),
1.30–1.25 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=173.0, 139.9,
137.9, 129.0, 128.6, 128.4, 126.8, 126.2, 125.9, 60.0, 57.6, 51.1, 46.4, 34.4,
28.0, 26.4, 25.3, 20.2 ppm; IR (KBr): n˜max =2937, 2857, 2764, 1631, 1450,
Fꢂlçp, Org. Lett. 2010, 12, 5584–5587; c) J. R. Mallareddy, A.
Borics, A. Keresztes, K. E. Kover, D. Tourwe, G. Toth, J. Med.
Chem. 2011, 54, 1462–1472.
[5] a) S. Ogawa, H. Kimura, C. Uchida, T. Ohashi, J. Chem. Soc. Perkin
Trans. 1 1995, 1695–1705; b) T. Eguchi, M. Fukuda, Y. Toyooka, K.
Kakinuma, Tetrahedron 1998, 54, 705–714.
[6] K. Saigo, H. Koda, H. Nohira, Bull. Chem. Soc. Jpn. 1979, 52, 3119–
3120.
1409, 755, 699 cmÀ1
;
HRMS (ESI+): m/z calcd for C23H30N2ONa:
373.2250 [C23H30N2O+Na]+; found: 373.2256.
Compound 4j: At 08C under N2 atmosphere, a solution of 6 (237 mg,
0.675 mmol) in dry THF (5 mL) was added dropwise to a suspension of
LiAlH4 (76.9 mg, 2.03 mmol) in dry THF (5 mL). After the addition was
complete, the reaction mixture was heated at reflux for 24 h. The reaction
was quenched at 08C by addition of ion-exchanged water (77.0 mL), 15%
aqueous NaOH solution (77.0 mL), and a second portion of ion-ex-
changed water (230 mL), then the cloudy reaction mixture was filtered
through Celite. The filtrate was concentrated under reduced pressure and
the residue was dissolved in 1m aqueous HCl solution (20 mL). The
aqueous solution was washed with EtOAc (2ꢄ10 mL) and basified (pH>
11) by addition of 6m aqueous NaOH solution. The resulting cloudy
aqueous layer was extracted with CHCl3 (3ꢄ10 mL) and the combined
organic layers were dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the residue was purified by silica gel
[7] a) X.-B. Wang, K. Kodama, T. Hirose, G.-Y. Zhang, Chin. J. Chem.
2010, 28, 61–68; b) X.-B. Wang, K. Kodama, T. Hirose, X.-F. Yang,
G.-Y. Zhang, Tetrahedron: Asymmetry 2010, 21, 75–80; c) T. Hirose,
K. Sugawara, K. Kodama, J. Org. Chem. 2011, 76, 5413–5428;
d) W.-H. Wang, X.-B. Wang, K. Kodama, T. Hirose, G.-Y. Zhang,
Tetrahedron 2010, 66, 4970–4976; e) W.-H. Wang, T. Abe, X.-B.
Wang, K. Kodama, T. Hirose, G.-Y. Zhang, Tetrahedron: Asymmetry
2010, 21, 2925–2933.
[8] L. C. C. Henry, R. Hebd. Sꢀances Acad. Sci. 1895, 120, 1265–1268.
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Soc. 1992, 114, 4418–4420.
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Saikia, N. C. Barua, Tetrahedron: Asymmetry 2006, 17, 3315–3326;
b) C. Palomo, M. Oiarbide, A. Laso, Eur. J. Org. Chem. 2007, 2561–
2574; c) G. Blay, V. Hernꢅndez-Olmos, J. R. Pedro, Synlett 2011, 9,
1195–1211.
PTLC (MeOH/CHCl3 =1:10) to afford diACTHUNTGRNEUNGamine 4j (198 mg, 0.587 mmol,
87%) as a pale yellow oil. [a]2D2 =À37.2 (c=1.06, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.36 (d, J=7.2 Hz, 4H), 7.27 (dd, J1 =J2 =7.4 Hz,
4H), 7.18 (t, J=7.2 Hz, 2H), 3.76 (d, J=14.4 Hz, 2H), 3.63 (d, J=
14.4 Hz, 2H), 2.72 (ddd, J1 =12.0 Hz, J2 =J3 =3.8 Hz, 1H), 2.62 (dd, J1 =
J2 =11.6 Hz, 1H), 2.41 (dd, J=12.0, 3.6 Hz, 1H), 2.24 (s, 6H), 1.90
(app. d, J=12.8 Hz, 1H), 1.74–1.65 (m, 2H), 1.39–1.11 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=141.2, 128.5, 128.2, 126.6, 61.9, 56.6,
55.6, 46.3, 35.5, 27.7, 26.5, 25.6, 20.6 ppm; IR (neat): n˜max =3084, 3061,
3026, 2931, 2855, 2814, 2762, 1494, 1454, 1260, 1030, 975, 854, 745,
[11] a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New
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metry 2008, 19, 2310–2315; b) Investigation of optimal CuII salts was
conducted prior to the investigation of 1,3-di
were as follows: Cu(OAc)2·H2O: 85% yield, 30% ee; Cu-
(ClO4)2·6H2O: 41% yield, 9% ee; CuSO4·5H2O: 82% yield, racemic
ACHTUNGTRENaNUNG mines and the results
698 cmÀ1
;
HRMS (ESI+): m/z calcd for C23H33N2: 337.2638
AHCTUNGTRENNUNG
[C23H32N2+H]+; found: 337.2639.
AHCTUNGTRENNUNG
(rac.); Cu(OH)2: 75% yield, rac.; CuCl2·2H2O: 61% yield, rac.;
CuBr2: 83% yield, rac. (the investigation was performed under the
conditions described in Table 1, entries 1–13 with 4b as a ligand).
Typical procedure D, for the enantioselective Henry reaction between al-
dehydes and nitromethane: CuACHTNUGRTNEUNG(OAc)2·H2O (9.98 mg, 0.05 mmol,
10 mol%) was added to a solution of 4h (14.8 mg, 0.05 mmol, 10 mol%)
in EtOH (1 mL, 99% solvent grade) and the mixture was stirred for 1 h
at RT, during which time the color of the solution turned from green to
Because the highest ee was obtained with Cu
ACHTUNGTREN(UNGN OAc)2·H2O, we deter-
mined Cu
AHCTUNGTRENNUNG
[13] Y. Sohtome, K. Takemura, R. Takagi, T. Iguchi, K. Nagasawa,
Chem. Asian J. 2007, 2, 1150–1160.
blue.
A solution of aldehyde 7 (0.5 mmol) and DABCO (1.12 mg,
0.01 mmol, 2 mol%) in EtOH (0.5 mL, 99% solvent grade) was added to
the blue solution and the reaction mixture was cooled to 08C over
15 min. CH3NO2 (8; 270 mL, 5 mmol) was added and the mixture was
stirred for 24 h at 08C. After 24 h, the mixture was filtered through a
silica gel column (10 cm3) with EtOAc (50 mL) to remove the catalyst.
The resulting colorless filtrate was concentrated under reduced pressure
at <308C (to avoid the dehydration reaction) and the residue was puri-
fied by silica gel PTLC (EtOAc/hexane) to give the corresponding enan-
tioenriched b-nitroalcohol 9. The diastereo- and enantioselective Henry
reaction was performed in the same way, with benzaldehyde (7a) and ni-
troethane (10). The ee value of the nitroalcohol was determined by chiral
HPLC analysis.[12a,14b,17]
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3597; b) R. Kowalczyk, J. Skarz˙ewski, Tetrahedron: Asymmetry
2009, 20, 2467–2473; c) W. Jin, X. Li, Y. Huang, F. Wu, B. Wan,
Chem. Eur. J. 2010, 16, 8259–8261; d) W. Jin, X. Li, B. Wan, J. Org.
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Received: July 12, 2011
Published online: October 25, 2011
13592
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13584 – 13592