Pyrrole macrocyclic ligands for Cu-catalyzed asymmetric henry reactions

Article abstract of DOI:10.1021/jo200318b

New chiral perazamacrocycles containing four pyrrole rings have been synthesized by the [2 + 2] condensation of (R,R)-diaminocyclohexane and 5,5′-(alkane-2,2-diyl)bis(1H-pyrrole-2-carbaldehydes). These macrocycles, differing for the alkyl/aryl meso-substi

Full text of DOI:10.1021/jo200318b

ARTICLE
pubs.acs.org/joc
Pyrrole Macrocyclic Ligands for Cu-Catalyzed Asymmetric
Henry Reactions
Andrea Gualandi,† Lucia Cerisoli,† Helen Stoeckli-Evans,‡ and Diego Savoia*,†
†Dipartimento di Chimica “G. Ciamician”, Universitꢀa di Bologna, via Selmi 2, 40126 Bologna, Italy
‡Institute of Physics, University of Neuch^atel, rue Emile-Argand 11, CH-2000 Neuch^atel, Switzerland
S Supporting Information
b
ABSTRACT: New chiral perazamacrocycles containing four pyrrole rings
have been synthesized by the [2 þ 2] condensation of (R,R)-diamino-
cyclohexane and 5,50-(alkane-2,2-diyl)bis(1H-pyrrole-2-carbaldehydes).
These macrocycles, differing for the alkyl/aryl meso-substituents, were
used as ligands in the copper-catalyzed Henry reactions of aromatic and
aliphatic aldehydes with nitroalkanes. In the optimized experimental
conditions, the condensations of nitromethane and aromatic and
aliphatic aldehydes in the presence of catalytic amounts of copper
diacetate and methyl-substituted macrocyclic ligand (2:1 ratio) in
ethanol at room temperature provided products often with high
enantiomeric excesses (up to 95% ee). The positive influence of the macrocyclic structure on the efficiency/enantioselectivity of
the catalytic system was demonstrated by comparison with the outcomes of Henry reactions performed using analogous macrocyclic
ligands (trianglamines) and open-chain ligands derived from (R,R)-diaminocyclohexane.
’ INTRODUCTION
which are active as catalysts in several organic reactions. Several
chiral ligands have been heretofore studied with this aim. For
example, the trianglamines 3 and 4 are comparably effective
ligands in Cu(OAc)2-catalyzed Henry reactions (Scheme 2) of
nitromethane with aromatic aldehydes (up to 87% ee with 4) and
aliphatic aldehydes (up to 93% ee with 3) in solvent-free con-
ditions. Analogous macrocycles with larger rings provided lower
ee’s.4c The complex formed by addition of 3 equiv of Et2Zn to the
Among the many synthetic tools of organic chemists, the
Henry reaction is prominent because of the versatile chemistry of
the nitro group. In particular, the asymmetric version of the
reaction affords enantiomerically enriched β-hydroxy nitroalk-
anes which are precursors of valuable bifunctional compounds,
such as β-amino alcohols and R-hydroxy carboxylic acids.1 Metal
complexes with chiral ligands are widely used as catalysts for
Henry reactions. Among these enantioselective protocols, those
exploiting copper complexes with a variety of ligands have
provided remarkably high levels of enantioselectivity.2
In the realm of chiral ligands participating in metal complexes
which are catalytically active in enantioselective organic reactions,
polyazamacrocycles3,4 and poly(oxaza)-5 and poly(thiaza)macro-
cycles6 have heretofore found a limited use. A simple and efficient
way to synthesize nitrogen-containing macrocycles relies on the
condensation of chiral diamines and aromatic dialdehydes both having
a rigid structure, such as trans-1,2-diaminocyclohexane and aromatic
dialdehydes (Scheme 1). Cyclic polyimines 1 (n = 1, 2, 3...) can be
obtained by [n þ n] cyclization of the reaction partners,3,7 often with
high selectivity depending on the structure of the dialdehyde and the
experimental conditions, particularly the use of metal templates. The
compounds 1 can be simply reduced to the corresponding saturated
compounds 2 but are also capable of undergoing diastereoselective
addition of carbon nucleophiles, so forming more complex com-
pounds with defined stereochemistry.8 Moreover, substituents at the
nitrogen atoms can be routinely introduced.
same ligand 3, formed in situ from its salt 3 (HBr)6 and 6 equiv
3
of triethylamine, catalyzed the enantioselective condensation
of acetone and p-nitrobenzaldehyde in DMSO providing a
moderate 56.7% ee.4b Moreover, a 75% ee was obtained in
the zinc-catalyzed Henry reaction (PhCHOꢀMeNO2, MS,
THF, ꢀ20 °C) using the ligand 6.6 We have recently demon-
strated that added steric complexity in the molecular structure
of the macrocycle was not useful, as the hexamethyl- and
hexaphenyl-substituted macrocycles 5 displayed a lesser de-
gree of asymmetric induction as compared to ligand 3 in the
Cu-catalyzed Henry reaction.8
We were surprised to observe that although a large number of
aromatic and heteroaromatic dialdehydes including pyridine,
furan- and thiophenedialdehydes had been used for the con-
struction of chiral macrocycles by condensation with optically
pure trans-1,2-diaminocyclohexane, the synthesis of analogous
chiral macrocycles from pyrroledialdehydes has been neglected.9
This contrasts with the ubiquitous presence of pyrrole rings in
The inherent symmetry of these chiral peraza macrocycles has
induced investigation of their potential as ligands of metal species
Received: February 21, 2011
Published: March 21, 2011
r
2011 American Chemical Society
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ARTICLE
biologically active macrocycles as well as unnatural macrocyclic
compounds, including porphyrins, expanded porphyrins, cryp-
tophyrins, calyxpyrroles, calyxphyrins, and sapphyrins, which are
mostly useful as ligands of metal ions and as receptors, carriers
and sensors of inorganic and organic anions.10 For example, the
anion-binding capabilities of calyxpyrroles7,11 and the partially
reduced calyxpyrrole12 have been documented.
Scheme 1. Synthesis of Chiral Perazamacrocycles from
Chiral Diamines and Aromatic Dialdehydes
As a continuation of our ongoing research on the synthesis of
(chiral) peraza macrocycles and on the use of chiral 2-pyrrole-
imines for the synthesis of stereochemically defined molecules,13
we now report the first preparation of C2-symmetric, optically
pure macrocycles containing pyrrole rings and their application
as ligands in enantioselective Henry reactions.
In this context, it is appropriate to note that chiral nonracemic
pyrrole derivatives have found limited use in asymmetric catalytic
reactions: 2-pyrroleimines provided low enantioselectivities in
rhodium-catalyzed hydrosilylation of acetophenone,14a,b whereas
excellent results were achieved with a 2-pyrrolethiazolidine.14c
On the other hand, a 2-pyrrole-imidazolidinone was an efficient
organocatalyst in a Mannich reaction leading to (þ)-epi-cytox-
azone with high levels of diastereo- and enantioselectivity.15
Similarly, a racemic trans-10,20-disubstituted calyxpyrrole acted
as an organocatalyst for a few regio- and diastereoselective re-
actions.16 Lastly, in the domain of supramolecular chemistry,
enantiomerically pure 2,5-bis(oxazolinyl)pyrroles, analogous to
the classic Pybox ligands were prepared from (R)- and (S)-valinol
and pyrrole-2,5-biscarbonitrile, lithiated and converted to en-
antiomerically pure double helical palladium complexes.17
which display binding properties toward transition-metal and
uranyl salts18aꢀc or anions18d and metallo-macrocycles.19
The choice of the dialdehydes 8 was dictated first of all by their
easy preparation. Moreover, they allow the study of the effect of
different substituents R in the macrocyclic ligand on the activity
and enantioselectivity of the derived catalysts. The dialdehydes 8
were prepared by formylation of the pyrrole nuclei of the dipyrrole
derivative 7, in turn obtained by reaction of pyrrole with different
ketones. Then, condensation of 8 with (R,R)-1,2-diaminocyclo-
hexane, formed in situ by treatment of the corresponding
L-tartrate salt with triethylamine, gave the expected macrocyclic
tetraimines 9 with good yields. The subsequent reduction of the
crude imines with sodium borohydride occurred without event
to give the octadentate macrocyclic ligands 10 with good overall
yields.
In order to evaluate the importance of the macrocyclic
structure of the ligands 10 on the stereoselectivity of the catalytic
system, we also synthesized the acyclic, tetraaza ligands 11 and
13,20 which feature different fragments present in the macro-
cyclic ligands (Scheme 3). The former was prepared from
dipyrroledialdehyde 8a, and the chirality was derived from
(S)-1-phenylethylamine. On the other hand, the ligand 13 was
formed from (R,R)-1,2-diaminocyclohexane and the two lateral
pyrrole rings were introduced by condensation with 2-pyrrole-
carboxaldehyde 12, followed by routine reduction.
With all these ligands in hand, the prototypical Henry reaction
between benzaldehyde and nitromethane was explored, first
looking for the optimal metal salt/ligand combination. The
reactions were carried out in ethanol as the solvent at room
temperature using 10 molar equiv of nitromethane and were
analyzed after 14 h (Scheme 4 and Table 1).
We observed that the methyl-substituted ligand 10a (5 mol %)
in the absence of a metal salt was an effective organocatalyst, as
the nitro alcohol 14a was produced with 90% yield by stirring
overnight (14 h) but, unfortunately, as a racemic compound
(entry 1). On the other hand, when the reaction was carried out
with the same ligand in the presence of either CuCl2 or Cu-
(OTf)2 (10 mol %), no reaction took place (entries 2 and 3).
However, the presence of a small amount of triethylamine had a
dramatic effect on the copper-catalyzed reaction, as an almost
complete formation of the product was observed. Therefore,
since a weakly basic medium was required, we directed our
attention to the use of zinc(II) and copper(II) acetates because
the acetate anion is more basic than chloride and triflate anions,
’ RESULTS AND DISCUSSION
We chose to begin our research by preparing several macro-
cycles 10 (Scheme 2) from (R,R)-1,2-diaminocyclohexane and
the meso-disubstituted diformyldipyrromethanes 8. The conden-
sation of the dialdehydes 8 with o-phenylenediamines has been
previously used to synthesize achiral macrocyclic tetraimines,18
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Scheme 2. Synthesis of Chiral Macrocyclic Ligands
Scheme 3. Synthesis of Acyclic Pyrrole Ligands
a different fragment of the macrocyclic ligands 10. Ligand 11,
which lacks rigidity of the peripheral chiral moieties, gave an
unsatisfactory performance, particularly in terms of enantioselec-
tivity (3% ee, entry 11). On the other hand, ligand 13 with the
rigid 1,2-diaminocyclohexane structure afforded 14a with excel-
lent yield and moderate stereocontrol (59% ee). Finally, we
demonstrated that copper acetate in the absence of the ligand was
unable to catalyze the reaction to a significant extent, as rac-14a
was formed in 10% yield (entry 13). Overall, it was demonstrated
that the combined use of copper acetate and the macrocyclic
polydentate ligand 10a was necessary for the efficient enantio-
selective catalysis.
The role of the solvent was investigated by performing the
reaction in other protic, polar aprotic and apolar solvents using
the Cu(OAc)2 H2O/10a (2:1 ratio) system (Table 2). It was
3
demonstrated that the nature of the solvent affected to a limited
extent the yield and the enantioselectivity. When the protic
solvents MeOH, i-PrOH, and H2O were used, comparable levels
of ee were achieved, but a lower yield of 14a was obtained in
water. Among the polar aprotic solvents, CH2Cl2 gave an un-
satisfactory performance in terms of both yield (81%) and ee
(60%, entry 5), whereas in MeCN an almost complete conver-
sion (99%) but a moderate ee (74%) were obtained (entry 6).
On the other hand, either in THF and in MeNO2 (entries 7 and
8, respectively) the levels of enantioselectivity were comparable
to or slightly higher than those obtained in alcoholic solvents, but
the yields were slightly lower. Finally, a 92% ee was obtained in
toluene, but the yield was very low (entry 9). In conclusion, it
appeared that the use of EtOH as the solvent gave a convenient
balance of yield and enantioselectivity.
The effect of the ligand/metal ratio and catalyst loading on
reaction rate and enantioselectivity was investigated next work-
ing in the previously established optimal conditions (Table 3).
Working with a fixed amount of the ligand (5% molar equiv-
alents), the loading of copper acetate was varied with respect to
the 2-fold amount previously employed. Thus, it was observed
that reducing to half the metal loading resulted in the decrease of
the enantioselectivity to 80% ee (entry 2), although a comparable
conversion was achieved. On the other hand, an increase of the
metal loading to 15 mol % had no influence on ee (entry 3).
Having so established the optimal ligand/metal ratio 1:2, we
Scheme 4
so that the presence of triethylamine should have been avoided.
As a matter of fact, the use of these salts enabled us to obtain
excellent conversions to the nitro alcohol 14a without the need
to use added base (entries 5 and 6). A strikingly different degree
of stereoocontrol was observed with the two salts, as only with
copper acetate a remarkable degree of enantioselectivity was
obtained (90% ee, entry 6). Moreover, when the reaction was
performed in the presence of triethylamine the ee decreased to
64% (entry 7).21
On the basis of these results, the following experiments were
carried out using the other ligands in the presence of Cu(OAc)2.
In this way, we assessed that increasing the size of the substit-
uents R on the carbon tether linking the pyrrole nuclei had a
detrimental effect on the enantioselectivity, which decreased
down to 75% ee for ligand 10b and 61% ee for ligand 10c
(entries 8 and 9). Successively, in order to verify the importance
of the macrocyclic structure of the ligand on the enantioselectivity,
we checked the acyclic ligands 11 and 13, each of them featuring
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Table 1. Copper-Catalyzed Enantioselective Henry Reaction of Benzaldehyde with Nitromethanea
entry
L* (mol %)
metal salt (mol %)
base (mol %)
14a (yield, %)b
eec (%)
1
2
10a (5)
10a (5)
10a (5)
10a (5)
10a (5)
10a (5)
10a (5)
10b (5)
10c (5)
11 (10)
13 (10)
90
0
0
0
CuCl2 (10)
3
Cu(OTf)2 (10)
Cu(OTf)2 (10)
0
0
4
Et3N (10)
Et3N (10)
98
99
95
99
99
85
59
99
10
8
5
Zn(OAc)2 2H2O (10)
5d
90
64
75
61
3
3
6
Cu(OAc)2 H2O (10)
3
7
Cu(OAc)2 H2O (10)
3
8
Cu(OAc)2 H2O (10)
3
9
Cu(OAc)2 H2O (10)
3
10
11
12
Cu(OAc)2 H2O (10)
3
Cu(OAc)2 H2O (10)
59
0
3
Cu(OAc)2 H2O (20)
3
a Conditions: 0.25 mmol of benzaldehyde, 2.5 mmol of nitromethane, 1.5 mL of EtOH, rt, 14 h. b Yield determined by 1H NMR. c Determined by HPLC
on chiral column. d A slight prevalence of the (S)-enantiomer was observed.
Table 2. Effect of Solvent in the Cu-Catalyzed Reaction of
Benzaldehyde and Nitromethane in the Presence of Ligand
10aa
Table 3. Effect of Cu/10a Ratio, Catalyst Loading, and
Temperature in the Henry Reactiona
entry
10a (mol %)
Cu (mol %)
14a (yield, %)b
eec (%)
entry
solvent
14a (yield, %)b
eec (%)
1
2
5
5
10
5
95
90
80
90
90
92
90
92
92
86
83
1
2
3
4
5
6
7
8
9
EtOH
MeOH
i-PrOH
H2O
95
84
92
94
81
99
84
79
35
90
91
89
71
60
74
92
91
92
92
3
5
15
20
6
92
4
10
3
94
99 (92)d
5
CH2Cl2
CH3CN
THF
6
1
2
93
7
0.2
4
0.4
8e
56 (42)d
97
8
9
1
2e
10g
82f
45f
CH3NO2
Toluene
10
5
a Conditions: 0.25 mmol of benzaldehyde, 2.5 mmol of nitromethane,
a Unless otherwise stated, the reactions were performed using 0.25
mmol of benzaldehyde, 2.5 mmol of nitromethane, and copper acetate as
the catalyst in 1.5 mL of EtOH at 22 °C for 14 h. b Determined by
Cu(OAc)2 H2O (0.025 mol), 10a (0.012 mmol), 1.5 mL of solvent,
3
1
c
rt, 14 h. b Yield determined by H NMR. Determined by HPLC on
c
1H NMR. Determined by HPLC on chiral column. d Isolated yield.
chiral column.
f
e Reaction performed at 0 °C. Reaction time: 48 h. g Reaction per-
formed at ꢀ25 °C.
performed a set of reactions by varying the loading of the catalytic
system. Using a 2-fold amount of the catalytic system 10a/
Cu(OAc)2 H2O (10/20 mol %) did not change the outcome of
aliphatic aldehydes were screened in the reaction with nitro-
3
the reaction (entry 4), although it is likely that a complete
conversion should have been accomplished in a reduced time. In
particular, reducing the L/Cu loading to 3/6 and then 1/2 mol %
hadnosignificant effect on the yield and enantioselectivity (entries 5
and 6), whereas a further reduction of the L/Cu loading to 0.2/
0.4 mol % slowed the reaction and a moderate yield of 14a was
obtained after the canonical 12 h, although the same level of
enantioselectivity was maintained (entry 7). At this point, we hoped
that higher ee could have been obtained at a lower temperature, so
we performed two tests at 0 °C using different catalyst loading. This
allowed us to establish that the same high levels of reactivity and
enantioselectivity were maintained using a L/Cu ratio of 4:8 mol %
(entry 8), but a further decrease of the loading to L/Cu 1:2 reduced
both the yield (82% after 48 h) and the ee (86%) (entry 9). This
negative trend was confirmed when the reaction was carried out
at ꢀ25 °C using a L/Cu loading of 5:10 mol %, when 45% yield
(after 48 h) and 83% ee were obtained.
methane in the optimized experimental conditions: Cu(OAc)2 H2O
3
(6 mol %), 10a (3 mol %), EtOH, 22 °C, 14 h (Scheme 5).
The results obtained showed that the protocol can be success-
fully applied to most aldehydes, although structural and elec-
tronic features of the substrate can affect significantly the reaction
outcome (Table 4). The results obtained with aromatic alde-
hydes did not allow a rationalization of steric and electronic
effects of the substituents. Methyl, methoxy, and fluoro ortho-
substituents (entries 1ꢀ3) on the phenyl ring allowed to
maintain or even increase the enantioselectivity observed with
benzaldehyde, and the highest ee was observed with 2-methox-
ybenzaldehyde (95% ee). On the other hand, lower yield and
enantioselectivity were obtained with 2-nitrobenzaldehyde (entry 4),
and the 2-hydroxybenzaldehyde reacted efficiently but produced
a racemic compound (entry 5). The variable effect of steric and
electronic factors was confirmed when para- and meta-substi-
tuted benzaldehydes, bearing either electron-withdrawing and
-donating substituents, such as 4-OH, 4-NO2, 4-Cl, 4-OMe,
4-OBoc, and 3-OMe (entries 6ꢀ11), were converted to the
The study was then extended to other aldehydes to verify the
full scope of the catalytic system. A number of aromatic and
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Scheme 5
Scheme 6
Table 4. Synthesis of β-Nitro Alcohols in the Optimized
Conditions. Structural Effects on the Enantioselectivitya
Entry
R
product, yieldb (%)
eec (%)
1
2
2-MeC6H4
2-MeOC6H4
2-F C6H4
14b, 91
14c, 90
14d, 80
14e, 66
14f, 87
14g, 40
14h, 96
14i, 78
14j, 61d
14k, 81
14l, 75
14m, 93
14n, 67
14o, 45
14p, 20
14q, 60
14r, 92
14s, 98e
14t, 98e
14u, 79
14v, 64g
14v, 94i
91
95
90
84
0
3
of fact, extensive decomposition of the products 14s (R = i-Bu)
and 14t (R = t-Bu) occurred during purification by chromatog-
raphy on a silica gel column, and only the cyclohexyl derivative
14u could be isolated.
4
2-NO2C6H4
2-HOC6H4
4-HOC6H4
4-NO2C6H4
4-ClC6H4
5
6
77
71
86
83
87
86
91
86
91
43
73
74
85f
89f
91
7
The reaction of nitromethane with racemic 2-phenylpropanal
under the standard conditions gave the nitro alcohol 14v as a
mixture of diastereoisomers, with a moderate prevalence of the
syn diastereoisomer, as the result of similar reactivities of the two
enantiomers of the aldehyde (entry 21). The enantioselectivity
for anti-14v (90% ee) was higher than for syn-14v (78% ee). For
both diastereomers, we assume that the asymmetric induction is
only slightly affected by the configuration of the starting aldehyde
and the OH-substituted stereocenter is prevalently formed with
the R configuration, by analogy with the reactions of achiral
aldehydes. An almost complete conversion and a similar out-
come was observed by performing the same reaction at 0 °C for
48 h, although increased yield and ee of syn-14v but slightly lower
ee of anti-14v were obtained (entry 22).
8
9
4-MeOC6H4
4-BocOC6H4
3-MeOC6H4
4-MeC6H4
2-naphthyl
PhCHdCH
ferrocenyl
N-Boc-3-indolyl
3-Py
10
11
12
13
14
15
16
17
18
19
20
21
22
i-Bu
t-Bu
cyclohexyl
rac-PhMeCH
rac-PhMeCHh
The nitro-aldol derivative 14k was then used to synthesize
(R)-isopropylnorsynephrine, alias N-isopropyloctopamine22
(Scheme 6), a member of the class of biologically active and
pharmacologically active 1-aryl-2-amino alcohols23 that have
been prepared by a variety of asymmetric methods.24 For that
purpose, the nitro group of 14k was reduced by heterogeneous
hydrogenation to give the β-hydroxy amine 15, and then
reductive amination with acetone and sodium borohydride
followed by removal of the Boc protection with a methanol
solution of hydrochloric acid afforded the hydrochloride salt of
(R)-isopropylnorsynephrine 16 with an overall yield of 47%.
Diastereoselectivity was further investigated by carrying out
reactions of benzaldehyde with nitroethane using ligands 10a and
10c (5 mol %) in the presence of Cu(OAc)2 (10 mol %), other
conditions being the same. In both cases, mixtures of syn and anti
β-nitro alcohols were obtained with almost no diastereoselec-
tivity and only moderate enantioselectivity, with ee’s falling in the
range of 39ꢀ68%.
syn 78, anti 90
syn 83, anti 87
a Conditions: aldehyde (0.25 mmol), nitroalkane (2.5 mmol), 10a
(3 mol %), Cu(OAc)2 (6 mol %), EtOH (1.5 mL), 22 °C, 14 h.
1
c
b Determined by H NMR. Determined by HPLC on chiral column.
d Reaction time: 48 h. e Yield of crude product, which decomposed
duringpurification. f Determinedonthecrudemixtures. g Syn/anti 61:39.
h Reaction performed at 0 °C. i Syn/anti 67:33.
corresponding products with variable yields and lower ee's (in
the range 74ꢀ86%), with the exception of p-tolualdehyde (93%
yield and 91% ee, entry 12). In particular, the behavior of
4-hydroxybenzaldehyde (40% yield, 77% ee, entry 6) was op-
posite to that of 2-hydroxybenzaldehyde. Moderate to good
yields and high ee's were obtained from 2-naphthylcarbaldehyde
and cinnamaldehyde (entries 13 and 14), whereas ferrocenylcar-
baldehyde proved to give a bad substrate yield and an especially
poor enantioselectivity (entry 15). Among the heterocyclic
aldehydes, N-Boc-3-indolylcarbaldehyde and 3-pyridinecarbal-
dehyde, which display opposite electronic effects, provided the
same level of enantioselectivity (73ꢀ74% ee, entries 16 and 17).
Aliphatic aldehydes with primary, secondary, and tertiary alkyl
substituents were efficiently converted to the expected products
with high levels of enantioselectivity (85ꢀ91% ee, entries
18ꢀ20), but problems were often encountered during the
isolation of the products, as previously observed.2 As a matter
Crystals of the solvated macrocyclic imine 9a (MeOH)4
3
were collected after slow evaporation of a methanolic solution
of 9a, and the structure was determined by X-ray crystal-
lographic studies (see the Supporting Information). The
macrocycle assumes a square geometry where at opposite
corners are placed the cyclohexane rings and the methyl-
substituted methylene carbons linking the pyrrole rings. The
four MeOH molecules are symmetrically positioned in the
inner space of the cavity, each of them forming two hydrogen
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ARTICLE
Scheme 7
closer to the copper-binding site and/or the more distant pyrrole
similarly stabilizes the nitroalkoxide.
’ CONCLUSION
C2-symmetric macrocycles containing two (R,R)-diaminocy-
clohexane moieties and four pyrrole nuclei have been synthesized
for the first time by an efficient two-step sequence. These com-
pounds exhibited enhanced usefulness as ligands in enantiose-
lective copper-catalyzed Henry reactions, e.g., the reactions of
nitromethane with aromatic and aliphatic aldehydes. Where up
to 95% of ee has been reached. Such levels of enantioselectivity
are superior to those obtained using analogous ligands, which
contain benzene or thiophene rings in the macrocyclic structure,
as well as acyclic ligands derived from 1,2-diaminocyclohexane
and bearing pyrrole nuclei. However, unsatisfactory diastereo-
selectivities were obtained using nitroethane. Further studies are
needed to understand the exact mechanism of the reaction and
especially the role of the pyrrole nuclei on the enantioselectivity.
This objective will be pursued by preparing modified macro-
cycles containing either pyrrole and/or different heteroaromatic
rings. Hopefully, the thorough screening of new pyrrole-containing
macrocyclic ligands will allow development of more efficient
and stereoselective protocols for Henry reactions and perhaps
expansion of their potential as ligands in other asymmetric
reactions.
Figure 1. X-ray structure of the compound 10a 2[Cu(OAc)2]. Hydro-
3
gen bonds are depicted as dotted lines (intramolecular: gray, intermo-
lecular: black) and copper atoms as spheres. Hydrogen atoms have been
omitted for clarity.
bonds with adjacent imino and pyrrole NH groups. Crystals of
the complex 10a 2[Cu(OAc)2] were then obtained by slow
3
evaporation of a solution of the amine and copper acetate (1:2
molar ratio) in methanol. The X-ray structure of the complex
(Figure 1) shows that both copper atoms assume the square
planar geometry, where the N,N-bidentate diaminocyclohexane
moiety and one oxygen of each carboxylate groups occupy cis-
equatorial positions in the plane. The other two oxygens are
oriented toward the vacant apical positions. Both cyclohexane
rings have the chair conformation and the amino groups are
equatorially disposed, and the dinuclear complex can be ideally
split in two identical halves.
’ EXPERIMENTAL SECTION
In both halves, the two acetate ligands are involved in
intramolecular hydrogen bonding: one equatorial oxygen atom
is linked to the adjacent pyrrole NꢀH group, and the axial-
oxygen of the other acetoxy ligand is oriented toward the non-
adjacent pyrrole NꢀH group. Moreover, intermolecular hydro-
gen-bonding interactions were observed between the oxygens of
the carboxylate groups occupying the apical positions and the
amino groups of adjacent macrocycles, thus determining the
formation of a chain with a helicity feature (see the Supporting
Information).
Concerning the mechanism, we are induced to think that the
mechanism previously proposed by Evans for the analogous
Henry reaction catalyzed by a chiral bis(oxazoline)ꢀCu(OAc)2
complexes is also operative with our catalytic system.2b Hence,
one acetate ligand is lost to leave room for coordination of both
nucleophile and electrophile reagents to the copper center. The
nitronate ion occupies the apical position, whereas the electro-
philic carbonyl compound is more activated in the more Lewis
acidic equatorial site. The model depicted in Scheme 7 appears to
be favored by the reduced steric interactions of both reagents
with the ligand backbone. Obviously, the sense of asymmetric
induction is determined by the chirality of the 1,2-diaminocy-
clohexane moiety; however, the eventual role of dipyrrole moiety
cannot be clearly evaluated at the moment, as different hypotheses
can be advanced. In principle, it is possible that the copper-bound
nitronate anion forms a hydrogen bond with the pyrrole ring
General Methods. Chemical shifts are reported in ppm from TMS
with the solvent resonance as the internal standard (deuterochloroform:
δ 7.27 ppm). Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = duplet, t = triplet, q = quartet, bs = broad singlet,
m = multiplet), coupling constants (Hz). Chemical shifts are reported
in ppm from TMS with the solvent as the internal standard (deutero-
chloroform: δ 77.0 ppm). GCꢀMS spectra were taken by EI ionization
at 70 eV. They are reported as m/z (relative intensity). Chromato-
graphic purification was done with 240ꢀ400 mesh silica gel. Determina-
tion of enantiomeric excess was performed on HPLC instrument
equipped with a variable-wavelength UV detector, using a DAICEL
Chiralpak columns (0.46 cm i.d. ꢁ 25 cm) and HPLC-grade 2-propanol
and n-hexane were used as the eluting solvents. Optical rotations were
determined in a 1 mL cell with a path length of 10 mm (NaD line).
Melting points are not corrected. Materials: All reactions were carried
out under inert gas and under anhydrous conditions. Commercially
available anhydrous solvents were used avoiding purification. N-Boc-
3-indolecarbaldehyde,25 4-tert-butylcarbonate benzaldehyde, and 2-tert-bu-
tylcarbonate benzaldehyde,26 compounds 7a,27 7b,28 7c,29 8a,30 8c,30
and 13,20 were prepared according to literature procedures. Spectro-
scopical details for compounds 14a,2f 14b,31 14c,2n 14d,32 14e,2n 14f,2i
14g,33 14h,2n 14i,2n 14j,2n 14l,2n 14m,2n 14n,2i 14o,2n 14p,34 14r,2i 14s,2i
14t,2n 14u,2n and 14v2n were already reported.
Synthesis of Dialdehyde 8b. POCl3 (0.13 mL, 1.4 mmol)
was added dropwise to a stirred solution of 2,20-(cyclohexane-1,1-diyl)
bis(1H-pyrrole) (150 mg, 0.7 mmol) in DMF (1 mL), which was cooled
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The Journal of Organic Chemistry
ARTICLE
at 0 °C. The mixture was stirred at room temperature for 1 h and then
cooled to 0 °C, and 10 N NaOH (10 mL) was added portionwise. The
resultant precipitate was filtered and washed with water until pH = 7 was
reached to obtain the crude product 8b as a white amorphous solid: 162 mg,
625.4 [M þ H]þ. Anal. Calcd for C38H56N8: C, 73.04; H, 9.03; N, 17.93.
Found: C, 73.26; H, 9.06;N, 17.88.
10b. White solid; 90%. Mp = 147.9ꢀ148.9 °C (MeCN).
1
[R]20 = ꢀ52.0 (c 1.0, CH2Cl2). H NMR (CDCl3, 400 MHz): δ =
D
1
(86%). Mp = 208.4ꢀ209.7 °C dec. H NMR (CDCl3, 400 MHz):
0.89ꢀ0.96 (m, 4 H), 1.15 (m, 8 H), 1.39ꢀ1.42 (m, 2 H), 1.45ꢀ1.53 (m,
8 H), 1.54ꢀ1.72 (m, 10 H), 1.86ꢀ1.93 (m, 8 H), 2.06ꢀ2.14 (m, 4 H),
3.60 (d, J = 13.7 Hz, 4 H), 3.81 (d, J = 13.7 Hz, 4 H), 5.82 (t, J = 2.8 Hz,
4 H), 5.90 (t, J = 2.8 Hz, 4 H), 8.78 (bs, 4 H). 13C NMR (CDCl3, 100
MHz): δ = 22.8, 25.0, 26.2, 31.5, 36.2, 39.1, 43.7, 60.6, 103.1, 106.1, 129.2.
IR (KBr): ν = 3439, 2929, 2854, 2361, 2342, 1636, 1448, 1105, 1036,
770 cmꢀ1. ESI-MS m/z: 705.5 [M þ H]þ. Anal. Calcd for C44H64N8: C,
74.96; H, 9.15; N, 15.89. Found: C, 75.11; H, 9.16; N, 15.87.
δ = 1.34 (m, 2 H), 1.61 (m, 4 H), 2.32 (t, J = 5.2 Hz, 4 H), 6.22 (d, J = 2.4
Hz, 2 H), 6.93 (d, J = 2.0 Hz, 2 H), 9.47 (s, 2 H), 10.45 (bs, 2 H). 13C
NMR (CDCl3, 100 MHz): δ = 22.5, 25.6, 34.9, 39.9, 108.7, 123.3, 132.6,
146.8, 179.5. IR (KBr): ν = 3281, 3198, 3131, 3109, 3093, 2925, 2856,
1679, 1472, 1269, 1193, 1052, 812, 776 cmꢀ1. ESI-MS m/z: 271.1 [M þ
H]þ, 293.1 [M þ Na]þ, 541.3 [2 M þ H]þ. Anal. Calcd for
C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.29; H, 6.74;
N, 10.40.
10c. Red amorphous solid; 80%. Mp = 230ꢀ231 °C dec.
[R]20 = ꢀ44.8 (c 0.8, CH2Cl2). 1H NMR (CDCl3, 400 MHz):
Synthesis of Imines 9aꢀc. General Procedure. To the suspen-
sion of (R,R)-1,2-diaminocyclohexane L-tartrate (0.580 g, 2.2 mmol) in
MeOH (25 mL) were added aldehyde 8a (0.51 g, 2.2 mmol) and
triethylamine (0.67 mL, 4.8 mmol). The reaction mixture was stirred
for 48 h, and the solvent was evaporated at reduce pressure. A saturated
aqueous solution of NaHCO3 (20 mL) was added, and the organic
material was extracted with dichloromethane (3 ꢁ 30 mL). The
collected organic layers were washed with brine (20 mL), dried over
Na2SO4, and concentrated to leave a white solid, which was crystallized
from MeOH to give pure 9a (0.63 g, 1.0 mmol, 90%) as colorless
crystals. Mp = 160ꢀ162 °C dec. [R]20D = þ689.2 (c 0.8, CHCl3). 1H
NMR (CDCl3, 400 MHz): δ = 1.34 (m, 4 H), 1.53 (m, 4 H), 1.64 (m,
4 H), 1.67 (s, 12 H), 1.78 (m, 4 H), 3.16 (m, 4 H), 6.11 (d, J = 3.6 Hz,
4 H), 6.29 (d, J = 3.6 Hz, 4 H), 7.90 (s, 4 H). 13C NMR (CDCl3,
100 MHz): δ = 24.7, 27.9, 34.1, 35.2, 73.5, 105.1, 115.1, 129.6, 142.8,
151.4. IR (KBr): ν = 3296, 2971, 2925, 2855, 1633, 1561, 1486, 1270,
1216, 1042, 776 cmꢀ1. ESI-MS m/z: 617.3 [M þ H]þ. Anal. Calcd
for C38H48N8: C, 73.99; H, 7.84; N, 18.17. Found: C, 74.28; H, 7.87;
N, 18.09.
D
δ = 0.77ꢀ0.82 (m, 6 H), 1.15ꢀ1.21 (m, 4 H), 1.27ꢀ1.49 (m, 6 H),
1.74ꢀ1.86 (m, 4 H), 1.99ꢀ2.16 (m, 4 H), 3.16 (m, 8 H), 5.79 (d,
J = 2.4 Hz, 4 H), 6.13 (d, J = 2.4 Hz, 4 H), 7.14ꢀ7.20 (m, 4 H), 7.21ꢀ7.30
(m, 4 H), 7.40ꢀ7.62 (m, 12 H). 13C NMR (CDCl3, 50 MHz): δ =
24.7, 25.9, 46.3, 47.6, 60.7, 102.3, 104.6, 127.3, 127.8, 129.2, 138.3,
140.2, 151.4. IR (KBr): ν = 3442, 2923, 2853, 2363, 1635, 1445,
1384, 1109, 1039, 700 cmꢀ1. ESI-MS m/z: 873.3 [M þ H]þ. Anal. Calcd
for C58H64N8: C, 79.78; H, 7.39; N, 12.83. Found: C, 79.99; H, 7.41;
N, 12.80.
Synthesis of the Copper Complex (10a 2[Cu(OAc)2]). To a
3
solution of 10a (0.075 g, 0.12 mmol) in CH2Cl2 (5 mL) was added
Cu(OAc)2 H2O (0.048 g, 0.024 mmol), and the solution was stirred for
3
1 h. The solvent was removed in vacuo, and the residue was washed with
pentane/Et2O 9/1 (2 ꢁ 10 mL) and dried under vacuum to obtain 0.113
g (95%, 0.11 mmol) of copper complex 10a 2[Cu(OAc)2] as a slightly
3
green solid. [R]20D = ꢀ47.1 (c 1.1, CHCl3). Mp = 180 °C dec. IR (KBr):
ν = 3405, 3239, 3160, 2966, 2932, 2859, 1559, 1404, 1211, 1050, 1003,
778, 680 cmꢀ1. ESI-MS m/z: 747 [M ꢀ 4 CH3COOH þ H]þ, 749
[M ꢀ 4 CH3COOH þ H]þ.
9b. Colorless crystals, 80%. Mp = 197ꢀ199 °C (MeCN). [R]20
=
D
þ379.5 (c 1.1, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.36ꢀ1.49
(m, 12 H), 1.52ꢀ1.52 (m, 4 H), 1.61ꢀ1.71 (m, 8 H), 1.78 (m, 4 H), 2.04
(m, 4 H), 2.25 (m, 4 H), 3.14 (m, 4 H), 6.08 (d, J = 3.6 Hz, 4 H), 6.26 (d,
J = 3.6 Hz, 4 H), 7.85 (s, 4 H). 13C NMR (CDCl3, 100 MHz): δ = 22.5,
24.6, 26.0, 33.3 35.3, 39.5, 73.5, 105.7, 115.6, 129.6, 142.1, 151.4. IR
(KBr): ν = 3447, 2929, 1633, 1560,1476, 1044, 775 cmꢀ1. ESI-MS m/z:
697.4 [M þ H]þ. Anal. Calcd for C44H56N8: C, 75.82; H, 8.10; N, 16.08.
Found: C, 76.10; H, 8.12; N, 16.03.
CCDC numbers 803953 (9a(MeOH)4) and 803954 (10a 2[Cu-
3
(OAc)2]) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of Amine 11. The dialdehyde 8a (200 mg, 0.87 mmol)
and (S)-phenylethylamine (0.22 mL, 1.74 mmol) were dissolved in
CH2Cl2 (10 mL), and then MgSO4 (0.500 g) was added. The mixture
was stirred at room temperature for 48 h and then filtered through a
short pad of Celite, which was washed with CH2Cl2. The solvent was
evaporated at reduced pressure. The crude product was dissolved in
MeOH (10 mL), NaBH4 (66 mg, 179 mmol) was added, and the
mixture was stirred at room temperature overnight. Water (5 mL) was
added, and the mixture was stirred 20 min and then concentrated at
reduced pressure to remove MeOH. The organic phase was extracted
with EtOAc (2 ꢁ 20 mL), and the collected organic layers were
concentrated at reduced pressure to leave a yellowish oil. Column
chromatography (SiO2, CH2Cl2/MeOH, 9:1) gave 11 as a colorless oil,
340 mg (90%). [R]20D = ꢀ22.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 200
MHz): δ = 1.36 (d, J = 6.6 Hz, 6H), 1.67 (s, 6 H), 1.88 (bs, 2 H), 3.48
(d, J = 13.6 Hz, 2 H), 3.57 (d, J = 13.6 Hz, 2 H), 3.73 (q, J = 6.6 Hz, 2 H),
5.94 (t, J = 2.7 Hz, 2 H), 6.00 (t, J = 2.9 Hz, 2 H), 7.25ꢀ7.41 (m, 10 H),
8.24 (bs, 2 H). 13C NMR (CDCl3, 50 MHz): δ = 23.9, 29.2, 35.3, 44.3,
57.4, 103.3, 105.5, 125.6, 126.5, 126.9, 128.4, 129.8, 138.6. ESI-MS m/z:
439.3 [M þ H]þ. Anal. Calcd for C29H36N4: C, 79.05; H, 8.24; N, 12.72.
Found: C, 79.22; H, 8.26; N, 12.69.
9c. Red amorphous solid, 40%. Mp = 158ꢀ160 °C. [R]20D = ꢀ498
(c 0.9, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.36 (m, 4 H), 1.57
(m, 4 H), 1.78ꢀ1.82 (m, 8 H), 3.05 (m, 4 H), 5.80 (d, J = 3.6 Hz, 4 H),
6.17 (d, J = 3.6 Hz, 4 H), 6.95ꢀ6.97 (m, 4 H), 7.21ꢀ7.23 (m, 16 H),
7.71 (s, 4 H). 13C NMR (CDCl3, 100 MHz): δ = 24.5, 32.7, 56.4, 72.9,
112.2, 114.6, 127.1, 127.8, 129.4, 129.6, 140.2, 144.3, 152.5. IR (KBr):
ν = 3439, 2924, 2853, 1632, 1445, 1182, 1044,734, 700 cmꢀ1. ESI-MS m/z:
865.4 [M þ H]þ. Anal. Calcd for C58H56N8: C, 80.52; H, 6.52; N, 12.95.
Found: C, 80.22; H, 6.55; N 12.97.
Synthesis of amines 10aꢀc. General procedure. NaBH4 (0.15g,
4.1 mmol) was added to the solution of 9a (0.50 g, 0.8 mmol) in MeOH
(20 mL) and the reaction mixture was stirred during 20 h, then a 1 M
NaOH solution (5 mL) was added and the solvent was evaporated
at reduced pressure. The organic material was extracted with EtOAc
(3 ꢁ 30 mL). The collected organic layers were washed with brine
(20 mL), dried over Na2SO4 and concentrated to leave 10a (0.47 g, 0.76
mmol, 95%) as a white solid: mp =166ꢀ167 °C; [R]D20 = ꢀ23.7 (c 0.8,
1
CHCl3). H NMR (CDCl3, 400 MHz): δ = 0.72ꢀ0.82 (m, 6 H),
Enantioselective Henry Reaction. Typical Procedure. To a
1.03ꢀ1.11 (m, 4 H), 1.46 (s, 12 H), 1.61 (m, 6 H), 1.99ꢀ2.09 (m, 4 H),
3.37 (d, J = 14.7 Hz, 4 H), 3.62 (d, J = 14.7 Hz, 4 H), 5.72 (d, J = 2.4 Hz, 4
H), 5.89 (t, J = 2.4 Hz, 4 H), 10.82 (bs, 4 H); 13C NMR (CDCl3, 100
MHz): δ = 25.2, 31.4, 33.0, 35.8, 42.9, 60.3, 103.4, 103.9, 130.1, 137.6. IR
(KBr): ν = 3442, 2928, 2856, 1646, 1456, 1075 cmꢀ1. ESI-MS m/z:
solution of Cu(AcO)2 H2O (0.003 g, 0.015 mmol) in EtOH
3
(1.5 mL) was added 10a (0.004 g, 0.007 mmol), and the reaction
mixture was stirred at room temperature for 30 min. Benzaldehyde
(30 μL, 0.25 mmol) and nitromethane (134 μL, 2.5 mmol) were added.
After 20 h, the reaction mixture was filtered through a small pad of silica,
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The Journal of Organic Chemistry
ARTICLE
which was washed with EtOAc. Column chromatography (SiO2, cyclohex-
ane/EtOAc, 9:1) gave (R)-14a: 0.181 g (92%). 92% ee was determined
by chiral HPLC (Chiralpak OD; 2-propanol/hexane 1:9, 0.8 mL/min.;
214 nm; 40 °C): retention times 14.5 min (S, minor enantiomer) and
17.4 min (R, major enantiomer).
14b. The ee was determined by chiral HPLC (Chiralpak OD; 2-propa-
nol/hexane 25:75, 0.5 mL/min; 214 nm; 40 °C): retention times 11.6 min
(S, minor enantiomer) and 15.1 min (R, major enantiomer).
Hz, 1 H), 7.63 (s, 1 H), 8.15 (d, J = 8.6 Hz, 1 H). 13C NMR (CDCl3, 100
MHz): δ = 28.1, 65.2, 80.0, 84.4, 115.6, 117.9, 119.0, 123.1, 125.1, 127.4,
135.7, 149.3. IR (neat): ν = 3468, 3054, 2979, 2928, 1735, 1555, 1373,
1155, 1097 cmꢀ1. ESI-MS m/z: 324.2 [M þ H2O]þ, 329.1 [M þ Na]þ.
Anal. Calcd for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15. Found: C,
58.78; H, 5.97; N, 9.11. The ee was determined by chiral HPLC
(Chiralpak OD; 2-propanol/hexane 1:9, 0.8 mL/min.; 214 nm;
40 °C): retention times 11.4 min (S, minor enantiomer) and 12.8 min
(R, major enantiomer).
14c. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 1:9, 0.8 mL/min; 214 nm; 40 °C): retention times
14.2 min (S, minor enantiomer) and 18.1 min (R, major enantiomer).
14d. The ee was determined by chiral HPLC (Chiralpak OJ;
2-propanol/hexane 2:98, 0.8 mL/min.; 214 nm; 40 °C): retention times
19.5 min (S, minor enantiomer) and 21.1 min (R, major enantiomer).
14e. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 1:9, 0.5 mL/min.; 214 nm; 40 °C): retention times
22.1 min (S, minor enantiomer) and 23.2 min (R, major enantiomer).
14f. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 1:9, 0.6 mL/min.; 214 nm; 40 °C): retention times
19.3 min (S, minor enantiomer) and 21.0 min (R, major enantiomer).
14g. The ee was determined by chiral HPLC (Chiralpak OJ;
2-propanol/hexane 3:7, 0.8 mL/min.; 214 nm; 40 °C): retention times
16.4 min (S, minor enantiomer) and 19.5 min (R, major enantiomer).
14h. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 2:8, 0.5 mL/min.; 214 nm; 40 °C): retention times
17.0 min (S, minor enantiomer) and 21.1 min (R, major enantiomer).
14i. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 2:8, 0.5 mL/min.; 214 nm; 40 °C): retention times
14.0 min (S, minor enantiomer) and 16.1 min (R, major enantiomer).
14j. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 2:8, 0.8 mL/min.; 214 nm; 40 °C): retention times
18.8 min (S, minor enantiomer) and 22.3 min (R, major enantiomer).
14k. White solid. [R]20D = þ25.3 (c 0.8, CHCl3). Mp = 85.4ꢀ86.0 °C
dec. 1H NMR (CDCl3, 400 MHz): δ = 1.53 (s, 9 H), 3.29 (bs, 1 H), 4.48
(dd, J = 3.3 Hz, J = 13.2 Hz, 1 H), 4.51 (dd, J = 9.5 Hz, J = 13.1 Hz, 1 H),
5.36 (dd, J = 3.3 Hz, J = 9.3 Hz, 1 H), 7.13ꢀ7.17 (m, 2 H), 7.34ꢀ7.38
(m, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 27.6, 70.3, 81.1, 84.0,
121.8, 127.1, 135.9, 151.1, 151.8. IR (neat): ν = 3489, 2990, 2935, 1732,
1556, 1286, 1221, 1149 cmꢀ1. ESI-MS m/z: 301.1 [M þ H2O]þ, 306.0
[M þ Na]þ, 322 Μ þ K]þ. Anal. Calcd for C13H17NO6: C, 55.12; H,
6.05; N, 4.94. Found: C, 55.00; H, 6.10; N, 4.99. The ee was determined
by chiral HPLC (Chiralpak OD; 2-propanol/hexane 1:9, 1.0 mL/min;
214 nm; 40 °C): retention times 11.9 min (S, minor enantiomer) and
13.71 min (R, major enantiomer).
14r. The ee was determined by chiral HPLC (Chiralpak IC; 2-propanol/
hexane 4:6, 0.5 mL/min.; 214 nm; 40 °C): retention times 14.3 min (S,
minor enantiomer) and 17.5 min (R, major enantiomer).
14s. The ee was determined by chiral HPLC (Chiralpak OJ; 2-propanol/
hexane 2:98, 0.5 mL/min.; 214 nm; 40 °C): retention times 35.1 min (S,
minor enantiomer) and 39.2 min (R, major enantiomer).
14t. The ee was determined by chiral HPLC (Chiralpak OD; 2-propa-
nol/hexane 2:98, 0.7 mL/min.; 214 nm; 40 °C): retention times 16.9 min
(S, minor enantiomer) and 18.9 min (R, major enantiomer).
14u. The ee was determined by chiral HPLC (Chiralpak IC;
2-propanol/hexane 5:95, 0.7 mL/min.; 214 nm; 40 °C): retention times
24.7 min (S, minor enantiomer) and 25.9 min (R, major enantiomer).
14v. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 1:9, 0.6 mL/min.; 214 nm; 40 °C): retention times
16.7 min (anti, S,S), 18.3 min (anti, R,R), 20.9 min (syn, R,S) and 22.9
(syn, S,R).
Preparation of Compound 16. To a solution of compound 14
(123 mg, 0.43 mmol) in EtOH (2 mL) was added 10% Pd/C (17 mg).
The mixture was stirred under a hydrogen atmosphere (balloon) for 22
h. The mixture was filtered through a short pad of Celite to remove the
catalyst. Removal of the solvent under reduced pressure afforded 73 mg
(70%) of primary amine. 1H NMR (CDCl3, 400 MHz): δ = 1.52
(s, 9 H), 2.74 (dd, J = 8 Hz, J = 13.2 Hz, 1 H), 2.91 (dd, J = 3.6 Hz, J =
12.8 Hz, 1 H), 4.57 (dd, J = 4 Hz, J = 8 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 2 H),
7.31 (d, J = 8 Hz, 2 H). A solution of amine (73 mg, 0.29 mmol), acetone
(34 μL, 0.46 mmol), and MgSO4 (40 mg) in EtOH (2 mL) was stirred at
rt overnight. Then the reaction mixture was cooled to 0 °C (ice bath),
and NaBH4 (16 mg, 0.43 mmol) was added. After being stirred for 1 h,
the reaction mixture was filtered through a small pad of Celite, which was
washed with EtOAc and MeOH to give 80 mg (94%) of compound 15.
1H NMR (CDCl3, 400 MHz): δ = 1.05 (d, J = 6.4 Hz, 6 H), 1.58 (s, 9 H),
2.62 (dd, J = 10 Hz, J = 13.2 Hz, 1 H), 2.78ꢀ2.85 (m, 1 H), 2.91 (dd, J =
3.6 Hz, J = 12.4 Hz, 1 H), 4.63 (dd, J = 4 Hz, J = 9.2 Hz, 1 H), 7.12 (d, J =
8.8 Hz, 2 H), 7.35 (d, J = 8 Hz, 2 H). A solution of HCl in MeOH,
prepared by addition of acetyl chloride (0.100 mL, 1.35 mmol) to
MeOH (2 mL), was added dropwise to a solution of 15 (80 mg, 0.27
mmol) in MeOH (7 mL) at room temperature. After 6 h, the mixture
was concentrated at reduced pressure. The solid was washed with Et2O
(3 ꢁ 3 mL) to give the crude salt 16 as a white solid, 0.04 g (0.22 mmol,
80%). Mp = 149ꢀ150 °C (lit. racemic compound, mp 151.5ꢀ152.5 °C).
[R]20D = ꢀ32.1 (c 1.2, MeOH). 1H NMR (CDCl3 with 10% DMSO,
400 MHz): δ = 1.41 (d, J = 6.4 Hz, 3 H), 1.44 (d, J = 6.4 Hz, 3 H),
2.89ꢀ2.98 (m, 1 H), 3.00ꢀ3.10 (m, 1 H), 3.35ꢀ3.42 (m, 1 H), 4.81 (dd,
J = 2.4 Hz, J = 10 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 7.14 (d, J = 8.4 Hz, 2
H). 13C NMR (DMSO, 100 MHz): δ = 18.5, 19.2, 49.8, 50.3, 56.1, 78.7,
115.9, 128.0, 128.5, 158.2. IR (KBr): ν = 3220, 2979, 1613, 1614, 1555,
1448, 1267, 1224, 1100, 838 cmꢀ1. ESI-MS m/z: 196.1 [M þ H]þ. Anal.
Calcd for C11H18ClNO2: C, 57.02; H, 7.83; N, 6.04. Found: C, 56.86; H,
7.85; N, 6.03.
14l. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 3:7, 0.6 mL/min.; 214 nm; 40 °C): retention times
12.0 min (S, minor enantiomer) and 14.1 min (R, major enantiomer).
14m. The ee was determined by chiral HPLC (Chiralpak OD;
2-propanol/hexane 2:8, 0.8 mL/min.; 214 nm; 40 °C): retention times
11.9 min (S, minor enantiomer) and 13.8 min (R, major enantiomer).
14n. The ee was determined by chiral HPLC (Chiralpak OD; 2-propa-
nol/hexane 1:1, 0.6 mL/min.; 214 nm; 40 °C): retention times 12.5 min (S,
minor enantiomer) and 15.5 min (R, major enantiomer).
14o. The ee was determined by chiral HPLC (Chiralpak IC; 2-propa-
nol/hexane 25:75, 0.5 mL/min.; 214 nm; 40 °C): retention times 22.6 min
(S, minor enantiomer) and 24.8 min (R, major enantiomer).
14p. The ee was determined by chiral HPLC (Chiralpak IC; 2-propa-
nol/hexane 5:95, 0.7 mL/min.; 214 nm; 40 °C): retention times 59.9 min
(S, minor enantiomer) and 62.7 min (R, major enantiomer).
14q. Yellow oil. [R]20D = þ15.5 (c 0.5, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 1.65 (s, 9 H), 3.00 (bs, 1 H), 4.65 (dd, J = 3.1 Hz, J = 13.3
Hz, 1 H), 4.77 (dd, J = 9.4 Hz, J = 13.3 Hz, 1 H), 5.81 (dt, J = 3.0 Hz,
J = 9.4 Hz, 1 H), 7.26 (ddd, J = 1.1 Hz, J = 7.3 Hz, J = 8.2 Hz, 1 H), 7.34
(ddd, J = 1.2 Hz, J = 7.3 Hz, J = 8.4 Hz, 1 H), 7.61 (dt, J = 0.9 Hz, J = 7.7
’ ASSOCIATED CONTENT
S
Supporting Information. X-ray crystallography details of
b
9a(MeOH)4 and 10a 2[Cu(OAc)2]; NMR spectra for all new
3
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The Journal of Organic Chemistry
ARTICLE
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Savoia, D.; Gualandi, A. Org. Biomol. Chem. 2010, 8, 3992–3996.
(9) To the best of our knowledge, only one chiral, racemic, macro-
cyclic diimine derived from trans-1,2-diaminocyclohexane and contain-
ing two pyrrole and one thiophene rings has been reported: Won, D.-H.;
Lee, C.-H. Tetrahedron Lett. 2001, 42, 1969–1972.
’ AUTHOR INFORMATION
(10) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coordinat. Chem. Rev.
2003, 240, 17–55.
(11) (a) Callaway, W. B.; Veauthier, J. M.; Sessler, J. L. J. Porphyrins
Phthalocyanines 2004, 8, 1–25. (b) Radecka-Paryzek, W.; Patroniak, V.;
Lisowski, J. Coord. Chem. Rev. 2005, 249, 2156–2175. (c) MacLachlan,
M. J. Pure Appl. Chem. 2006, 78, 873–888.
Corresponding Author
*Fax: int-051-2099456. E-mail: diego.savoia@unibo.it.
’ ACKNOWLEDGMENT
This work was carried out under the auspices of the PRIN
Project: “Sintesi e stereocontrollo di molecole organiche per lo
sviluppo di metodologie innovative”.
(12) (a) Blangy, V.; Heiss, C.; Khlebnikov, V.; Letondor, C.; Stoeckli-
Evans, H.; Neier, R. Angew. Chem., Int. Ed. 2009, 48, 1688–1691. (b)
Journot, G.; Letondor, C.; Neier, R.; Stoeckli-Evans, H.; Gualandi, A.;
Savoia, D. Chem.—Eur. J. 2010, 16, 4224–4230.
(13) (a) Alvaro, G.; Di Fabio, R.; Gualandi, A.; Savoia, D. Eur. J. Org.
Chem. 2007, 72, 5573–5582. (b) Albano, V. G.; Gualandi, A.; Monari,
M.; Savoia, D. J. Org. Chem. 2008, 73, 8376–8381. (c) Savoia, D.;
Gualandi, A.; Bandini, M. Lett. Org. Chem. 2009, 434–438.
(14) (a) Brunner, H.; Riepl, G. Angew. Chem., Int. Ed. Engl. 1982,
21, 377–378. (b) Brunner, H.; Reiter, B.; Riepl, G. Chem. Ber. 1984,
117, 1330–1354. (c) Brunner, H.; Becker, R.; Riepl, G. Organometallics
1984, 3, 1354–1359.
’ REFERENCES
(1) For reviews on the asymmetric Henry reaction, see: (a) Shibasaki,
M.; Grc-ger, H In Comprehensve Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, pp 1075ꢀ1090.
(b) Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon: New York, 1991; Vol. 2, pp 321ꢀ340.
(c) Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (d) Ono, N. The Nitro
Group in Organic Synthesis; Wiley-VCH: New York, 2001. (e) Shibasaki, M.;
Grc-ger, H.; Kanai, M. In Comprehensive Asymmetric Catalysis Supplement 1;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 2004;
pp 131ꢀ133. (f) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315–3326. (g) Palomo, C.; Oiarbide,
M.; Laso, A. Eur. J. Org. Chem. 2007, 2561–2574.
(15) Kim, S.-G.; Park, T.-H. Tetrahedron: Asymmetry 2008, 19,
1626–1629.
(16) (a) Cafeo, G.; De Rosa, M.; Kohnke, F. H.; Neri, P.; Soriente,
A.; Valenti, L. Tetrahedron Lett. 2008, 49, 153–155. (b) Cafeo, G.; De
Rosa, M.; Kohnke, F. H.; Neri, P.; Soriente, A.; Valenti, L. Tetrahedron
Lett. 2008, 50, 4138–4140. (c) Zhang, X.; Du, H.; Wang, Z.; Wu, Y.-D.;
Ding, K. J. Org. Chem. 2006, 12, 4321–4332.
(2) (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun.
2001, 2222–2223. (b) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.;
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693. (c)
Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004,
43, 5442–5444. (d) Blay, G.; Climent, E.; Fernandez, I.; Hernandez, V.;
Pedro, J. Tetrahedron: Asymmetry 2006, 17, 2046–2049. (e) Maheswaran,
H.; Prasanth, K. L.; Krishna, G. G.; Ravikumar, K.; Sridhar, B.; Kantam,
M. L. Chem. Commun. 2006, 4066–4068. (f) Bandini, M.; Piccinelli, F.;
Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem. Commun. 2007,
616–618. (g) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y. H.; Feng, X. M.
Chem.—Eur. J. 2007, 13, 829–833. (h) Blay, G.; Climent, E.; Fernandez, I.;
Hernandez, V.; Pedro, J. Tetrahedron: Asymmetry 2007, 18, 1603–1612.
(i) Ma, K. Y.; You, J. S. Chem.—Eur. J. 2007, 13, 1863–1871. (j) Bandini,
M.; Benaglia, M.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. Org. Lett. 2007,
9, 2151–2153. (k) Arai, T.; Watanabe, M.; Yanagisaka, A. Org. Lett. 2007,
9, 3595–3597. (l) Qin, B.; Xiao, X.; Liu, X. H.; Huang, J. L.; Wen, Y. H.;
Feng, X. M. J. Org. Chem. 2007, 72, 9323–9328. (m) Arai, T.; Yokoyama, N.;
Yanagisawa, A. Chem.—Eur. J. 2008, 14, 2052–2059. (n) Blay, G.;
Domingo, L. R.; Hernandez-Olmos, V.; Pedro, J. R. Chem.—Eur. J. 2008,
14, 4725–4730. (o) Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.;
Yanagisawa, A. J. Org. Chem. 2008, 73, 4903–4906. (p) Zhang, G. Q.;
Yashima, E.; Woggon, W. D. Adv. Synth. Catal. 2009, 351, 1255–1262.
(q) Selvakumar, S.; Sivasankaran, D.; Singh, V. K. Org. Biomol. Chem. 2009,
7, 3156–3162. (r) Spangler, K. Y.; Wolf, C. Org. Lett. 2009, 11, 4724–4727.
(s) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann, C.
Chem.—Eur. J. 2009, 15, 12764–12769. (t) Noole, A.; Lippur, K.; Metsala,
A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313–1316.
(17) Mazet, C.; Gade, H. Chem.—Eur. J. 2002, 8, 4308–4318.
(18) (a) Love, J. B. Chem. Commun. 2009, 3154–3165. (b) Arnold, P. L.;
Potter, N. A.; Carmichael, C. D.; Slawin, A. M. Z.; Roussel, P.; Love, J. B.
Chem. Commun. 2010, 46, 1833–1835. (c) Veauthier, J. M.; Cho, W.-S.;
Lynch, V. M.; Sessler, J. L. Inorg. Chem. 2004, 43, 1220–1228. (d)Sessler, J. L.;
Roznyatovskyi, V.; Dan Pantos, G.; Borisova, N. E.; Reshetova, M. D.; Lynch,
Vi. M.; Khrustalev, V. N.; Ustynyuk, Y. A. Org. Lett. 2005, 7, 2277–2280.
(19) Beer, P. D.; Cheetham, A. G.; Drew, M. G. B.; Fox, O. D.;
Hayes, E. J.; Rolls, T. D. Dalton Trans. 2003, 603–611.
(20) Savoia, D.; Gualandi, A.; Bandini, M. Lett. Org. Chem.
2009, 434–438.
(21) Base-catalyzed, nonselective Henry reactions have been known
for a long time. Such a process has incidence in the efficiency of
asymmetric catalysis: Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2002, 67, 4875–4881.
(22) Chen, J. US 2005/0250944 A1, 2005; Chem. Abstr. 2005,
143, 460316.
(23) (a) Brittain, R. T.; Jack, D.; Ritchie, A. C. Adv. Drug Res. 1970,
5, 197–253. (b) Lunts, L. H. C.; Main, B. G.; Tucker, H. In Medicinal
Chemistry, The Role of Organic Chemistry in Drug Research; Roberts, S. M.,
Price, B. J., Eds.; Academic Press: New York, 1985. (c) Pharmaceutical
Chemistry of Antiyhpertensive Agents; Szasz, G., Budvari-Barany, Z., Eds.;
CRC Press: Boston, 1991. (d) Ohkubo, K.; Moro-oka, Y.; Fukuzumi, S.
Org. Biomol. Chem. 2006, 4, 999–1001.
(24) For recent asymmetric syntheses of this class of compounds,
including applications of Henry reactions, see: (a) Singer, R. A.; Carreira,
E. M. Tetrahedron Lett. 1997, 38, 927–930. (b) Kumar, P.; Kumar
Upadhyay, R.; Kumar Pandey, R. Tetrahedron: Asymmetry 2004,
15, 3955–3959. (c) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R. Tetra-
hedron: Asymmetry 2010, 21, 578–581. (d) Lai, G.; Guo, F.; Zheng, Y.;
Fang, Y.; Song, H.; Xu, K.; Wang, S.; Zha, Z.; Wang, Z. Chem.—Eur.
J. 2011, 17, 1114–1117.
(3) For recent reviews on chiral perazamacrocycles, see: (a) Savoia,
D.; Gualandi, A. Curr. Org. Synth. 2009, 102–118. (b) Savoia, D.;
Gualandi, A. Curr. Org. Synth. 2009, 119–142.
(4) (a) Gran, U.; Wennerestr€om, O.; Westman, G. Tetrahedron:
Asymmetry 2000, 11, 3027–3040. (b) Gao, J.; Martell, A. E. Org. Biomol.
Chem. 2003, 1, 2795–2800. (c) Tanaka, K.; Hachiken, S. Tetrahedron
Lett. 2008, 49, 2533–2536.
(25) Molinaro, C.; Jamison, T. F. Angew. Chem., Int. Ed. 2005,
44, 129–132.
(5) Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett.
2001, 3, 165–167.
(26) Houlihan, F.; Bouchard, F.; Frꢁechet, J. M. J.; Willson, C. G. Can.
J. Chem. 1985, 63, 153–162.
(27) Bucher, C.; Zimmerman, R. S.; Lynch, V.; Krꢀal, V.; Sessler, J. L.
J. Am. Chem. Soc. 2001, 123, 2099–2100.
(6) Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2801–2806.
(7) Vigato, P. A.; Tamburini, S.; Bertolo, L. Coord. Chem. Rev. 2007,
251, 1311–1492.
3407
dx.doi.org/10.1021/jo200318b |J. Org. Chem. 2011, 76, 3399–3408

The Journal of Organic Chemistry
ARTICLE
(28) Swartz, D. L., II; Odom, A. L. Dalton Trans. 2008, 4254–4258.
(29) Freckmann, D. M. M.; Dubꢁe, T.; Bꢁerubꢁe, C. D.; Gambarotta, S.;
Yap, G. P. A. Organometallics 2002, 21, 1240–1246.
(30) Love, J. B.; Blake, A. J.; Wilson, C.; Reid, S. D.; Novak, A.;
Hitchcock, P. Chem. Commun. 2003, 4, 1682–1683.
(31) Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 1999, 64, 4298–4303.
(32) Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis 2004,
12, 1947–1950.
(33) Fan, J.; Sun, G.; Wan, C.; Wang, Z.; Li, Y. Chem. Commun. 2008,
32, 3792–3794.
(34) Niazimbetova, Z. I.; Evans, D. H.; Guzei, I. A.; Incarvito, C. D.;
Rheingold, A. L. J. Electrochem. Soc. 1999, 146, 1492–1495.
3408
dx.doi.org/10.1021/jo200318b |J. Org. Chem. 2011, 76, 3399–3408