C2-Symmetric hemiaminal ethers and diamines: New ligands for copper-catalyzed desymmetrization of meso-1,2-diols and asymmetric Henry reactions

Article abstract of DOI:10.1016/j.tetasy.2013.09.011

The synthesis of novel, enantiomerically pure C₂-symmetrical hemiaminal ethers and diamines containing piperazine core is presented. The key steps of the synthesis involve the dimerization of an in situ generated α-amino aldehyde into the corresponding cyclic bis-hemiaminal, followed by dehydration in the presence of a base to give a 7-oxa-2,5-diaza-bicyclo[2.2.1] heptane derivative, which can be regarded as a bicyclic bis-hemiaminal inner ether. These compounds represent a new class of molecule, with a structure unambiguously established for the first time. Finally, sodium triacetoxy-borohydride reduction gave the corresponding diamines. Both classes of compounds, new diamines and hemiaminal ethers, were shown to be good ligands for the copper(II)-catalyzed desymmetrization of meso-diols (up to 87% ee) and Henry reactions (up to 84% ee).

Full text of DOI:10.1016/j.tetasy.2013.09.011

Tetrahedron: Asymmetry 24 (2013) 1435–1442
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
C2-Symmetric hemiaminal ethers and diamines: new ligands
for copper-catalyzed desymmetrization of meso-1,2-diols
and asymmetric Henry reactions
a,
b
a
a
a
⇑
´
_
Zbigniew Kałuza , Krzysztof Bielawski , Rafał Cwiek , Piotr Niedziejko , Przemysław Kaliski
a Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b Medical University of Bialystok, Department of Synthesis and Technology of Drugs, Jana Kilin´skiego 1, 15-089 Białystok, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of novel, enantiomerically pure C2-symmetrical hemiaminal ethers and diamines contain-
Received 12 August 2013
Accepted 13 September 2013
Available online 29 October 2013
ing piperazine core is presented. The key steps of the synthesis involve the dimerization of an in situ gen-
erated a-amino aldehyde into the corresponding cyclic bis-hemiaminal, followed by dehydration in the
presence of a base to give a 7-oxa-2,5-diaza-bicyclo[2.2.1]heptane derivative, which can be regarded as a
bicyclic bis-hemiaminal inner ether. These compounds represent a new class of molecule, with a struc-
ture unambiguously established for the first time. Finally, sodium triacetoxy-borohydride reduction gave
the corresponding diamines. Both classes of compounds, new diamines and hemiaminal ethers, were
shown to be good ligands for the copper(II)-catalyzed desymmetrization of meso-diols (up to 87% ee)
and Henry reactions (up to 84% ee).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
copper-catalyzed desymmetrization of meso-1,2-diols and asym-
metric Henry reaction.
Chiral bis-tertiary diamines, both natural and synthetic, are
widely used in catalytic asymmetric synthesis as organocatalysts1a
or ligands1b in catalytic processes based on metal complexes. They
have been successfully applied in diverse asymmetric processes,
for example, Henry reactions,2 desymmetrization of meso-diols,3
deprotonations,4 oxidative couplings,5 cyclopropanations,6 and
many others. The rapid development of this field over the past
two decades has created a rapidly growing need for new chiral
amines. Due to a very limited number of readily available natural
compounds that are able to catalyze stereoselective reactions,
many research groups have concentrated on the design and syn-
thesis of novel diamine ligands.
From the large number of reported bis-tertiary diamines, the
derivatives of piperazine have been shown to be very effective chi-
ral inducers3c,7a–j (Fig. 1). Furthermore, a facile synthesis of dia-
mines of this class can provide a vast array of compounds
containing two stereogenic centers within the piperazine ring
C2-symmetrical 1–4,3c,7b,e,j four centers 67c or only one center 8,
and 9.7a Alternatively, the asymmetric center can also be posi-
tioned at the nitrogen substituent 5 and 7.7f–i
2. Results and discussion
2.1. Synthesis of C2-symmetrical diamines
As part of a current project aimed at the synthesis of isoquino-
line alkaloids, we have developed a stereoselective method for the
preparation of enantiomerically pure dihydroxy-hexahydro-pyr-
rolo-iso-quinolines with a quaternary carbon stereocenter, starting
from L
-tartaric acid.8a,b Further studies have shown that diols of
type 10 undergo sodium periodate glycolic cleavage to give a dia-
stereomeric mixture of cyclic hemiacetals 118c (Scheme 1). We
have shown, using phenyl derivative 11a as an example, that base
hydrolysis of the nitrogen substituent in the product of glycolic
cleavage led to the intermediary a-aminoaldehyde 12a. The latter
readily dimerized, probably via hemiaminal 13a, and afforded the
hemiaminal inner ether 14a.
It is well known that both N-formyl9a and nonenolizable
a-ami-
no aldehydes9b–e undergo facile dimerization to give the cyclic
hemiaminals, which contain a piperazine skeleton. The formation
of an amino aldehyde dimer of a different structure is very rare.10
On the basis of the above literature reports and available spectro-
scopic data, the structure of isolated 14a was initially incorrectly
identified as a C2-symmetrical hemiaminal 13a.8c However, because
of the inconsistent elementary analysis of the amino aldehyde
dimer, we performed a single crystal X-ray diffraction analysis.11
Herein we report the synthesis of novel C2-symmetrical dia-
mines that contain a piperazine core and their application in the
⇑
Corresponding author. Tel.: +48 22 343 2142; fax: +48 22 632 6681.
_
E-mail address: zbigniew.kaluza@icho.edu.pl (Z. Kałuza).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.09.011

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Z. Kałuza et al. / Tetrahedron: Asymmetry 24 (2013) 1435–1442
1436
n-Bu
N
Ph
Ph
N
N
N
N
N
H
R
R
N
N
N
Ph
n-Bu
3
2
; R = H
1
4; R = Me
5
OR
N
N
N
N
N
N
H
N
N
N
Ph
OH
7
9
6
8
Figure 1. Tertiary diamines containing the piperazine skeleton.
OMe
OMe
OMe
OMe
HO
O
HO
O
R
N
R
N
L-tartaric
NaIO4
Na2CO3
acid
O
HO
H2O,
H2O,
MeCN
MeCN
HO
10
11
OMe
R = aryl, alkyl
OMe
OMe
OH
OH
Ph
OMe
Ph
N
- H2O
11a
N
O
R = Ph
HN
Ph
MeO
OMe
12a
13a
OMe
OMe
OMe
OMe
Ph
N
Ph
N
N
NaHB(OAc)3
DCM
O
N
Ph
Ph
MeO
MeO
OMe
OMe
14a
15a
Scheme 1. Previous work: synthesis of C2-symmetrical hemiaminal ether 14a.
The analysis showed that dimer 14a had a unique structure of a
bis-hemiaminal inner ether (Fig. 2). A thorough search of the
literature revealed a single report of the synthesis of cyclic bis-
hemiaminal ether derivatives. In 1960 Ogloblin12 described the
preparation of compounds of this type by thermal or base induced
approach to C2-symmetrical diamines with a piperazine core. The
sodium triacetoxy-borohydride reduction of 14a gave an enantio-
merically pure diamine 15a in excellent yield (93%) (Scheme 1).
In order to assess the scope of this new methodology, we
prepared several derivatives of general structure 14 and 15,
varying the substituent at the bridged quaternary carbon atom
(cf. Scheme 2). The synthesis of 10b-substituted hexahydro-
pyrrolo[2,1-a]isoquinolines was carried out by applying our
optimized procedure.8b The addition of a Grignard reagent to imide
dehydration of a-amino aldehyde dimers. However, the author did
not provide any spectroscopic data, and the proposed structure
was postulated exclusively on the basis of elementary analysis.
Therefore, the herein reported 7-oxa-2,5-diaza-bicyclo[2.2.1]
heptane derivative 14a that can be described as a bicyclic bis-
hemiaminal inner ether (Fig. 3), represents a new class of mole-
cules, whose structure was unambiguously established for the first
time.
16, derived from L-tartaric acid, followed by acetylation and the
BF3ꢀEt2O induced cyclization furnished a diastereomeric mixture
of C-10b epimers 17b,c,e [(S),(R)] in good overall yields and with
respectable diastereoselectivity [(S),(R) = 17–22:1]. Cyclization of
10b-benzyl derivatives 17d was less stereoselective [(S),(R) = 6:1],
and, in addition, the main product was accompanied by
Inspired by this observation, we realized that the reduction of a
hemiaminal ether of type 14 could potentially open up a novel

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Z. Kałuza et al. / Tetrahedron: Asymmetry 24 (2013) 1435–1442
1437
Table 1
The J1,2 value of isolated enantiomerically pure 10b-substituted hexahydro-pyrrol-
o[2,1-a]iso-quinolin-3-ones
C-10b
J1,2 (Hz)
17aa
17ba
17c
17d
19e
(S)
(R)
6,8
2,7
7,9
0
6,9
—
8,4
0
8,3
4,1
a
Previously reported.8b
The alkaline deprotection of hydroxy groups for the parent
compounds 17b–d and 19e led to diols 10b–e. The glycolic
cleavage using sodium periodate followed by sodium carbonate
hydrolysis yielded aminal ethers 14b–e. Compounds 14 and 14e
were isolated by flash chromatography. The unstable 14b and
14d, because of their rapid decomposition on silica gel, were used
in the following step without any purification. Finally, the
reduction of bis-hemiaminal ethers 14b–e with sodium triacet-
oxy-borohydride provided C2-symmetrical diamines 15b–e.
Figure 2. View of 14a, as determined by single crystal X-ray crystallography.
hexahydro-1H-benzo[d]pyrrolo[1,2-a]azepine 18, which was
isolated in approximately 8% yield as a single stereoisomer. The
configuration at the newly generated stereocenters was not
established. The enantiomerically pure hexahydro-pyrrolo[2,1-
a]isoquinolines were isolated either via single crystallization
17b,c or via flash chromatography 17d or as a monopivalate 19e.13
The proton NMR spectrum derived J1,2 values for 17b–d and 19e
were in a range of 6.9–8.4 Hz (Table 1), which according to our
semi-empirical rule,8b confirmed that all compounds possessed a
10b(S) configuration.
2.2. Cu-catalyzed asymmetric acylation of meso-diols using
ligands of types 14 and 15
In order to evaluate the catalytic efficiency of the new ligands,
we selected the asymmetric acylation of meso-diols3 as a model
reaction. Benzoylation of several cyclic and acyclic meso-1,2-diols
20–23, catalyzed by 3 mol % of CuCl2–diamines 15a–e complexes,
was carried out following Nakamura’s procedure.3c Acylation with
complexes of diamines with aryl substituents at the bridged
quaternary carbon atom 15a, 15c, and 15e provided the corre-
sponding monobenzoates with moderate to high enantioselectivity
(ee 41–87%; Table 2). The methyl- and benzyl analogues 15d and
15e showed very low levels of stereoselectivity for substrate 23
(ee 3–9%).
NH
O
HN
Figure 3. 7-Oxa-2,5-diaza-bicyclo[2.2.1]heptane.
OMe
OMe
ref.7b
OMe
OMe
1. RMgBr/THF
2. Ac2O/MeCN
DMAP
3. BF3.Et2O
DCM, 0oC
OMe
O
AcO
O
AcO
2
R
N
R
TMSO
TMSO
A. crystallization
N
R1
10b
1
10b(S)
N
or
AcO
AcO
B.
chromatography
O
O
16
17b
17c
;
(SR) R = Me
17b
17c
17d
A
(S),73% ( )
R1=
;
(SR) R = 3,5-xylyl
S = 10b(S) epimer
A
(S),78% (
)
B
)
OMe
17d(SR); R = Bn
R = 10b(R) epimer
17e(SR); R = 2-naphthyl
(S),42% (
OMe
OMe
OMe
Ph
OMe
AcO
HO
1. MeONa
MeOH
R
N
AcO
17e (SR)
N
PivO
2. Py, Piv-Cl
DMAP
O
18 (8%)
O
19e (S),74% (B)
OMe
OMe
OMe
OMe
OMe
OMe
R
R
N
HO
O
R
N
1. NaIO4
2. Na2CO3
N
N
R
NaHB(OAc)3
DCM
MeONa
MeOH
O
17b-d,19e
HO
N
H2O/MeCN
R
MeO
MeO
OMe
OMe
15b-e
10b-e
14b-e
Scheme 2. Current work: synthesis of a new C2-symmetrical hemiaminal ether 14b–d and diamines 15b–d.

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Z. Kałuza et al. / Tetrahedron: Asymmetry 24 (2013) 1435–1442
1438
Table 2
Asymmetric benzoylation of meso-diols catalyzed by CuCl2 complexes with diamines 15a–e and hemiaminal ethers 14a and 14ca
lig.-CuCl2 (3% mol)a)
BzCl, DIEPA
CH2Cl2, -78 oC
(R)
OH
OH
OBz
OH
(S)
meso-Diol
No
15a
15b
15c
15d
15e
14a
14c
Yieldb (%) eec (%) Yield (%) ee (%) Yield (%) ee (%) Yield (%) ee (%) Yield (%) ee (%) Yield (%) ee (%) Yield (%) ee (%)
OH
OH
20
21
22
63 60
78 48
78 72
—
—
25 53
66 41
77 66
—
—
47 56
84 56
65 74
62 60
78 48
69 86
68 44
82 31
79 82
OH
95 rac.
54 rac.
OH
OH
OH
—
—
9
—
—
3
Ph
Ph
OH
23
56 74
73
93 87
44
66 75
56 34
52 30
OH
a
b
c
Reaction condition: meso-diol (0.5 mmol), CuCl2ꢀLig. complex (0.015 mmol, 3 mol %), BzCl (1.2 mmol), DIEPA (1 mmol), CH2Cl2 (5,2 mL), ꢁ78 °C, 1–3 days.
Isolated yield.
Determined by chiral HPLC using a Chiralpack AS-H column.
When diol 21 was used, only racemic mixtures of monoesters
appeared logical to test them in the Henry reaction as well. The
results of a model reaction between benzaldehyde and nitrometh-
ane catalyzed by complexes of anhydrous copper(II) chloride with
the new ligands (10 mol % each) are listed in Table 3. All reactions
were performed at ꢁ20 °C with 10 mol % of triethylamine as a base.
The solvent of choice for the nitroaldol reaction is typically an alco-
hol such as methanol,2a ethanol,2b or iso-propanol,2f but sometimes
THF2e or a mixture of solvents was used.2d
Due to the limited alcohol solubility of the complexes generated
in dichloromethane, the test reactions were carried out either in
2-propanol/THF or in ethanol/nitromethane mixtures. Nitroaldol
reactions, conducted in the presence of copper complexes with
diamines 15a, 15c, and 15e, furnished the corresponding b-nitroal-
cohol in good chemical yield and with high enantioselectivity (ee
were isolated. These results indicated that the high stereo selectiv-
ity of this reaction is linked to the presence of a ligand with a bulky
aryl substituent at the bridged quaternary carbon atom.
Recently, Wolf et al. proposed new C2-symmetric bis-1,3-oxa-
zolidine ligands and their application in metal based asymmetric
catalysis.14 Since a 1,3-oxazolidine can be regarded as a cyclic
hemiaminal ether derived from an aldehyde or ketone, we antici-
pated that our new bis-hemiaminal ether 14 could also be applied
for the desymmetrization of meso-diols. We found that the com-
plexes of bis-hemiaminal ethers 14a,c with CuCl2 efficiently cata-
lyzed the benzoylation reaction and furnished the corresponding
monoesters in good yields.
The enantiomeric excess found for the products was either sim-
ilar to that obtained by applying analogous diamines (diols 20 and
21), or was substantially higher (for 22), or was much lower (for
23, cf. Table 1). We assume that these results can be attributed
to the differences in size of the ligand cavity in which the copper
cation is coordinated by two nitrogen atoms.
Table 3
Asymmetric Henry reaction catalyzed by the CuCl2 complexes with diamines 15a–e
and hemiaminal ether 14ca
In comparison to diamines, the cavity in the respective bis-
hemiaminal inner ether should be considerably narrower due to
the presence of an oxygen bridge (see Fig. 2). This may explain
the higher stereoselectivity observed for small diol 23, which
can more deeply penetrate into the chiral cavity compared to
the bulky diphenyl analogue 24. In all desymmetrization experi-
ments, the main enantiomer of the monoester had the same
configuration: (1R,2S) for the diols 21, 22, and 24 and (2R,3S)
for diol 23.
Lig.-CuCl2 (10% mol)
TEA (10% mol)
OH
*
NO2
PhCHO + MeNO2
Ph
(A)
i-PrOH/THF 2/1
or
EtOH/MeNO2 1/1 (B)
-20 oC
Ligand
Solventb
Time (days)
Yieldc (%)
eed (%)
Configuration
15a
15b
15c
15e
14c
A
B
A
A
B
3
5
4
3
4
72
28
66
73
45
82
62
81
85
22
(S)
(R)
(S)
(S)
(S)
2.3. Cu-catalyzed asymmetric Henry reactions using ligands of
type 14 and 15
a
Reaction condition: CuCl2ꢀLig. (complex generated in DCM, 0.05 mmol,
10 mol %), beznaldehyde (0.5 mmol), solvent A or B.
Chiral diamine–copper complexes are widely utilized in asym-
metric Henry reactions, a useful carbon–carbon bond forming
process.2 Since our C2-symmetric diamines were shown to be
promising ligands for the asymmetric acylation of meso-diols, it
b
2 mL, nitrometane (5 mmol, only when solvent A was used), TEA (0.05 mmol,
10 mol%), ꢁ20 °C. A: i-PrOH/THF 2:1, B: EtOH/MeNO2 1:1.
c
Isolated yield.
d
Determined by chiral HPLC using an OD-H Chiralpack column.

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Z. Kałuza et al. / Tetrahedron: Asymmetry 24 (2013) 1435–1442
1439
81–85%). The (S)-configured products were preferentially formed
in all cases. For ligand 15b with a methyl group instead of an aryl
at the stereogenic center, the reaction rate was considerably
slower and the reaction predominantly gave the (R)-enantiomer
with an enantiomeric excess of 62%. In contrast to diamines 15a–
c and 15e, the bis-hemiaminal ether 14c showed a relatively low
enantioselectivity (ee 22%) and a low reaction rate at the same
time.
6.63 (m, 2H), 5.96 (d, 1H, J = 6.9 Hz), 5.72 (d, 1H, J = 6.9 Hz), 3.92
(s, 3H), 3.88 (s, 3H), 3.82 (m, 1H), 3.46 (m, 1H), 2.79 (m, 1H), 2.50
(m, 1H), 2.26 (2s, 6H), 2.13 (s, 3H), 1.87 (s, 3H); 13C NMR (CDCl3,
125 MHz): 170.2, 169.9, 166.2, 148.6, 147.7, 138.3, 137.8, 131.4,
129.7, 126.7, 125.1, 111.6, 109.3, 78.3, 74.6, 67.8, 56.3, 55.9, 37.7,
26.2, 21.5, 20.7, 20.7; MS (ES, HR) m/z: (M+Na+), calcd for C26H29-
NO7Na: 490.1836. Found: 490.1855. Anal. Calcd for: C, 66.80; H,
6.25; N, 3.00; Found: C, 66.77; H, 6.52; N, 2.98.
4.2.2. (1S,2R,10bS)-10b-Benzyl-8,9-dimethoxy-3-oxo-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline-1,2-diyl diacetate 17d(S)
Imide 16 (0.879 g, 2.0 mmol) was used. Isolated from the crude
reaction mixture of 10b epimers via flash chromatography, (MTBE/
hexane, 7:3 v/v) yield: 0.382 g, 42%; colorless crystals; mp 188–
3. Conclusion
In conclusion, we have reported on the preparation of new
C2-symmetrical bis-hemiaminal ethers and diamine ligands,
starting from L-tartaric acid. The unique structure of the bis-
hemiaminal inner ether moiety was unambiguously documented
for the first time. The catalytic effectiveness of both types of
ligands was evaluated in the copper catalyzed asymmetric acyla-
tion of meso-diols (ee up to 87%) and Henry reactions (ee up to
85%). Further applications of these new ligands in asymmetric
catalysis are currently under investigation.
189 °C (AcOEt); ½a D23
ꢂ
= +111.5 (c 0.4, CH2Cl2); IR (CH2Cl2): 2939,
1753, 1715 cmꢁ1 1H NMR (CDCl3, 500 MHz): 7.25 (m, 3H), 7.07
;
(m, 2H), 6.72 (s, 1H), 6.55 (s, 1H), 5.44 (d, 1H, J = 8.4 Hz), 5.05 (d,
1H, J = 8.4 Hz), 4.29 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.33 (2d,
2H, J = 14.1 Hz), 2.85 (m, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 2.29 (s,
3H), 2.04 (s, 3H); 13C NMR (CDCl3, 125 MHz): 170.3, 169.5, 165.3,
148.7, 148.3, 135.0, 130.7, 129.8, 128.5, 127.5, 125.2, 111.8,
107.5, 80.2, 73.7, 62.9, 56.0, 55.9, 42.5, 35.2, 27.8, 21.0, 20.6; MS
(ES, HR) m/z: (M+Na+) calcd for C25H27NO7Na: 476.1680; Found:
476.1695. Anal. Calcd for C25H27NO7: C, 66.21; H, 6.00; N, 3.09;
Found: C, 66.23; H, 5.90; N, 3.15.
4. Experimental
4.1. General information
4.2.3. (1S,2R,10bR)-10b-Benzyl-8,9-dimethoxy-3-oxo-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline-1,2-diyl diacetate 17d(R)
Isolated from the crude reaction mixture of 10b epimers via
flash chromatography, (MTBE/hexane 7:3 v/v) yield: 66 mg, 7%.
NMR spectra were recorded in CDCl3 at room temperature
(except where indicated otherwise) using a Bruker AVANCE 500
or Varian VNMR500 spectrometer. Chemical shifts are quoted in
parts per million relative to TMS for 1H and CDCl3 for 13C NMR.
Coupling constants J are reported in Hertz (Hz). IR spectra were
obtained using a FTIR Jasco 6200 or FTIR Spectrum 2000 Perkin
Elmer and reported in reciprocal centimeters (cmꢁ1). Optical
rotations were measured at 23 °C with a JASCO P2000 digital
polarimeter. Mass spectra were recorded using an AMD-604
Colorless crystals; mp 128–131 °C (MeOH), ½a D23
ꢂ
¼ ꢁ47:6 (c 0.56,
CH2Cl2); IR (CH2Cl2): 2940, 1754, 1705 cmꢁ1
;
1H NMR (CDCl3,
500 MHz): 7.21 (m, 3H), 6.87 (m, 2H), 6.52 (s, 1H), 6.49 (s, 1H),
5.66 (s, 1H), 5.14 (s, 1H), 4.14 (m, 1H), 3.87 (s, 3H), 3.79 (s, 3H),
3.43 (d, 1H, J = 13.5 Hz), 3.20 (d, 1H, J = 13.5 Hz), 2.72 (m, 1H),
2.43 (m, 1H), 2.28 (m, 1H), 2.16 (s, 3H), 1.67 (s, 3H); 13C NMR
(CDCl3, 125 MHz): 169.4, 169.1, 167.1, 148.0, 147.2, 134.9, 130.5,
128.4, 127.3, 127.2, 125.1, 111.3, 109.6, 75.6, 74.6, 68.6, 55.9,
55.7, 47.1, 36.3, 28.2, 20.7, 20.5; MS (ES, HR) m/z: (M+Na+) calcd
for C25H27NO7Na: 476.1680; Found: 476.1703. Anal. Calcd for
C25H27NO7: C, 66.21; H, 6.00; N, 3.09; Found: C, 65.34; H, 5.92;
N, 3.07.
Intectra GmbH or
a Mariner Perseptive Biosystem mass
spectrometer. X-ray analysis was performed on Bruker AXSAPEX
diffractometer. Thin-layer chromatography was carried out on
precoated silica gel (Merck Kieselgel 60 F254, 0.2 mm layer
thickness). Visualization of the developed chromatogram was per-
formed by UV absorbance and cerium molybdate water solution.
Flash column chromatography was performed using Merck
Kieselgel (230–400 mesh). All air and moisture sensitive reactions
were carried out under an argon atmosphere in flame-dried glass-
ware using anhydrous solvents. Most reagents were obtained from
commercial suppliers and were used without further purification,
unless noted. THF was distilled from Na and benzophenone,
dichloromethane and toluene were distilled from CaH2.
4.2.4. (1S,2R)-8,9-Dimethoxy-3-oxo-11-phenyl-2,3,5,6,11,11a-
hexahydro-1H-benzo[d]pyrrolo[1,2-a]azepine-1,2-diyl diacetate 18
Isolated from the crude reaction mixture via flash chromatogra-
phy, (MTBE/hexane 7:3 v/v) yield: 75 mg, 8% oil; 1H NMR (CDCl3,
500 MHz): 7.28 (m, 2H), 7.20 (m, 1H), 7.09 (m, 2H), 6.84–6.88
(m, 2H), 6.21 (dd, 1H, J = 4.4, 2.1 Hz), 5.99 (d, 1H, J = 2.1 Hz); 5.35
(d, 1H, J = 4.4 Hz), 3.89–3.85 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H),
2.94 (m, 3H), 2.16 (s, 3H), 1,61 (s, 3H); 13C NMR (CDCl3,
125 MHz): 169.8, 169.7, 167.4, 149.1, 148.0, 135.6, 134.5, 130.4,
128.3, 128.0, 126.7, 120.8, 112.2, 111.5, 106.7, 74.4, 71.5, 55.9,
55.9, 42.3, 32.2, 20.5, 20.0; MS (ES, HR) m/z: (M+Na+) calcd for
4.2. Preparation of the 10b-substituted hexahydro-pyrrolo[2,1-
a]isoquinolines 17a–e
Compounds 17a(S) and 17b(S) were synthesized as previously
reported.8b The same procedure8b was applied for the preparation
of 17c–e. The overall chemical yield from imide 16 is given below
for each product separately.
C25H27NO7Na: 476.1680; Found: 476.1683.
4.2.5. 10b-Epimeric mixture of (1S,2R)-8,9-dimethoxy-10b-
(naphthalen-2-yl)-3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]-
isoquinoline-1,2-diyl diacetate 17e(S) and 17(R)
4.2.1. (1S,2R,10bS)-10b-(3,5-Dimethylphenyl)-8,9-dimethoxy-3-
oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-1,2-diyl
diacetate 17c(S)
Imide 16 (4.84 g, 11.0 mmol) was used. Flash chromatography,
(AcOEt/hexane 4:6 v/v). Yield 4.85 g, 90%. Selected data were taken
from the chromatographically inseparable mixture of C-10b
epimers 17e(S):17e(R) = 16:1.
Imide 16 (9.10 g, 26.4 mmol) was used. Isolated from the crude
reaction mixture of 10b epimers via crystallization from
EtOH; yield: 7.54 g, 78%; colorless crystals; mp 213–215 °C;
17e(S): 1H NMR (CDCl3, 500 MHz): 7.73–7.83 (m, 3H), 7.49 (m,
3H), 7.17–7.19 (m, 2H), 6.65 (s, 1H), 6.07 (d, 1H, J = 6.8 Hz), 5.80
(d, 1H, J = 6.8 Hz), 3.93 (s, 3H), 3.88 (s, 3H), 3.82–3.89 (m, 1H),
½
a 2D3
ꢂ
¼ ꢁ70:7 (c 1.0, CH2Cl2); IR (CH2Cl2): 2940, 1752, 1711 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): 7.13 (s, 1H), 6.91 (m, 1H), 6.64 (s, 1H),

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Z. Kałuza et al. / Tetrahedron: Asymmetry 24 (2013) 1435–1442
1440
3.47 (m, 1H), 2.81 (m, 1H), 2.47 (m, 1H), 2.13 (s, 3H), 1.79 (s, 3H);
13C NMR (CDCl3, 125 MHz): 170.2, 169.9, 166.2, 148.7, 136.0,
132.7, 130.9, 128.3, 128.0, 127.4, 126.7, 126.7, 126.6, 126.5,
125.2, 111.6, 109.1, 78.5, 74.7, 67.9, 56.2, 55.9, 37.7, 26.2, 20.7,
20.7.
14c, and 14e were purified on silica gel and/or by crystallization.
Due to the rapid decomposition on silica gel, compounds 14b
and 14d were used in the following step without any purification.
The overall chemical yield from 17a–d or 19e is given.
17e(R): 1H NMR (CDCl3, 500 MHz): 6.11 (t, J = 2.8 Hz, 1H), 4.24
(m, 1H), 3.02 (m, 1H), 2.65 (m, 1H), 2.02 (s, 3H), 1.93 (s, 3H).
4.3.1. (8R,8aS,16R,16aS)-2,3,10,11-Tetramethoxy-8a,16a-di-
phenyl-5,6,8,8a,13,14,16,16a-octahydro-8,16-epoxypyrazino
[2,1-a:5,4-a0]diisoquinoline 14a
4.2.6. Preparation of 10b(S) and 10b(R) epimers (1S,2R)-1-hyd-
roxy-8,9-dimethoxy-10b-(naphthalen-2-yl)-3-oxo-1,2,3,5,6,
10b-hexahydropyrrolo[2,1-a]isoquinolin-2-yl pivalate 19e(S)
and 19e(R)
Acetate 17a (2.15 g, 5.0 mmol) was used. Isolated via flash chro-
matography (CH2Cl2/hexane/AcOEt 65:20:15 v/v). Yield: 0.705 g,
49%; colorless crystals; mp 264–266 °C (AcOEt); ½a D23
¼ þ193:9 (c
ꢂ
1.2, CH2Cl2); IR (CH2Cl2): 2937, 1610 cmꢁ1
;
1H NMR (CDCl3,
A mixture of 17e(S) and 17e(R) (16:1, respectively) (4.03 g,
8.24 mmol), was deacetylated applying our procedure.8b The crude
diols obtained were dissolved in pyridine (40 mL), after which
DMAP (100 mg, 0.824 mmol) was added and the solution was
cooled to 0 °C. To the intensively stirred resulting solution, pivav-
olyl chloride (2.02 mL, 16.47 mmol) was added dropwise. The mix-
ture was stirred at this temperature for 15 min. then temperature
was brought to room temperature and stirring was continued until
the disappearance of substrate ꢃ1.5 h (TLC control). The mixture
was poured into water (80 mL) and extracted with CH2Cl2
(3 ꢄ 150 mL). The collected extracts were washed with 0.5 M
HCl/water (3 ꢄ 100 mL) and brine, then dried over MgSO4, and
evaporated under reduced pressure. The residue was purified by
flash column chromatography (AcOEt/hexane 4:6 v/v) to give
enantiomerically pure derivatives 19e(S) and 19e(R).
500 MHz): 2.46 (m, 2H), 2.88 (m, 2H), 3.36 (m, 4H), 3.78 (s, 12H),
5.39 (s, 2H), 6.51(s, 2H), 6.93 (s, 2H), 7.03 (m, 10H); 13C NMR:
27.5, 49.0, 55.7, 56.2, 73.9, 104.0, 109.9, 111.4, 125.1, 126.7,
127.8, 130.1, 131.1, 144.7, 147.3, 147.4; MS (ES, HR) m/z: (M+H+)
calcd for C36H37N2O5: 577.2697. Found: 577.2719; Anal. Calcd for
C36H36N2O5: C, 74.98; H, 6.29; N, 4.86. Found: C, 75.02; H, 6.34;
N, 4.69.
4.3.2. (8R,8aS,16R,16aS)-8a,16a-Bis(3,5-dimethylphenyl)-2,3,10,
11-tetramethoxy-5,6,8,8a,13,14,16,16a-octahydro-8,16-epox-
ypyrazino[2,1-a:5,4-a0]diisoquinoline 14c
Acetate 17c (2.33 g, 5.0 mmol) was used. Isolated via flash chro-
matography (AcOEt/hexane, 4:6 v/v). Yield: 0.745 g, 47%; semi-
solid; ½a 2D3
ꢂ
¼ þ113:1 (c 1.0, CH2Cl2); IR (CH2Cl2): 3687, 2996,
2938, 1607, 1512 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): 7.01 (s, 2H),
19e(S): Yield: 3,142 g, 78%; colorless crystals; mp 116–118 °C
6.68 (m, 6H), 6.50 (s, 2H), 3,81 (s, 6H), 3,78 (s, 6H), 3.38 (m, 2H),
3.26 (m, 2H), 2.82 (m, 2H), 2.44 (m, 2H), 2.14 (s, 12H). 13C NMR
(CDCl3, 125 MHz): 147.3, 147.3, 144.6, 135.6, 131.5, 130.2, 127.0,
126.0, 111.4, 109.9, 103.7, 73.9, 56.2, 55.8, 49.1, 27.6, 21.4; MS
(ES, HR) m/z: (M+H+) calcd for C40H45N2O5: 633.3323. Found:
633.3333.
(AcOEt/hexane); ½a D23
¼ ꢁ130:4 (c 1.0, CH2Cl2); IR (CH2Cl2): 2937,
ꢂ
1737, 1709 cmꢁ1 1H NMR (CDCl3, 400 MHz): 7.80 (m, 3H), 7.60
;
(m, 1H), 7.49 (m, 2H), 7.42 (s, 1H), 7.32 (m, 1H), 6.65 (s, 1H),
5.44 (d, 1H, J = 8.3 Hz) 4.72 (d, 1H, J = 8.3 Hz), 4.02 (s, 3H), 3.89
(s, 3H), 3.79 (m, 1H), 3.64 (m, 1H), 2.79 (m, 1H), 2.53 (m, 1H),
1.27 (s, 9H); 13C NMR (CDCl3, 100 MHz): 179.7, 166.5, 148.6,
147.9, 135.4, 132.8, 137.7, 132.1, 128.3, 128.2, 127.5, 126.7,
126.6, 126.4, 125.4, 111.2, 108.9, 80.3, 77.3, 67.3, 56.4, 55.9, 38.9,
37.9, 27.1, 26.2 ; MS (EI, HR) m/z: (M+) calcd for C29H31NO6:
489.2151; Found: 489.2164. Anal. Calcd for C29H31NO6: C, 71.15;
H, 6.38; N, 2.86; Found: C, 71.24; H, 6.53; N, 2.72.
4.3.3. (8R,8aS,16R,16aS)-2,3,10,11-tetramethoxy-8a,16a-di(naph-
thalen-2-yl)-5,6,8,8a,13,14,16,16a-octahydro-8,16-epoxypyraz-
ino[2,1-a:5,4-a0]diisoquinoline 14e
Pivaloate 19e (1.26 g, 2.59 mmol) was used. Isolated via flash
chromatography (CH2Cl2/hexane/AcOEt 2:2:1 v/v). Yield: 0.440 g,
19e(R): Yield: 78 mg, 2%; oil; IR (CH2Cl2): 2959, 2928, 2855,
50%; semisolid; ½a D23
ꢂ
¼ þ46:2 (c 1.0, CH2Cl2); IR (CH2Cl2): 3684,
1737, 1706 cmꢁ1 1H NMR (CDCl3, 500 MHz): 7.80 (m, 2H), 7.73
;
2938, 1734, 1608, 1513 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): 7.63
(m, 1H), 7.63 (m, 1H), 7.48 (m, 3H), 6.67 (s, 1H), 5.13 (d, 1H,
J = 4.1 Hz), 4.72 (d, 1H, J = 4.1 Hz), 4.14 (m, 1H), 3.94 (s, 3H), 3.89
(s, 3H), 3.29 (m, 1H), 2.98 (m, 1H), 2.59 (m, 1H), 1.06 (s, 9H); MS
(EI, HR) m/z: (M+) calcd for C29H31NO6: 489.2151; Found:
489.2136.
(m, 2H), 7.47 (m, 2H), 7.30–7.25 (m, 4H), 7.21 (m, 2H), 7.09–
7.06 (m, 4H), 6.89 (m, 2H), 6.52 (s, 2H), 5.59 (s, 2H), 3.80
(s, 6H), 3.77 (s, 6H), 3.50 (m, 2H), 3.36 (m, 2H), 2.87 (m, 2H),
2.50 (m, 2H); 13C NMR (CDCl3, 125 MHz): 147.5, 147.5, 141.9,
132.8, 131.5, 131.0, 130.3, 127.8, 126.8, 126.7, 126.3, 125.8,
125.0, 124.9, 111.5, 109.9, 103.8, 74.2, 56.3, 55.8, 49.4, 27.7; MS
(ES, HR) m/z: (M+Na+) calcd for C44H40N2O5Na: 699.2829. Found:
699.2827.
4.3. Preparation of the bicyclic bis-hemiaminal inner ethers 14a–e
1,2-Dihydroxy-hexahydro-pyrrolo-isoquinolines 10a–e were
obtained from the corresponding enantiomerically pure diacetates
17a–d and mono-pivaloylate 19e applying our procedure8b and
used in the following step without further purification. Crude diols
10a–e were subjected to glycolic cleavage with sodium periodate
using our procedure.8c Compounds 14a–e were synthesized apply-
ing our modified procedure.8c
General procedure: A crude diastereomeric mixture of hemiace-
tals 11 (obtained in two steps from 5 mmol of respective acetate
17) was dissolved in acetonitrile (55 mL) and sodium carbonate
(22 mmol, 55 mL of 0.4 M Na2CO3/H2O) was added in one portion.
The mixture was stirred gently at room temperature until the
starting material was completely consumed, as judged by TLC
analysis (5–7 days). The solution was concentrated to half of its
initial volume (approx.), and then extracted with ethyl acetate
(3 ꢄ 50 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated in vacuo. The crude products 14a,
4.4. Preparation of diamines 15a–e
General procedure: A mixture of DCM (15 mL) and acetic acid
(7 mL) was cooled to 0 °C, and during intensive stirring NaBH4
(8.7 mmol, 328 mg) was added portionwise (ꢃ10 min). Into the
resulting solution, hemiaminal ether 14 (1.25 mmol) dissolved in
DCM (10 mL) was added dropwise. The reaction mixture was
allowed to warm to rt, and stirring was continued until the
disappearance of the substrate (ꢃ30 min, TLC control). The solu-
tion was cooled to ꢃꢁ5 °C, and during intensive stirring, NaOH
(aq) (15 mL 30%) was carefully added. The resulting mixture was
extracted with DCM (3 ꢄ 30 mL). The collected extracts were
washed with water (2 ꢄ 30 mL) and brine, then dried over MgSO4,
and evaporated under reduced pressure. The residue was purified
by flash column chromatography.

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Z. Kałuza et al. / Tetrahedron: Asymmetry 24 (2013) 1435–1442
1441
4.4.1. (8aS,16aS)-2,3,10,11-Tetramethoxy-8a,16a-diphenyl-5,6,8,
8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a0]diisoquinoline
15a
115.5, 114.6, 63.1, 57.0, 56.2, 55.4, 47.5, 25.8; MS (ES, HR) m/z:
(M+H+) calcd for C44H43N2O4: 663.3217; Found: 663.3190.
Compound 14a (0.722 g, 1.25 mmol) was used (MTBE/hexane/
4.5. General procedure for the asymmetric acylation of meso-1,
2-diols catalyzed by CuCl2 complexes with ligands 14 and 15
NH3/aq 50:50:0.5 v/v/v). Yield: 0.654 g, 93%; semisolid; ½a D23
ꢂ
¼ þ107:3
(c 0.55, CH2Cl2); IR (CH2Cl2): 3002, 2937, 2850, 1608, 1513 cmꢁ1
;
1H NMR (toluene-d8, 80 °C, 500 MHz): 7.67 (m, 4H), 7.18 (m, 4H),
7.06 (m, 2H), 6.77 (s, 2H), 6.42 (s, 2H), 3.55 (s, 6H), 3.52 (s, 6H),
3.46 and 3.40 (2d, 4H, J = 13.4 Hz), 3.07 (m, 2H), 2.80 (m, 2H), 2.67
(m, 2H), 2.46 (m, 2H); 13C NMR (toluene-d8, 80 °C, 125 MHz):
149.9, 149.0, 148.1, 132.8, 129.3, 128.1, 126.8, 115.5, 114.6, 63.0,
57.0, 56.2, 55.7, 47.4, 27.0; MS (EI, HR) m/z: (M+) calcd for
The asymmetric benzoylation of meso-diols was carried out by
following the reported procedure.3c
Ligand 14 or 15 (0.016 mmol) and CuCl2 (2.0 mg, 0.015 mmol)
were stirred in DCM (2.4 mL) until complete dissolution of copper
salt (4–24 h). A green solution of the generated complex was added
to a solution of meso-1,2-diol (0.5 mmol) in DCM (4.0 mL) and the
mixture was cooled to ꢁ78 °C. Next, diisopropylethylamine
C36H38N2O4: 562.2832; Found: 562.2845.
(170 lL, 1.0 mmol) and benzoyl chloride (0.26 mL, 2.4 mmol) were
added. The reaction mixture was stirred until the 1,2-diol was con-
sumed (TLC control), after which the mixture was quenched by the
addition of 0.1 M aqueous citric acid. The resulting mixture was
extracted with ethyl acetate (3 ꢄ 10 mL). The combined organic
layers were washed sequentially with 0.1 M aqueous citric acid,
water, and brine, dried over anhydrous MgSO4, and the solvent
was removed in vacuo. The crude product was purified by silica
gel flash chromatography (n-hexane/ethyl acetate 9:1–7:3) to give
the desired monobenzoate.
The analytical and spectroscopic data of the obtained monoben-
zoate were found to be in agreement with the reported data.3c The
enantiomeric excess was determined by HPLC methods using
DAICEL Chiralpack AS-H column, as described by Nakamura.3c
The absolute configuration of compounds 5 was assigned by
comparison of the retention times in HPLC with the literature
data.3c
4.4.2. (8aS,16aS)-2,3,10,11-Tetramethoxy-8a,16a-dimethyl-5,6,8,
8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a0]diisoquinoline
15b
(MTBE/MeOH/NH3/aq 95:5:0.2 v/v/v). Yield: 0.169 g, 29%; semi-
solid; ½a 2D3
ꢂ
¼ þ206:2 (c 1.0, CH2Cl2); IR (CH2Cl2): 2962, 2937, 2834,
1610, 1511 cmꢁ1
;
1H NMR (toluene-d8, 90 °C, 500 MHz): 6.72 (s,
2H), 6.35 (s, 2H), 3.63 (s, 6H), 3.49 (s, 6H), 3.25 (m, 2H), 3.01–
2.90 (2d, 4H, J = 11.6 Hz), 2.78 (m, 2H), 2.68 (m, 2H), 2.27 (m,
2H), 1.47(s, 6H); 13C NMR (toluene-d8, 90 °C, 125 MHz): 149.5,
149.4, 135.4, 127.6, 114.8, 112.4, 58.6, 57.2, 57.0, 56.3, 46.5, 26.5,
24,0; MS (ES, HR) m/z: (M+H+) calcd for C26H35N2O4: 439.2591;
Found: 439.2599.
4.4.3. (8aS,16aS)-8a,16a-Bis(3,5-dimethylphenyl)-2,3,10,11-tetra-
methoxy-5,6,8,8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a0]
diisoquinoline 15c
Compound 14c(S) (0.506 g, 0.8 mmol) was used (MTBE/hexane/
4.6. General procedure for the asymmetric Henry reaction cata-
lyzed by CuCl2 complexes with ligands 14 and 15
NH3/aq 40:60:0.5 v/v/v). Yield: 426, 86%; semisolid; ½a D23
¼ þ83:8 (c
ꢂ
0.5, CH2Cl2); IR (CH2Cl2): 2928, 1514 cmꢁ1 1H NMR (toluene-d8,
;
80 °C, 500 MHz): 7.39 (s, 4H), 6.82 (s, 2H), 6.76 (m, 2H), 6.40 (s,
2H), 3.55 (s, 6H), 3.48 (s, 6H), 3.45–3.38 (2d, 4H, J = 13.3 Hz),
3.12 (m, 2H), 2.78 (m, 2H), 2.68 (m, 2H), 2.45 (m, 2H), 2.22 (s,
12H); 13C NMR (toluene-d8, 80 °C, 125 MHz): 149.8, 148.9, 148.0,
137.5, 137.9, 137.0, 133.2, 128.4, 128.2, 127.6, 115.5, 114.5, 62.9,
57.0, 56.2, 56.0, 47.2, 27.0, 21.7; MS (ES, HR) m/z: (M+H+) calcd
for C40H47N2O4: 619.3530; Found: 619.3523.
A complex of CuCl2 (6.7 mg, 0.05 mmol) with ligand 14 or 15
(0.05 mmol) was generated as described above. The obtained clear
green solution was evaporated in vacuo, the residue was dissolved
in 2 mL of an appropriate solvent A or B (A: i-PrOH/THF 2:1, B:
EtOH/MeNO2 1:1) cooled to ꢁ20 °C, and nitromethane was added
(271
amine (0.05 mmol, 50
(0.5 mmol, 51 L) were added. The reaction mixture was stirred
lL, 5 mmol, only when solvent A was used). Next triethyl-
lL of 1 M TEA/i-PrOH) and benzaldehyde
l
4.4.4. (8aS,16aS)-8a,16a-Dibenzyl-2,3,10,11-tetramethoxy-5,6,8,
8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a0]diisoquinoline
15d
until the benzaldehyde was consumed (TLC control), then the mix-
ture was quenched by the addition of 2 mL of saturated ammo-
nium chloride, stirred for 2 min, poured into water (5 mL) and
extracted with DCM (3 ꢄ 10 mL). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, and the
solvent was removed in vacuo. Flash chromatography purification
(n-hexane/ethyl acetate, 9:1) gave the known b-nitroalcohol.2a
The enantiomeric excess was determined by HPLC methods
Compound 17d(S) (0.315 g, 0.695 mmol) was used (AcOEt/
hexane 30:70 v/v). Yield: 35 mg; 17%; viscous oil; ½a D23
¼ þ134:4
ꢂ
(c 0.735, CH2Cl2); IR (CH2Cl2): 2934, 1513 cmꢁ1 1H NMR (tolu-
;
ene-d8, 80 °C, 500 MHz): 7.11–7.02 (m, 10H), 6.34 (s, 2H), 6.18 (s,
2H), 3.46 (s, 6H), 3.42 (d, 2H, J = 13.0 Hz), 3.42 (s, 6H), 3.32 (m,
2H), 3.14 (d, 2H, J = 11.8 Hz), 3.01 (d, 2H, J = 13.0 Hz), 2.95 (d, 2H,
J = 11.8 Hz), 2.70 (m, 4H), 2.26 (m, 2H); MS (ES, HR) m/z: (M+H+)
calcd for C38H43N2O4: 591.3217; Found: 591.3224.
using
a DAICEL Chiralpack OD-H column as described by
Maheswaran.2a The absolute configuration of the major enantio-
mer was assigned by comparison with the literature-known
retention times on chiral HPLC.2a
4.4.5. (8aS,16aS)-2,3,10,11-Tetramethoxy-8a,16a-di(naphthalen-
2-yl)-5,6,8,8a,13,14,16,16a-octahydro-pyrazino[2,1-a:5,4-a0]diiso-
quinoline 15e
Acknowledgement
Compound 14e(S) (0.335 g, 0.495 mmol) was used (MTBE/
hexane/NH3/aq 50:50:0.5 v/v/v). Yield: 0.279 g; 90%; semisolid,
The authors are grateful to the National Science Centre (Grant
NN204 271538) for financial support.
½
a 2D3
ꢂ
¼ þ76:9 (c 1.0, CH2Cl2); IR (CH2Cl2): 3688, 2937, 1609,
1513 cmꢁ1 1H NMR (toluene-d8, 60 °C, 500 MHz): 8.12 (s, 2H),
;
References
7.78 (m, 2H), 7.63 (m, 2H), 7.55 (m, 2H), 7.52 (m, 2H), 7.20 (m,
4H), 6.83 (s, 2H), 6.45 (s, 2H), 3.53 (m, 4H), 3.52 (s, 6H), 3.51 (s,
6H), 3.11 (m, 2H), 2.88 (m, 2H), 2.70 (m, 2H), 2.51 (m, 2H); 13C
NMR (toluene-d8, 60 °C, 125 MHz): 150.0, 149.1, 145.6, 134.0,
133.4, 132.6, 128.7, 128.6, 127.9, 127.8, 127.5, 125.9, 125.9,
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