An Acid/Base-Regulated Recyclable Strategy for Homogeneous Cinchona Alkaloid-Derived Primary Amine Organocatalysts in Aldol, Vinylogous Michael and Double-Michael Cascade Reactions

Article abstract of DOI:10.1002/ejoc.201500566

A practical, recyclable strategy for homogeneous cinchona alkaloid-derived primary amine organocatalysts was developed by controlling the solubilities in an aqueous/organic biphasic system through regulating the pH of the aqueous phase, effecting the prot

Full text of DOI:10.1002/ejoc.201500566

FULL PAPER
DOI: 10.1002/ejoc.201500566
An Acid/Base-Regulated Recyclable Strategy for Homogeneous Cinchona
Alkaloid-Derived Primary Amine Organocatalysts in Aldol, Vinylogous
Michael and Double-Michael Cascade Reactions
Jingwei Wan,[a] Zhiwei Zhao,[a] Falu Wang,[a] and Xuebing Ma*[a]
Keywords: Organocatalysis / Catalyst recycling / Aldol reactions / Cascade reactions / Michael addition
A practical, recyclable strategy for homogeneous cinchona
alkaloid-derived primary amine organocatalysts was devel-
oped by controlling the solubilities in an aqueous/organic bi-
phasic system through regulating the pH of the aqueous
phase, effecting the protonation and deprotonation of pri-
mary amino, tertiary amino and pyridyl groups. By means of
model aldol, vinylogous Michael and double-Michael cas-
cade reactions, the reusability of the organocatalysts epi-
CDNH2, DeMe-QNNH2 and H-CDNH2 over three cycles was
investigated in detail. It was found that the organocatalysts
were highly effective with respect to catalytic performance,
including the yields and stereoselectivities. Furthermore, the
recovered organocatalysts in the tenth cycle retained similar
excellent enantioselectivities to fresh organocatalysts. How-
ever, the formation of inactive intermediates between or-
ganocatalyst and reactants resulted in decreased yields.
Introduction
catalysts were seen as the most valuable alternative, where
a reaction can be run under homogeneous conditions while
the organocatalyst itself can be precipitated and easily re-
covered by filtration.[9] Recently, the homogenization of in-
organic material-supported catalysts was also realized in
asymmetric catalysis.[10] Even though better catalytic prop-
erties were obtained for a few examples due to the contri-
bution of the site-isolation and steric confinement effects,
most of them suffered from lowered catalytic activity and
enantioselectivity due to the restrictions of supporting ma-
trix.
Natural cinchona alkaloid-derived primary amines have
proved to be among the most powerful asymmetric organo-
catalysts capable of efficiently promoting a variety of asym-
metric organocatalytic reactions,[1] including iminium catal-
ysis,[2] enamine catalysis,[3] dienamine catalysis[4] and cas-
cade reactions.[5] From the perspective of green chemistry,
the potential application of homogeneous organocatalysts
in the chemical industry is rather limited due to their high
cost and difficult isolation from reaction mixtures. One ef-
ficient strategy to overcome this problem is heterogeniz-
ation by entrapment or grafting of organocatalysts on the
surfaces or inside the pores of solid supports, including or-
ganic polymers,[6] inorganic materials[7] and magnetic nano-
particles.[8] However, in heterogeneous catalysis, diffusion of
molecules is the sum of two contributions: the diffusion of
molecules in the solvent and diffusion of molecules inside
the pore of the supporting matrix, which generally results
in decreased catalytic performance. At this point, homogen-
eous catalysis theoretically has an advantage over hetero-
geneous catalysis. To combine the advantages of both
homogeneous and heterogeneous catalysis, one-phase catal-
ysis and two-phase separation of supported catalysts pro-
vides an ideal strategy to achieve homogeneous-like hetero-
geneous catalysis, avoiding the mass transfer limitations.
Among them, soluble organic polymer-supported organo-
In this paper, based on the concept of one-phase catalysis
and two-phase separation, we provide a practical solution
to the easy recovery and recycling of free homogeneous cin-
chona alkaloid-derived primary amine organocatalysts
[a] Key Laboratory of Applied Chemistry of Chongqing
Municipality, College of Chemistry and Chemical Engineering,
Southwest University
Chongqing 400715, P. R. China
E-mail: zcj123@swu.edu.cn
http://www.swu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500566.
Figure 1. A depiction of one-phase catalysis and two-phase separa-
tion and recycling of free primary amine organocatalyst.
Eur. J. Org. Chem. 2015, 5755–5763
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J. Wan, Z. Zhao, F. Wang, X. Ma
FULL PAPER
(Figure 1). Due to the protonation of primary and tertiary
amines and pyridyl groups in acidic medium, cinchona al-
kaloid-derived primary amine organocatalysts had a high
partition coefficient in an aqueous/organic biphasic system,
which could facilitate organocatalyst recovery from reaction
mixtures by liquid/liquid separation. This recoverable strat-
egy without structural modification of the organocatalyst
efficiently avoided the restrictions of supporting matrix and
possessed the merits of both homogeneous and hetero-
geneous catalysis. Furthermore, the reusability and struc-
tural changes of the organocatalysts were evaluated by three
model asymmetric reactions including aldol, vinylogous
Michael and double-Michael cascade reactions.
Results and Discussion
Acid/Base-Regulated Recyclable Strategy
Due to the protonation of primary amino, tertiary amino
and pyridyl groups, cinchona alkaloid-derived organocata-
lysts epi-CDNH2, DeMe-QNNH2 and H-CDNH2 easily af-
ford their corresponding ammonium salts in acidic me-
dium.[11] Generally, it is well known that the protonated
ammonium salts possess better water solubilities than the
original unprotonated structures. The concentrations of or-
ganocatalysts epi-CDNH2, DeMe-QNNH2 and H-CDNH2
in aqueous/organic biphasic systems can be expressed by
the distribution coefficient (D). Most importantly, the dis-
tribution coefficient of homogeneous organocatalysts in
aqueous/organic biphasic systems is a crucial parameter in
achieving the concept of one-phase homogeneous catalysis
and two-phase separation, where the high D values in aque-
ous and organic phases favor two-phase separation and
one-phase catalysis, respectively.
Figure 2. The UV spectra and distribution coefficients of epi-
CDNH2 in the aqueous phase: a) water/cyclohexanone system at
different pH values; b) water/various solvents at pH = 0.
The distribution coefficients of epi-CDNH2 in an aque-
ous/organic biphasic system could be accurately determined
by ultraviolet spectroscopy at λ = 320 nm. In the aqueous/
cyclohexanone (CYC) system, the effect of pH on the D
values of epi-CDNH2 is shown in Figure 2 (a). It was found
that the distribution coefficients were similar (D = 0.15–
0.33) in the pH = 1–4 range. However, there was a sharp
increase in D value at pH = 0, due to the full protonation
of primary and tertiary amines and pyridyl groups. Theore-
tically, a value of D = 5.3 at pH = 0 in water/cyclohexanone
implied that 99.6% of epi-CDNH2 could be recovered after
being extracted three times by isometric aqueous solution.
In place of cyclohexanone, trichloromethane (TCM),
dichloromethane (DCM), ethyl acetate (EA) and toluene,
also gave good D values (D = 4.0–4.9) in water at pH = 0,
as shown in Figure 2 (b). These high D values in aqueous
phase provided a powerful theoretical principle for the re-
covery of epi-CDNH2 from organic medium upon the com-
pletion of reaction.
Figure 3. Distribution coefficients in the aqueous phase of: a)
DeMe-QNNH2 at different pH, b) DeMe-QNNH2 in various sol-
vents at pH = 0, c) H-CDNH2 at different pH, and d) H-CDNH2
in various solvents at pH = 0.
The distribution coefficients of DeMe-QNNH2 in an
aqueous/trichloromethane (TCM) system at different pH
values and an aqueous/organic system at pH = 0 were also increased distribution coefficients (D = 0.68Ǟ2.02) in aque-
determined quantitatively by ultraviolet spectroscopy at ous solution with a pH decrease from 4 to 1. At pH = 0,
252 nm. As in Figure 3 (a and b), DeMe-QNNH2 exhibited DeMe-QNNH2 had a high distribution coefficient (D =
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A Recyclable Strategy for Cinchona Alkaloid Derived Organocatalysts
3.27), which implied that 98.7% of DeMe-QNNH2 could be Asymmetric Aldol Reaction
theoretically recovered by three extractions using isometric
aqueous solution with pH = 0. Similar trends in the distri-
The asymmetric aldol reaction provided straightforward
bution coefficient of H-CDNH2 in aqueous solution were access to the optically active β-hydroxycarbonyl structural
also observed, and are shown in Figure 3 (c, d).
unit found in natural drugs.[12] From the standpoint of a
Based on the fact that the distribution coefficients of or- green economy, a perfect asymmetric aldol reaction requires
ganocatalysts epi-CDNH2, DeMe-QNNH2 and H-CDNH2 a reusable organocatalyst, a green solvent and high stereo-
in aqueous or organic phase could be controlled by means selectivity under mild conditions. Based on the concept of
of regulating the pH of the aqueous phase, one-phase or- two-phase separation and one-phase catalysis, the model
ganocatalysis was carried out in the organic phase with pH asymmetric aldol reaction of cyclohexanone with benzalde-
Ͼ 1. After the completion of the reaction, over 98% of hyde derivatives in aqueous solution was used to evaluate
protonated epi-CDNH2, DeMe-QNNH2 and H-CDNH2 the reusability of homogeneous epi-CDNH2 according to
could be transferred into the aqueous phase by three extrac- the technology route shown in Figure 1.
tions using an isometric aqueous solution with pH = 0.
The catalytic performances of epi-CDNH2 in the first
Subsequently, the pH of the combined aqueous solutions and 3rd uses are listed in Table 1. It was found that the
was adjusted by adding aqueous ammonia to pH = 9–10, asymmetric aldol reaction of cyclohexanone with various
and deprotonation of the catalyst occurred. Therefore, free benzaldehyde derivatives catalyzed by epi-CDNH2 showed
epi-CDNH2, DeMe-QNNH2 and H-CDNH2 could be reco- higher yields, diastereoselectivities and enantioselectivities
vered by extraction using organic solvents such as toluene than the reported results,[13] and remained unchanged dur-
and reused directly without any treatment in the following ing the first three runs due to good recovery of epi-CDNH2.
catalytic cycle.
Based on the distribution coefficients (D = 0.15–0.33) of
Table 1. The asymmetric aldol reaction of cyclohexanone with various benzaldehydes in the first and 3rd uses.[a]
Entry
1
R
Time [h]
Yield [%][b]
dr (anti/syn)[c]
% ee anti[d]
2-NO2
24 (1st)
24 (3rd)
24 (1st)
24 (3rd)
8 (1st)
Ͼ99
Ͼ98
Ͼ99
97
Ͼ99
98
92
90
95
93
87
86
86
85
97
95
84
83
92
90
97
96
35
32
59
58
88:12
84:16
90:10
89:11
90:10
88:12
86:14
84:16
82:18
80:20
98:2
96:4
94:6
95:5
94:6
94:6
90:10
89:1
89:11
89:11
94:6
98
98
97
96
97
97
97
96
95
95
97
96
96
95
93
93
89
88
86
85
80
80
92
90
91
91
80
80
2
3-NO2
4-NO2
2-CN
3
16 (3rd)
24 (1st)
24 (3rd)
24 (1st)
24 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
48 (1st)
48 (3rd)
4
5
3-CN
6
2-Cl
7
3-Cl
8
4-Cl
9
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
10
11
12
13
14
95:5
96:4
94:6
84:16
86:14
88:12
87:13
60
57
[a] 20 °C, benzaldehyde (0.4 mmol), cyclohexanone (0.7 g, 7.1 mmol), 7.5 mol-% epi-CDNH2, water (1.0 mL), 15 mol-% TfOH (9.0 mg,
1
0.06 mmol). [b] Isolated yield. [c] Determined by H NMR spectroscopy. [d] Monitored by chiral HPLC with Daicel Chiralpak AD-H/
OD-H column.
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J. Wan, Z. Zhao, F. Wang, X. Ma
FULL PAPER
epi-CDNH2 in water/cyclohexanone in the pH = 1–3 range,
From Table 2, it was found that DeMe-QNNH2 exhib-
it was known that 75.2–87.0% of epi-CDNH2 existed in the ited good to excellent catalytic performances (68–96% yield
cyclohexanone phase during the aldol addition. Even so, and 86–99%ee) in the asymmetric vinylogous Michael ad-
epi-CDNH2 could be recovered in 95–98% yields from the dition of 3-methylcyclohex-2-enone to β-nitrostyrene deriv-
reaction mixture after being extracted three times with atives bearing electron-withdrawing and -donating groups
water at pH = 0 and subsequently with cyclohexanone at at the o-, m- or p-positions. Regardless of the electronic
pH = 9–10 due to the high distribution coefficients in aque- properties and o-, m- or p-positions, all the substituents at-
ous solution or organic phase, respectively, at different pH tached to β-nitrostyrene were well tolerated. It was note-
values. To further investigate the reusability of epi-CDNH2, worthy that β-nitrostyrene derivatives bearing strong elec-
the aldol reaction between cyclohexanone with 4-nitrobenz- tron-withdrawing substituents such as nitro groups at the
aldehyde was carried out under the same conditions over o-, m- or p-positions gave relatively low yields (68–80%).
repeated cycles. As shown in Figure 4, it was found that Compared with the reported results of β-nitrostyrene pos-
the high yields and excellent enantioselectivities of the aldol sessing 2-Cl, 4-CH3 and 4-OCH3 substituents, better iso-
adduct were almost constant after the sixth cycle. However, lated yields with the same enantioselectivities were ob-
the catalytic performance decreased gradually after the sev- served.[14]
enth cycle, especially the loss in diastereoselectivity from
Table 2. The asymmetric vinylogous Michael reaction of β-substi-
anti/syn = 9.0 to 2.0.
tuted cyclohexenone with β-nitrostyrene derivatives.[a]
[c]
Entry
1
R
H
Times
Yield [%][b] % ee (R)
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
88
87
68
68
78
76
80
78
87
85
90
90
93
92
85
85
90
88
92
91
90
89
93
92
96
95
98
98
92
92
95
1
2-NO2
3-NO2
4-NO2
2-Cl
2
95
3
Ͼ99
Ͼ99
98
98
97
97
99
99
Ͼ99
Ͼ99
86
86
98
98
99
99
97
4
Figure 4. The reusability of homogeneous epi-CDNH2 in the asym-
metric aldol reaction of cyclohexanone with 4-nitrobenzaldehyde.
5
3-Cl
6
4-Cl
Furthermore, a huge amount of cyclohexanone with re-
spect to aldehyde was crucial for epi-CDNH2 to achieve
excellent stereoselectivity. It was found that catalytic per-
formance declined with the decreased molar ratio of cyclo-
hexanone to 4-nitrobenzaldehyde. The good to excellent
catalytic performances (95–99% yield, 91–97% ee and
anti/syn = 4.9–9.0) were achieved in the molar ratio range
of 3–24. The optimum molar ratio of cyclohexanone to 4-
nitrobenzaldehyde was found to be 20. Unfortunately, un-
satisfactory catalytic performances (23% yield, 89% ee and
anti/syn = 4.6) were obtained at a 1:1 molar ratio of cyclo-
hexanone to 4-nitrobenzaldehyde. Therefore, excess cyclo-
hexanone played two pivotal roles: as the solvent and also
as an accelerating agent.
7
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
8
9
10
13
11
97
98
98
[a] 40 °C, 48 h, toluene (1.0 mL), 3-methylcyclohex-2-enone
(44.1 mg, 0.4 mmol), β-nitrostyrene (0.2 mmol), 2-F-PhCO2H
(20mol-%). [b] Isolated yield. [c] Monitored by chiral HPLC with
Daicel Chiralpak AD-H column.
After the completion of the vinylogous Michael addition,
97–98% of DeMe-QNNH2 could be recovered in each cata-
Vinylogous Michael Reaction
To date, vinylogous addition of a nucleophile is the most lytic run through extraction three times by isometric aque-
effective enantioselective carbon–carbon bond formation γ ous solution with pH = 0 and subsequent with toluene at
to a carbonyl group. Within this context, the recycled be- pH = 9–10. In the third cycle, DeMe-QNNH2 satisfactorily
havior of versatile DeMe-QNNH2 was investigated by retained its high catalytic performance, including the yields
means of a vinylogous Michael reaction of cyclohexenone and enantioselectivities for various β-nitrostyrene deriva-
with β-nitrostyrene as a model reaction.[14]
tives. Using a model vinylogous Michael addition of 3-
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A Recyclable Strategy for Cinchona Alkaloid Derived Organocatalysts
methylcyclohex-2-enone to β-nitrostyrene, the reusability of recovered in each recycle due to the high distribution coeffi-
DeMe-QNNH2 was further investigated, as shown in Fig- cients in the water/toluene system related to pH (Figure 3).
ure 5. The excellent enantioselectivities (98% ee) remained
Table 3. The catalytic asymmetric double-Michael cascade reaction
unchanged during the ten catalytic runs. However, the
yields gradually decreased to 70% at the tenth run.
of an α,β-unsaturated ketone with β-nitrostyrene derivatives.[a]
Entry
1
R
H
Yield [%] (run)[b] dr (trans/cis)[c] % ee trans[d]
84 (1st)
83 (3rd)
76 (1st)
75 (3rd)
81 (1st)
79 (3rd)
76 (1st)
76 (3rd)
80 (1st)
79 (3rd)
81 (1st)
82 (3rd)
82 (1st)
79 (3rd)
80 (1st)
80 (3rd)
86 (1st)
84 (3rd)
10.0
10.5
8.9
8.8
2.0
94
93
90
90
94
94
90
91
93
92
89
89
93
93
93
92
90
90
2
3
4
5
6
7
8
9
2-ClC6H4
3-ClC6H4
2.1
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-OCH3C6H4
3-OCH3C6H4
4-OCH3C6H4
14.3
14.0
4.2
4.2
7.7
Figure 5. The reusability of DeMe-QNNH2 in the vinylogous
Michael addition of 3-methylcyclohex-2-enone to β-nitrostyrene.
7.8
24.5
24.4
9.4
9.4
11.1
11.0
Double-Michael Cascade Reaction
Recently, chiral primary amine organocatalysts, particu-
larly cinchona alkaloid-derived primary amine organocata-
lysts, have offered a powerful alternative in the design of
novel and synthetically useful organocascade reactions,
which have provided highly efficient, operationally simple
and atom-economical approaches to one-pot construction
of complex chiral molecules useful for modern chemistry
and drug discovery.[15]
[a] 40 °C, 48 h, 20 mol-% H-CDNH2, 30 mol-% o-FC6H4CO2H,
toluene (1.0 mL), nitrostyrene (0.2 mmol), (E)-4-phenylbut-3-en-2-
one (58.5 mg, 0.4 mmol). [b] Isolated yield. [c] Isolated yield. [d]
Monitored by chiral HPLC with Daicel Chiralpak AD-H column.
Herein, the enamine–iminium activation of cinchona al-
kaloid-derived primary amines for a double-Michael se-
quence between an acyclic α,β-unsaturated ketone and β-
nitrostyrene derivatives to furnish complex cyclohexanones
with multiple stereocenters was selected as a model reac-
tion, and is listed in Table 3.[16] We were pleased to find
that the double Michael reaction catalyzed by H-CDNH2
(20 mol-%), in combination with 30 mol-% of 2-fluoro-
benzoic acid as a co-catalyst, showed moderate to high
stereocontrol (trans/cis = 4.2–24.5, 89–94% ee trans) with
preferential formation of the formal trans-products, except
that β-nitrostyrene bearing a m-Cl substituent gave low dia-
stereoselectivity (trans/cis = 2.0) owing to its weak steric
hindrance. Compared with the reported results of β-nitro-
Figure 6. The reusability of H-CDNH2 in the stereoselective
Michael/Michael cascade reaction of (E)-4-phenylbut-3-en-2-one
styrene possessing a 4-OCH3 substituent, better yield and with β-nitrostyrene.
diastereoselectivity were achieved.[16] Satisfactorily, in the
third cycled run, H-CDNH2 retained its original catalytic
performance, including the yield and stereoselectivity.
The Structural Change of Organocatalysts
Furthermore, the reusability of H-CDNH2 was investigated
in detail by means of a double-Mannich cascade reaction
In order to find out the reasons why the yields gradually
of (E)-4-phenylbut-3-en-2-one to β-nitrostyrene as a model decreased, we endeavored to isolate the byproducts by col-
example (Figure 6). In the tenth run, H-CDNH2 still re- umn chromatography after the completion of the tenth cy-
tained high stereoselectivity (trans/cis = 9.4, 91% ee, trans). clic reaction. Several isolated byproducts were monitored
However, the isolated yields in each run gradually decreased by HRMS. From Figure 7, HRMS indicated that several
from 84–60%, although 95–98% of H-CDNH2 could be inactive intermediates – adducts of the primary amine to
Eur. J. Org. Chem. 2015, 5755–5763
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Wan, Z. Zhao, F. Wang, X. Ma
FULL PAPER
Figure 7. The mass spectrum of the isolated intermediates.
the carbonyl compounds, A and B and thermodynamic ex-
In the reaction of β-nitrostyrene bearing an o-Cl substit-
tended dienamine, C and D – were found, respectively, in uent scaled up to 10 mmol according to the general pro-
the aldol and vinylogous Michael reactions. Due to the cedure for cyclic vinylogous Michael and double-Michael
irreversible consumption, the effective content of the organ- reactions, the organocatalysts DeMe-QNNH2 and H-
ocatalyst isolated from each run contained less organocata- CDNH2 showed good reusability. In the third cyclic vin-
lyst than we weighed. It was concluded that the formation ylogous Michael reaction, the recovered DeMe-QNNH2
of byproducts of organocatalysts epi-CDNH2 and DeMe- gave excellent ee (98%) in 86% yield. Similarly, excellent
QNNH2 was responsible for the declined yields of the de- catalytic performance of recovered H-CDNH2, with
sired products.
trans/cis = 8.7 and 90% ee (trans) in 73% yield was also
achieved in the third cyclic double-Michael cascade reac-
tion. Compared with the fresh organocatalysts, the reco-
vered DeMe-QNNH2 and H-CDNH2 afforded the same
stereoselectivity and slightly lower yields in the third cycle.
In conclusion, the acid/base-regulated recyclable strategy
provided a bright prospect for the homogeneous organocat-
alysts DeMe-QNNH2, H-CDNH2 and epi-CDNH2 to be
reused in the large-scale synthesis in industrial application.
The Practical Study
In order to demonstrate the practicality of this technique,
the reusability of organocatalysts epi-CDNH2, DeMe-
QNNH2 and H-CDNH2 was investigated on a large scale
(Ͼ10 mmol) in enantioselective aldol, vinylogous Michael
and double-Michael organocascade reactions, respectively.
In the large-scale enantioselective aldol reaction, we ob-
served decreased yield (99Ǟ92%) and improved stereoselec-
tivity (anti/syn = 88:12Ǟ95:5) compared with the aldol re-
action on Ͻ1 mmol scale. The recovered epi-CDNH2
Conclusions
Based on the catalytic concept of one-phase catalysis and
showed a small decrease in the yield (90%) with the same two-phase separation, we developed a practical acid/base-
stereoselectivity in the third cycle. However, consuming a regulated recyclable strategy for cinchona alkaloid-derived
huge amount of cyclohexanone was a limiting factor, al- primary amine organocatalysts by means of the protonation
though cyclohexanone could be recycled for further cyclic and deprotonation of primary amine, tertiary amine and
reactions by means of distillation.
pyridyl groups. In the asymmetric aldol, vinylogous
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A Recyclable Strategy for Cinchona Alkaloid Derived Organocatalysts
bined aqueous phases was adjusted by aqueous ammonia to pH =
9–10, extracted with toluene (5 mLϫ3) and concentrated under
reduced pressure to one-fifth of its original volume. The recovered
DeMe-QNNH2 was used directly for the following cyclic asymmet-
ric vinylogous Michael reaction. The data of new products are
shown as follows.
Michael and double-Michael cascade reactions, the reco-
vered organocatalysts retained excellent stereoselectivity as
compared to fresh organocatalysts. This acid/base-regulated
recyclable strategy provided a potential avenue for the ap-
plication of homogeneous cinchona alkaloid-derived pri-
mary amine organocatalysts in large-scale synthesis.
(R)-3-[3-Nitro-2-(2-nitrophenyl)propyl]cyclohex-2-enone: 41.4 mg,
68%, 92% ee, [α]D = –17.2 (c = 1.06, CHCl3). 1H NMR
3
3
(600.1 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 1 H), 7.63 (t, J =
Experimental Section
3
3
7.8 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1 H),
5.72 (s, 1 H), 4.74 (dd, J = 13.8, 7.8 Hz, 1 H), 4.64 (dd, J = 13.8,
6.6 Hz, 1 H), 4.43–4.48 (m, 1 H), 2.77 (dd, J = 13.8, 7.8 Hz, 1 H),
2.64 (dd, J = 13.8, 7.2 Hz, 1 H), 2.30–2.34 (m, 4 H), 1.93–2.02 (m,
2 H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 198.9, 159.8, 150.1,
133.4, 132.7, 129.0, 128.9, 128.1, 125.3, 78.5, 41.4, 37.1, 35.9, 29.0,
22.5 ppm. MS: m/z = 305.1 [M + H]+. C15H16N2O5 (304.30): calcd.
C 59.21, H 5.30, N 9.21; found C 59.18, H 5.34, N 9.12.
General Remarks: All chemicals were obtained from commercial
suppliers and used without further purification. The organocata-
[17]
lysts were prepared according to the literature procedures
All
reactions were monitored by thin-layer chromatography with Hai-
yang GF254 silica gel plates. Flash column chromatography was
carried out using 230–400 mesh silica gel under increased pressure.
The enantiomeric excess was determined with an Agilent LC-1200
HPLC using Daicel Chiralpak OD-H/AD-H 4.6 mmϫ25 cm col-
umns. 1H and 13C NMR spectra were recorded with Bruker av-300
and av-600 NMR instruments. Low-resolution mass spectrometry
(MS) was performed with a mass spectrometer (Bruker Daltonics,
USA, Bruker Co.) with an HCT ultra ion trap. C, H, N elemental
analysis was obtained using a FLASHEA1112 automatic elemental
analyzer instrument (Italy).
(R)-3-[3-Nitro-2-(3-nitrophenyl)propyl]cyclohex-2-enone: 47.4 mg,
78%, 95% ee, [α]D = –20.0 (c = 1.30, CHCl3). 1H NMR
3
(600.1 MHz, CDCl3): δ = 8.17 (s, 1 H), 8.10 (s, 1 H), 7.55 (d, J =
4.8 Hz, 2 H), 5.77 (s, 1 H), 4.61–4.68 (m, 2 H), 3.89–3.94 (m, 1 H),
2.71 (dd, J = 15.0, 6.6 Hz, 1 H), 2.65 (dd, J = 14.4, 9.0 Hz, 1 H),
2.23–2.35 (m,
4 H), 1.91–1.99 (m, 2
H) ppm. 13C NMR
(150.9 MHz, CDCl3): δ = 198.7, 159.5, 148.8, 140.3, 133.6, 130.3,
128.7, 123.4, 122.2, 79.3, 41.6, 41.2, 37.1, 29.5, 22.5 ppm. MS: m/z
= 305.1 [M + H]+. C15H16N2O5 (304.30): calcd. C 59.21, H 5.30,
N 9.21; found C 59.20, H 5.32, N 9.18.
General Procedure for Cyclic Aldol Addition: In a 25-mL vial, the
reaction mixture of epi-CDNH2 (8.2 mg, 2.8ϫ10–2 mmol), cyclo-
hexanone (0.7 g, 7.2 mmol), TfOH (8.4 mg, 5.6ϫ 10–2 mmol) and
water (1 mL) was stirred at 20 °C for 15 min, and then p-nitrobenz-
aldehyde (57.4 mg, 0.38 mmol) was added and allowed to react for
24 h (monitored by TLC). After the completion of the reaction, the
organic phase was extracted with hydrochloric acid solution (pH =
0, 2 mLϫ3). The organic phase was dried with anhydrous Na2SO4,
evaporated under reduced pressure and purified by flash column
chromatography eluting with petroleum ether/ethyl acetate (v/v =
8:1) to afford the pure aldol adduct. The combined aqueous phases
were adjusted by aqueous ammonia to pH = 9–10, extracted with
cyclohexanone (6 mLϫ3) and concentrated under reduced pres-
sure to one-fifth of the original volume to afford the recovered epi-
CDNH2 cyclohexanone solution, which was reused directly for the
following cyclic aldol addition.
(R)-3-[2-(3-Chlorophenyl)-3-nitropropyl]cyclohex-2-enone: 52.7 mg,
90%, 97% ee, [α]D = –16.1 (c = 0.82, CHCl3). 1H NMR
3
3
(600.1 MHz, CDCl3): δ = 7.28 (d, J = 3.0 Hz, 1 H), 7.27 (d, J =
3
6.0 Hz, 1 H), 7.18 (s, 1 H), 7.07 (t, J =2.4 Hz, 1 H), 5.78 (s, 1 H),
4.57 (d, 3J = 7.2 Hz, 2 H), 3.74 (m, 1 H), 2.64 (dd, J = 13.8, 6.0 Hz,
1 H), 2.58 (dd, J = 14.4, 9.0 Hz, 1 H), 2.29–2.31 (m, 2 H), 2.17–
2.26 (m, 2 H), 1.91–1.97 (m, 2 H) ppm. 13C NMR (150.9 MHz,
CDCl3): δ = 198.7, 160.0, 140.2, 135.2, 130.5, 128.6, 128.5, 127.5,
125.5, 79.7, 41.8, 41.4, 37.1, 29.6, 22.5 ppm. MS: m/z = 294.1 [M
+ H]+. C15H16ClNO3 (293.75): calcd. C 61.33, H 5.49, N 4.77;
found C 61.21, H 5.52, N 4.68.
(R)-3-[2-(4-Chlorophenyl)-3-nitropropyl]cyclohex-2-enone: 54.5 mg,
93%, 99% ee, [α]D = –25.0 (c = 1.32, CHCl3). 1H NMR
(600.1 MHz, CD3COCD3): δ = 7.42 (dd, J = 8.4, 1.8 Hz, 2 H), 7.36
(dd, J = 8.4, 1.8 Hz, 2 H), 5.69 (s, 1 H), 4.83–4.92 (m, 2 H), 3.84–
3.89 (m, 1 H), 2.76 (dd, J = 13.2, 6.0 Hz, 1 H), 2.68 (dd, J = 12.6,
9.0 Hz, 1 H), 2.27–2.40 (m, 2 H), 2.15–2.23 (m, 2 H), 1.85–1.92 (m,
2 H) ppm. 13C NMR (150.9 MHz, CD3COCD3): δ = 198.2, 161.8,
138.9, 133.3, 130.0, 129.2, 128.2, 80.0, 42.0, 41.5, 37.3, 29.8,
22.9 ppm. MS: m/z = 294.1 [M + H]+. C15H16ClNO3 (293.75):
calcd. C 61.33, H 5.49, N 4.77; found C 61.26, H 5.49, N 4.66.
Large-Scale Cyclic Aldol Reaction: Cyclohexanone (71.0 g), epi-
CDNH2 (0.825 g), TfOH (0.9 g) and water (45 mL) were stirred at
room temperature for 30 min. o-Nitrobenzaldehyde (5.6 g,
38 mmol) was added and allowed to stir for another 48 h. The reac-
tion mixture was washed by hydrochloric acid solution (30 mLϫ3,
pH = 0). The organic phase was dried with anhydrous Na2SO4 and
evaporated under reduced pressure to afford the crude product,
which was purified by flash column chromatography, eluting with
petroleum ether/ethyl acetate (v/v = 8:1) to give the pure aldol ad-
duct with 98% ee (anti) and anti/syn = 95:5 in 92% yield.
(R)-3-[3-Nitro-2-(o-tolyl)propyl]cyclohex-2-enone: 46.4 mg, 85%,
1
Ͼ99% ee, [α]D = –16.7 (c = 1.20, CHCl3). H NMR (600.1 MHz,
General Procedure for Cyclic Vinylogous Michael Reaction: To a
3
CDCl3): δ = 7.17–7.20 (m, 2 H), 7.13 (d, J = 7.2 Hz, 1 H), 5.78
toluene
(3 mL)
solution
of
DeMe-QNNH2
(6.2 mg,
3
3
(s, 1 H), 4.55 (d, J = 7.8 Hz, 2 H), 4.06–4.11 (m, 1 H), 2.61 (d, J
2ϫ10–2 mmol), o-fluorobenzoic acid (5.6 mg, 4ϫ10–2 mmol) was
added at room temperature whilst stirring. After 10 min, the reac-
tion was started with the addition of 3-methylcyclohex-2-enone
(44.1 mg, 0.4 mmol) immediately followed by and β-nitrostyrene
(29.8 mg, 0.2 mmol). The reactants were allowed to reach 40 °C
and were stirred for another 48 h. The organic phase was extracted
with hydrochloric acid solution (pH = 0, 3 mLϫ3), dried with an-
hydrous Na2SO4, evaporated under reduced pressure and purified
by flash column chromatography using hexane/ethyl acetate (v/v =
4:1) as eluent to yield the vinylogous adduct. The pH of the com-
3
3
= 7.2 Hz, 2 H), 2.38 (s, 3 H), 2.28 (t, J = 6.6 Hz, 2 H), 2.19 (t, J
= 6.0 Hz, 2 H), 1.89–1.93 (m, 2 H) ppm. 13C NMR (150.9 MHz,
CDCl3): δ = 198.7, 160.9, 136.4, 136.0, 131.3, 128.3, 127.8, 126.9,
125.6, 79.6, 41.4, 37.2, 37.1, 29.7, 22.6, 19.4 ppm. MS: m/z = 274.2
[M + H]+. C16H19NO3 (273.33): calcd. C 70.31, H 7.01, N 5.12;
found C 70.27, H 7.06, N 5.07.
(R)-3-[3-Nitro-2-(m-tolyl)propyl]cyclohex-2-enone: 49.1 mg, 90%,
86% ee, [α]D = –15.6 (c = 0.92, CHCl3). 1H NMR (600.1 MHz,
3
3
CDCl3): δ = 7.21 (t, J = 7.8 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H),
Eur. J. Org. Chem. 2015, 5755–5763
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5761

J. Wan, Z. Zhao, F. Wang, X. Ma
FULL PAPER
3
6.96–6.97 (m, 2 H), 5.77 (s, 1 H), 4.56 (d, J = 7.2 Hz, 2 H), 3.68–
3.73 (m, 1 H), 2.57–2.64 (m, 2 H), 2.33 (s, 3 H), 2.26–2.29 (m, 2
H), 2.14–2.24 (m, 2 H), 1.88–1.93 (m, 2 H) ppm. 13C NMR
(150.9 MHz, CDCl3): δ = 199.1, 161.1, 138.9, 137.9, 129.0, 128.9,
128.3, 128.0, 124.3, 80.1, 42.1, 41.5, 37.1, 29.5, 22.5, 21.4 ppm. MS:
m/z = 274.2 [M + H]+. C16H19NO3 (273.33): calcd. C 70.31, H 7.01,
N 5.12; found C 70.24, H 7.02, N 5.10.
5.4 Hz, 1 H), 3.85–3.90 (m, 2 H), 3.33 (cis, dd, J = 16.2, 10.2 Hz,
0.5 H), 3.26 (dd, J = 16.2, 8.4 Hz, 1 H), 3.08 (cis, dd, J = 15.6,
6.0 Hz, 0.56 H), 3.01 (trans, dd, J = 16.2, 5.4 Hz, 1.13 H), 2.75–
2.91 (m, cis, 1 H, trans, 2 H) ppm. 13C NMR (150.9 MHz, CDCl3):
δ = (trans) 206.6, 141.3, 136.5, 135.2, 130.6, 129.0, 128.5, 128.4,
127.6, 127.2, 125.4, 91.0, 43.6, 42.6, 42.0, 41.9; (cis) 206.9, 139.2,
138.9, 134.9, 130.2, 129.4, 128.6, 128.2, 127.8, 127.5, 125.6, 91.3,
42.9, 42.5, 41.3, 41.2 ppm. MS: m/z = 330.1 [M + H]+ .
C18H16ClNO3 (329.78): calcd. C 65.56, H 4.89, N 4.25; found C
65.49, H 4.91, N 4.21.
(R)-3-[2-(2-Methoxyphenyl)-3-nitropropyl]cyclohex-2-enone:
1
52.0 mg, 90%, 99% ee, [α]D = –10.6 (c = 1.00, CHCl3). H NMR
3
3
(600.1 MHz, CDCl3): δ = 7.24 (d, J = 7.2 Hz, 1 H), 7.06 (d, J =
7.8 Hz, 1 H), 6.87–6.91 (m, 2 H), 5.74 (s, 1 H), 4.71 (dd, J = 12.6, (3S,4R,5S)-4-Nitro-3-phenyl-5-(o-tolyl)cyclohexanone: 47.0 mg,
6.6 Hz, 1 H), 4.63 (dd, J = 12.6, 7.8 Hz, 1 H), 4.01–4.06 (m, 1 H), 76%, dr (trans/cis) = 14.3:1, 90% ee (trans), [α]D = –71.7 (c = 1.35,
3.86 (s, 3 H), 2.75 (dd, J = 13.8, 9.6 Hz, 1 H), 2.63 (dd, J = 13.8,
CHCl3). 1H NMR (600.1 MHz, CDCl3): δ = 7.31–7.34 (m, 3 H),
6.0 Hz, 1 H), 2.17–2.30 (m, 4 H), 1.81–1.92 (m, 2 H) ppm. 13C 7.19–7.23 (m, 4 H), 7.07 (d, 3J = 6.0 Hz, 2 H), 5.25 (dd, J = 6.6,
NMR (150.9 MHz, CDCl3): δ = 199.2, 162.0, 157.2, 129.3, 128.9, 4.8 Hz, 1 H), 4.17 (trans, q, 3J = 7.2 Hz, 1 H), 4.09 (cis, q, 3J =
128.0, 125.8, 121.0, 111.3, 78.7, 55.4, 39.9, 38.1, 37.2, 29.5,
5.4 Hz, 0.07 H), 3.83–3.86 (m, 1 H), 3.33 (dd, J = 15.6, 9.0 Hz, 1
22.6 ppm. MS: m/z = 290.1 [M + H]+. C16H19NO4 (289.33): calcd. H), 3.03 (dd, J = 16.2, 6.0 Hz, 1 H), 2.88 (dd, J = 16.2, 6.0 Hz, 1
C 66.42, H 6.62, N 4.84; found C 66.37, H 6.70, N 4.75.
H), 2.73 (dd, J = 16.2, 7.8 Hz, 1 H), 2.33 (trans, s, 3 H), 1.90 (cis,
s, 0.20 H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 207.7, 137.9,
137.0, 136.0, 131.4, 129.0, 128.3, 127.8, 127.5, 127.0, 125.5, 90.2,
43.4, 42.3, 41.9, 38.3, 19.2 ppm. MS: m/z = 310.2 [M + H]+.
(R)-3-[2-(3-Methoxyphenyl)-3-nitropropyl]cyclohex-2-enone:
53.7 mg, 93%, 97% ee, [α]D = –8.7 (c = 1.10, CHCl3). 1H NMR
3
3
(600.1 MHz, CDCl3): δ = 7.25 (t, J = 7.8 Hz, 1 H), 7.06 (d, J =
C
19H19NO3 (309.36): calcd. C 73.77, H 6.19, N 4.53; found C
3
7.8 Hz, 1 H), 6.81 (dd, J = 8.4, 2.4 Hz, 1 H), 6.76 (d, J = 7.2 Hz,
73.70, H 6.14, N 4.46.
3
1 H), 6.70 (s, 1 H), 5.78 (s, 1 H), 4.57 (d, J = 7.2 Hz, 2 H), 3.79
(s, 3 H), 2.57–2.64 (m, 2 H), 2.26–2.30 (m, 2 H), 2.15–2.25 (m, 2 (3S,4R,5S)-4-Nitro-3-phenyl-5-(m-tolyl)cyclohexanone: 49.5 mg,
H), 1.89–1.94 (m, 2 H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 80%, dr (trans/cis) = 4.2:1, 93% ee (trans), [α]D = –95.7 (c = 1.18,
198.9, 160.8, 160.2, 139.6, 130.3, 128.4, 119.5, 113.8, 113.1, 80.1,
CHCl3). 1H NMR (600.1 MHz, CDCl3): δ = 7.30–7.34 (m, 3 H),
7.24–7.27 (m, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.04–7.08 (m, 4 H),
3
55.3, 42.2, 41.5, 37.2, 29.6, 22.6 ppm. MS: m/z = 290.1 [M + H]+.
C
16H19NO4 (289.33): calcd. C 66.42, H 6.62, N 4.84; found C
5.29 (dd, J = 7.2, 4.8 Hz, 1 H), 3.95 (cis, dd, J = 13.8, 6.6 Hz, 0.24
H), 3.90 (trans, dd, J = 13.8, 6.6 Hz, 1 H), 3.78–3.81 (m, 1 H), 3.32
(dd, J = 15.6, 9.0 Hz, 1 H), 3.35 (dd, J = 16.2, 6.0 Hz, 1 H), 2.81–
2.86 (m, 2 H), 2.35 (trans, s, 3 H), 2.31 (cis, s, 0.71 H) ppm. 13C
NMR (150.9 MHz, CDCl3): δ = 207.5, 139.4, 139.1, 136.9, 129.2,
128.9, 128.8, 128.3, 128.0, 127.5, 124.1, 91.6, 43.2, 42.5, 42.1, 41.7,
21.4 ppm. MS: m/z = 310.2 [M + H]+. C19H19NO3 (309.36): calcd.
C 73.77, H 6.19, N 4.53; found C 73.67, H 6.21, N 4.49.
66.40, H 6.69, N 4.78.
General Procedure for Cyclic Double-Michael Organocascade Reac-
tion: To toluene (1 mL) solution of H-CDNH2 (11.8 mg,
4ϫ10–2 mmol), o-fluorobenzoic acid (8.4 mg, 6ϫ10–2 mmol) was
added at room temperature whilst stirring. After 10 min, (E)-4-
phenylbut-3-en-2-one (58.4 mg, 0.4 mmol) was added, immediately
followed by β-nitrostyrene (29.8 mg, 0.2 mmol). The reaction mix-
ture was stirred at 40 °C for 48 h. To the organic phase was added
toluene (4 mL), and the mixture was extracted with hydrochloric
(3S,4R,5S)-4-Nitro-3-phenyl-5-(p-tolyl)cyclohexanone: 50.1 mg,
81%, dr (trans/cis) = 7.7:1, 89% ee (trans), [α]D = –108.6 (c = 1.27,
acid solution (pH = 0, 5 mLϫ3), dried with anhydrous Na2SO4, CHCl3). 1H NMR (600.1 MHz, CDCl3): δ = 7.30–7.36 (m, 3 H),
evaporated under reduced pressure and purified by flash column
chromatography using petroleum ether/ethyl acetate (v/v = 8:1) as 4.8 Hz, 1 H), 3.91 (dd, J = 13.8, 7.2 Hz, 1 H), 3.75–3.79 (m, 1 H),
7.12–7.18 (m, 4 H), 7.06 (d, 3J = 6.6 Hz, 2 H), 5.26 (dd, J = 6.6,
eluent to afford the pure adduct. The pH of the combined aqueous
phases was adjusted by aqueous ammonia to pH = 9–10, extracted
with toluene (5 mLϫ3) and concentrated under reduced pressure
to one-fifth of its original volume. The recovered H-CDNH2 was
used directly for following Michael/Michael cascade reactions. The
data of the new products are shown as follows.
3.33 (dd, J = 15.6, 9.0 Hz, 1 H), 3.13 (cis, dd, J = 6.6, 4.8 Hz, 1
H), 3.05 (trans, dd, J = 16.2, 6.0 Hz, 1 H), 2.80–2.85 (m, 2 H), 2.34
(trans, s, 2.6 H), 2.32 (cis, s, 0.35 H) ppm. 13C NMR (150.9 MHz,
CDCl3): δ = 207.6, 137.8, 136.9, 136.4, 129.9, 129.6, 129.3, 128.9,
128.3, 127.5, 127.1, 91.7, 43.1, 42.3, 41.9, 41.7, 21.0 ppm. MS: m/z
= 310.2 [M + H]+. C19H19NO3 (309.36): calcd. C 73.77, H 6.19, N
4.53; found C 73.69, H 6.22, N 4.51.
(3S,4R,5S)-3-(2-Chlorophenyl)-4-nitro-5-phenylcyclohexanone:
50.0 mg, 76%, dr (trans/cis) = 8.9:1, 90% ee (trans), [α]D = –80.3 (c
(3S,4R,5S)-3-(2-Methoxyphenyl)-4-nitro-5-phenylcyclohexanone:
53.3 mg, 82%, dr (trans/cis) = 24.5:1, 93%ee (trans), [α]D = –105.2
1
= 0.96, CHCl3). H NMR (600.1 MHz, CDCl3): δ = 7.44 (dd, J =
7.8, 1.8 Hz, 1 H), 7.27–7.35 (m, 6 H), 7.06 (d, 3J = 6.0 Hz, 2 H),
(c = 1.36, CHCl3). H NMR (600.1 MHz, CDCl3): δ = 7.27–7.32
1
3
5.36 (t, J = 4.8 Hz,1 H), 4.42 (dd, J = 12.6, 6.6 Hz, 1 H), 3.71–
(m, 4 H), 7.14 (d, 3J = 7.2 Hz, 1 H), 7.07 (d, J = 7.2 Hz, 2 H),
3
3.74 (m, 1 H), 3.38 (dd, J = 16.2, 10.8 Hz, 1 H), 3.19 (dd, J = 16.2,
6.93–6.96 (m, 2 H), 5.39 (t, J = 4.8 Hz, 1 H), 4.17 (t, J = 6.6 Hz,
6.6 Hz, 1 H), 2.83 (trans, dd, J = 16.2, 6.0 Hz, 2 H), 2.78 (cis, dd, 1 H), 3.88 (s, 3 H), 3.72–3.75 (m, 1 H), 3.35 (dd, J = 16.2, 11.4 Hz,
J = 17.4, 3.0 Hz, 0.22 H) ppm. 13C NMR (150.9 MHz, CDCl3): δ
= 207.6, 139.2, 134.2, 133.7, 129.9, 129.4, 129.3, 128.2, 128.1, 127.5,
127.5, 89.5, 43.7, 41.2, 39.9, 36.9 ppm. MS: m/z = 330.1 [M +
H]+. C18H16ClNO3 (329.78): calcd. C 65.56, H 4.89, N 4.25; found
C 65.51, H 4.93, N 4.18.
1 H), 3.07 (dd, J = 16.2, 6.6 Hz, 1 H), 2.97 (dd, J = 16.8, 7.2 Hz,
1 H), 2.77 (trans, dd, J = 16.2, 4.8 Hz, 1 H), 2.66 (cis, dd, J = 16.8,
3.6 Hz, 0.04 H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 208.5,
156.7, 137.2, 129.3, 128.9, 128.8, 128.1, 127.6, 127.4, 121.2, 111.2,
89.6, 55.4, 41.9, 41.4, 41.0, 39.1 ppm. MS: m/z = 326.1 [M + H]+.
C19H19NO4 (325.36): calcd. C 70.14, H 5.89, N 4.31; found C
70.08, H 5.92, N 4.29.
(3S,4R,5S)-3-(3-Chlorophenyl)-4-nitro-5-phenylcyclohexanone:
53.3 mg, 81%, dr (trans/cis) = 2.0:1, 94% ee trans, [α]D = –98.6 (c
1
= 1.19, CHCl3). H NMR (600.1 MHz, CDCl3): δ = 7.31–7.33 (m, (3S,4R,5S)-3-(3-Methoxyphenyl)-4-nitro-5-phenylcyclohexanone:
3 H), 7.27–7.29 (m, 4 H), 7.05–7.07 (m, 2 H), 5.30 (dd, J = 7.8, 52.0 mg, 80%, dr (trans/cis) = 9.4:1, 93% ee (trans), [α]D = –118.9
5762
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5755–5763

A Recyclable Strategy for Cinchona Alkaloid Derived Organocatalysts
1
Z. Zhou, R. Zhou, Q. Q. Zhou, L. Dong, Y. C. Chen, J. Am.
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(c = 1.32, CHCl3). H NMR (600.1 MHz, CDCl3): δ = 7.25–7.31
(m, 4 H), 7.05 (d, J = 6.0 Hz, 2 H), 6.82 (d, 3J = 6.6 Hz, 2 H), 6.77
3
3
(s, 1 H), 5.29 (t, J = 4.8 Hz, 1 H), 3.89 (q, J = 6.6 Hz, 1 H), 3.77
(s, 3 H), 3.73–3.75 (m, 1 H), 3.29 (trans, dd, J = 16.2, 9.6 Hz, 1 H),
3.14 (cis, dd, J = 17.4, 6.0 Hz, 0.11 H), 3.03 (dd, J = 16.2, 5.4 Hz,
1 H), 2.79–2.85 (m, 2 H) ppm. 13C NMR (150.9 MHz, CDCl3): δ
= 207.5, 160.2, 141.0, 136.8, 130.3, 128.9, 128.3, 127.5, 119.2, 113.4,
113.1, 91.4, 55.2, 43.1, 42.5, 42.1, 41.7 ppm. MS: m/z = 326.1 [M
+ H]+. C19H19NO4 (325.36): calcd. C 70.14, H 5.89, N 4.31; found
C 70.11, H 5.90, N 4.27.
[5]
[6]
[7]
(3S,4R,5S)-3-(4-Methoxyphenyl)-4-nitro-5-phenylcyclohexanone:
55.9 mg, 86%, dr (trans/cis) = 11.1:1, 90% ee (trans), [α]D = –71.1
1
(c = 0.92, CHCl3). H NMR (600.1 MHz, CDCl3): δ = 7.30–7.31
(m, 3 H), 7.16 (d, 3J = 8.4 Hz, 2 H), 7.06 (d, 3J = 6.6 Hz, 2 H),
3
3
6.88 (d, J = 7.8 Hz, 2 H), 5.28 (cis, t, J = 5.4 Hz, 0.09 H), 5.23
(trans, t, 3J = 5.4 Hz, 1 H), 3.89 (q, 3J = 6.6 Hz, 1 H), 3.79 (s, 3
H), 3.74–3.77 (m, 1 H), 3.31 (dd, J = 16.2, 9.6 Hz, 1 H), 3.04 (dd,
J = 16.2, 5.4 Hz, 1 H), 2.79–2.84 (m, 2 H) ppm. 13C NMR
(150.9 MHz, CDCl3): δ = 207.7, 159.2, 136.9, 131.3, 128.9, 128.3,
128.2, 127.5, 114.6, 91.8, 55.3, 43.1, 41.9, 41.8, 41.7 ppm. MS: m/z
= 326.1 [M + H]+. C19H19NO4 (325.36): calcd. C 70.14, H 5.89, N
4.31; found C 70.12, H 5.90, N 4.29.
[8]
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Received: May 4, 2015
Published Online: July 31, 2015
Eur. J. Org. Chem. 2015, 5755–5763
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5763