Concerted catalysis by nanocellulose and proline in organocatalytic Michael additions

Article abstract of DOI:10.3390/molecules24071231

Cellulose nanofibers (CNFs) have recently attracted much attention as catalysts in various reactions. Organocatalysts have emerged as sustainable alternatives to metal-based catalysts in green organic synthesis, with concerted systems containing CNFs that are expected to provide next-generation catalysis. Herein, for the first time, we report that a representative organocatalyst comprising an unexpected combination of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized CNFs and proline shows significantly enhanced catalytic activity in an asymmetric Michael addition.

Full text of DOI:10.3390/molecules24071231

molecules
Communication
Concerted Catalysis by Nanocellulose and Proline in
Organocatalytic Michael Additions
Naliharifetra Jessica Ranaivoarimanana , Kyohei Kanomata and Takuya Kitaoka *
Department of Agro-Environmental Sciences, Graduate School of Bioresource and Bioenvironmental Sciences,
Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; jessi@agr.kyushu-u.ac.jp (N.J.R.);
kanomata@agr.kyushu-u.ac.jp (K.K.)
* Correspondence: tkitaoka@agr.kyushu-u.ac.jp; Tel.: +81-92-802-4665
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Theo Van de Ven and Amir Sheikhi
Received: 12 March 2019; Accepted: 27 March 2019; Published: 29 March 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Cellulose nanofibers (CNFs) have recently attracted much attention as catalysts in various
reactions. Organocatalysts have emerged as sustainable alternatives to metal-based catalysts in
green organic synthesis, with concerted systems containing CNFs that are expected to provide
next-generation catalysis. Herein, for the first time, we report that a representative organocatalyst
comprising an unexpected combination of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized
CNFs and proline shows significantly enhanced catalytic activity in an asymmetric Michael addition.
Keywords: nanocellulose; TEMPO-oxidized cellulose nanofiber; Michael addition; nitroalkene;
organocatalysis; proline
1. Introduction
In the last two decades, cellulose nanofibers (CNFs) have emerged as a promising state-of-the-art
nanomaterial with a wide range of applications [
1]. Cellulose, which is a homopolymer of D-glucose
that is connected by a -1,4 linkage, is the most abundant, carbon-neutral, and renewable natural
β
biomass on Earth. The regular assembly of dozens of molecular cellulose chains in one direction
forms highly crystalline CNFs. CNFs are mainly derived from woody secondary cell walls and they
possess an uncommon combination of features, such as high strength, high transparency, a large
specific surface area, a well-defined nanoarchitecture, and a highly functionalized and chemically
modifiable crystalline surface [
2,
3]. Taking advantage of these physicochemical properties, CNFs have
been widely explored in polymer nanocomposite reinforcement [4] as high performance gas-separation
films and purification membranes [5,6] and in the confection of electroactive paper [7,8].
Among the reported CNFs, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized cellulose
nanofibers (TOCNs) are fascinating, owing to their simple and environmentally benign preparation
method and unique nanoarchitecture [9]. In TOCNs, carboxylates are introduced onto native
cellulose crystals at regular intervals and with high density, resulting in a core–shell structure, in
which a glucose/glucuronic acid alternating copolymer covers native crystalline cellulose bundles.
Furthermore, TEMPO oxidation of wood pulp affords completely individualized cellulose microfibrils,
whose widths are the narrowest within the reported CNFs (3–4 nm). Therefore, the TOCN-derived
materials have superior physical properties in gas-barrier films [10], free-standing aerogels [11], and
nanocomposites [12].
While the material-oriented applications of CNFs have been extensively studied, another
promising application of this new nanomaterial in catalytic molecular transformations has
emerged [13–15]. The readily functionalizable nature of cellulose makes CNFs, especially TOCNs,
a matrix of choice in the immobilization of metal nanoparticles and cations as catalysts [16]. We have
recently reported the novel ability of TOCNs to accelerate catalytic reactions, in which TOCNs in
Molecules 2019, 24, 1231; doi:10.3390/molecules24071231
www.mdpi.com/journal/molecules

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protonated form (TOCN-H) act as a promising solid acid catalyst for the hydrolysis of acetals in
their protonated form [17]. The surface carboxylic acids on TOCN-H behave as heterogeneous acid
catalysts with activity that outperforms the corresponding homogeneous catalysts, such as acetic acid.
Furthermore, we reported the ability of TOCNs, in their sodium form (TOCN-Na), to improve the
efficiency of proline-catalyzed aldol reactions [18]. This finding provided a new method for enhancing
less-efficient proline, which is a representative organocatalyst that has attracted considerable attention,
owing to its environmentally benign nature, low cost, and wide availability [19]. Adding an external
catalyst to TOCNs is an attractive method, owing to its potential applicability to a wide range of
catalytic reactions. However, the scope of this methodology has yet to be explored.
The Michael reaction is an important carbon–carbon/heteroatom bond forming reaction in
organic synthesis [20
which are essential building blocks in the preparation of various physiologically active compounds
and pharmaceuticals [24 26 27]. Although proline is a promising catalyst in terms of its cost
and availability for the synthesis of such compounds, high catalyst loading is required and the
enantioselectivity is poor [28 29]. Much effort has been concentrated on remedying these issues by
designing more efficient catalysts that are derived from the proline structure [21 30 31], or by pairing
proline with small organic molecules to form significantly more active complexes [32 33]. Methods
using ionic liquids as solvents [34 35] and covalent anchoring to polymers, such as polyethylene
glycol or polystyrene, to allow catalyst recovery, have also been investigated [36 37]. However, these
–25]. The Michael addition of ketones to nitroalkenes affords γ-nitroketones,
,
,
,
,
,
,
,
,
strategies require additional catalyst preparation steps, resulting in additional costs that hamper their
industrial application.
Herein, we report a new approach to enhancing the proline-catalyzed Michael reaction that
takes advantage of CNFs. Adding TOCN-Na to the reaction medium greatly reduced the required
proline catalyst loading and markedly enhanced the catalytic performance, rendering the process more
economical, practical, and sustainable.
2. Results and Discussion
2.1. Effects of Cellulose Nanofibers on Proline-Catalyzed Michael Additions
The investigation into TOCN/proline-concerted catalysis of the Michael addition started with
the reaction of cyclohexanone (1a) with trans-
β-nitrostyrene (2a), which has been widely employed
as a benchmark reaction to assess the related catalytic systems [38
,39] (Table 1). The reaction with
proline alone resulted in a low yield and poor enantioselectivity (entry 1). In contrast, adding the
TOCN sodium salt (TOCN-Na) to the reaction medium significantly enhanced the yield under the
same reaction conditions (entry 2). Notably, the diastereoselectivity and the enantioselectivity were
somewhat improved in the presence of TOCNs, which is in contrast to our previous TOCN-assisted
aldol reaction, resulting in poor stereoselectivity [18]. In this TOCN/proline-concerted system, an
aqueous TOCN suspension was employed, replacing the water with MeOH by repetitive centrifugation
before use. MeOH is known to improve the enantioselectivity of the proline-catalyzed Michael
additions, although these reactions require several days to reach completion [29] (Table S1). Previous
theoretical studies have shown that the explicit participation of MeOH molecules in the transition
state influences the preferred approach between the enamine, which formed from proline and
cyclohexanone, and nitrostyrene as the electrophile, leading to higher enantioselectivity in the
formation of 3aa [40]. Accordingly, dissolving the proline in a small portion of MeOH prior to
its addition to N,N-dimethylformamide (DMF) further increased both the yield and enantioselectivity
(entry 3). No additional effects were recorded while using the same amount of MeOH in the reaction
without TOCNs (56% yield, syn:anti = 96:4, 34% ee for syn in 24 h). Using TOCNs alone without proline
did not promote the reaction, clearly suggesting that the cooperation of catalytically inactive TOCNs
and low-activity proline was critical in enhancing the reaction efficiency of this Michael addition
(entry 4). Interestingly, freeze-dried TOCNs, which were poorly dispersed in the solvent, owing to

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severe aggregation [11], also achieved a high yield, but the enantioselectivity remained low (entry 5).
The intrinsic chirality of TOCNs might not be involved in imparting enantioselectivity, because using
(R)-proline provided the same type of enhancement (entry 6). A plausible factor was the numerous
carboxylate groups that are present on the TOCN surface, as confirmed by using homogeneously
dispersed sodium acetate with an equivalent carboxy group content to the TOCNs used, which also
slightly augmented the reaction yield (entry 7). However, this was not a dominant factor. The influence
of functional groups was also investigated while using freshly prepared TOCNs with low carboxy
contents (entry 9), which resulted in lower yields, but similar improvements in enantioselectivity.
Furthermore, the crystalline nature of TOCN would be essential in the present catalytic system,
with amorphous carboxymethylcellulose failing to promote the reaction at all (entry 8), despite both
of the cellulose derivatives containing plentiful carboxy groups in their structures. Consequently,
TOCN-Na containing 1.61 mmol/g of –COONa groups (entry 3) gave the best compromise in the
yield/enantioselectivity enhancements, and it was used in subsequent experiments.
Table 1. Catalytic behavior of proline combined with cellulose nanofibers and additives in the Michael
addition a.
Yield (%) b
Entry
Additive
syn:anti c
ee for syn (%) c
1
2 d
3
None
TOCN
TOCN
TOCN
TOCN
35
78
88
Trace
81
86
41
34
89:11
90:10
90:10
-
95:5
93:7
89:11
90:10
32
35
43
-
33
-39
6
4 e
5 f
6 g
7
TOCN
Sodium acetate
Carboxymethylcellulose
TOCN/low
carboxylate
8 h
27
9 i
42
82:18
42
a
Unless otherwise noted, the reaction was performed using cyclohexanone (1a) (4 mL, excess), trans-
β-nitrostyrene
(
2a) (74.6 mg, 0.50 mmol), (S)-proline (7.5 mol%), and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized
cellulose nanofibers-Na (TOCN-Na) (100 mg dry weight) in a mixture of DMF (14 mL) and MeOH (2 mL). Aqueous
medium of TOCN suspension was replaced with MeOH by repetitive centrifugation prior to reaction; b Isolated
yield; c Determined by chiral stationary phase supercritical fluid chromatography (SFC) analysis; d Without MeOH;
e
Without (S)-proline; f Freeze-dried TOCN was added to the reaction; g (R)-Proline was used instead of (S)-proline;
h
For entries 6 and 7, additive amount adjusted to 1 eq. of –COO− groups contained in 100 mg of TOCN (entry 3);
i
TOCN with –COO− group content of 0.94 mmol/g.
2.2. Optimization of Reaction Conditions
Different catalyst amounts and reaction temperatures were screened to identify the optimum
conditions (Table 2). A lower amount of (S)-proline remained effective when combined with TOCNs
(Table 2, entry 1), while higher catalyst loading led to a decrease in diastereoselectivity (entry 2). The
optimum loading of (S)-proline was 7.5 mol%, relative to nitroalkene 2a (Table 1, entry 3). The yield and
diastereoselectivity increased with an increasing temperature for reactions with and without TOCNs
(Table 2, entries 3 and 4). The best result was obtained at 40 ◦C for 11 h in the presence of TOCNs
(entry 4). With respect to green chemistry and sustainability, further reactions were conducted at room
temperature, because the (S)-proline/TOCNs system efficiency at this temperature was close to that
at 40 ◦C. Testing different nitrostyrene/TOCNs ratios (entries 5–9) showed that the optimum weight

Molecules 2019, 24, 1231
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ratio was 1:1.34 (entry 7). Indeed, increasing the TOCN quantity from 25 mg to 100 mg (entries 5–7)
improved the catalytic efficiency from modest to high, while further increasing the amount of fibers
gradually impeded the reaction. This might be attributed to reaction mixture thickening that causes
crowding in the reaction medium (entries 8 and 9).
Table 2. Fine-tuning of catalyst amount, reaction temperature, and cellulose nanofiber quantity a.
Yield (%) b
Entry
Conditions
TOCN
syn:anti c
ee for syn (%) c
−
37
74
87:13
93:7
29
39
5 mol% catalyst, rt
1
+
−
58
77
69:31
69:31
26
39
15 mol% catalyst, rt
2
3
+
−
9
23
77:23
74:26
19
39
◦
7.5 mol% catalyst, 0 C
+
−
66
91
94:6
94:6
32
42
◦
4 d
7.5 mol% catalyst, 40 C
+
5
6
7
8
9
Substrate/TOCN (mg/mg) 74.6/25
Substrate/TOCN (mg/mg) 74.6/50
Substrate/TOCN (mg/mg) 74.6/100
Substrate/TOCN (mg/mg) 74.6/150
Substrate/TOCN (mg/mg) 74.6/200
+
+
+
+
+
51
66
88
63
43
92:8
94:6
90:10
71:29
83:17
41
43
41
41
43
a
Unless otherwise noted, the reaction was performed using cyclohexanone (1a) (4 mL, excess), trans-β-nitrostyrene (2a)
(74.6 mg, 0.50 mmol), (S)-proline (7.5 mol%), and TOCN-Na (100 mg dry weight) in a mixture of DMF (14 mL) and
MeOH (2 mL). Aqueous medium of TOCN suspension was replaced with MeOH by repetitive centrifugation prior to
reaction; b Isolated yield; c Determined by chiral stationary phase SFC analysis; d Stirred for 11 h.
2.3. Substrate Scope
With optimum conditions in hand, the substrate scope of the present catalyst system was
investigated (Table 3). TOCNs clearly enhanced the reaction efficiency and the stereoselectivity
of proline-catalyzed Michael additions of various substrates.
Both electron-donating and
electron-withdrawing groups on the nitrostyrene phenyl ring were compatible with the catalytic
system, affording moderate to high yields and excellent diastereoselectivities in the presence of
TOCNs (entries 1 and 2). In both cases the enantioselectivity was increased. Naphthyl-substituted
nitroalkene, which has inherently high reactivity, as exemplified by a high yield without TOCNs,
also benefited from the effect of TOCNs, which afforded increased enantioselectivity (entry 3). The
generality of ketones, as the nucleophile activated by proline, was also studied in the reaction with
trans-β-nitrostyrene. A significant increase in yield was observed for 4-oxothiane, which is a cyclic
ketone bearing a heteroatom (entry 4). Unfortunately, the reaction yield with cyclopentanone was
diminished in the presence of TOCNs, despite markedly increased enantioselectivity (entry 5). Acetone,
the simplest ketone without a cyclic structure, was also applicable to the present catalytic system
(entry 6).

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Table 3. Substrate scope a.
Time
Entry
Substrates
Product
TOCN
syn:anti
ee for syn (%) c
Yield (%) b
(h)
48
48
90:10 d
93:7 d
−
26
68
31
35
1
+
24
24
−
59
83
96:4 c
95:5 c
28
50
2
3
4
5
6
+
87:13 d
87:13 d
48
48
−
75
71
10
21
+
94:6 d
97:3 d
24
24
−
18
76
24
38
+
24
24
−
43
12
61:39 c
72:28 c
29
59
10
+
24
24
−
32
70
-
-
+
23
a
Unless otherwise noted, the reactions were performed using an excess of ketone
1
(4 mL for all entries, except 10 eq. of
1b in entry 4) and nitrostyrene (
2
) (0.50 mmol); b Isolated yield; c Determined by chiral stationary phase SFC analysis;
d
Determined by 1H-NMR.
3. Materials and Methods
3.1. General
Nippon Paper Industries Co., Ltd. (Tokyo, Japan) kindly supplied TEMPO-oxidized cellulose
nanofibers (TOCNs, carboxylate content: 1.61 mmol/g), and they were used in reactions, except for
Table 1, entry 9. TOCNs with a low carboxylate content used in Table 1, entry 8, were prepared
from cellulose nanofibers purchased from Sugino Machine Limited (BiNFi-s AFo-10002, Uozu,
Japan) according to a literature method [17,41]. Transmission electronic microscopy (TEM) with
a JEM-2100HCKM microscope (JEOL, Tokyo, Japan) at the Ultramicroscopy Research Center, Kyushu
University and powder X-ray diffraction (XRD) using a Rigaku MultiFlex diffractometer (Rigaku
Corporation., Tokyo, Japan) at the Center of Advanced Instrumental Analysis, Kyushu University (see
Figures S1 and S2, respectively, in Supplementary Materials) characterized the TOCN samples. The
substrates 2c and 2d were synthesized according to a previously-reported method (detailed in the
Supplementary Materials) [42]. Other reagents were purchased from Sigma-Aldrich Co. LLC. (Tokyo,
Japan), FUJIFILM Wako Pure Chemical Industries, Ltd. (Osaka, Japan), and Tokyo Chemical Industry
Co., Ltd. (Tokyo, Japan), and they were used without further purification. Thin-layer chromatography
(TLC) analysis was performed on glass-backed plates precoated with silica gel (silica gel 60 GF254,
0.25 mm Merck, Tokyo, Japan). Column chromatography was performed while using an automated
flash chromatography system (Smart Flash EPCLC-AI-580S, Yamazen, Osaka, Japan). The 1H- and
13C-NMR spectra were recorded on a JNM-ECZ400 spectrometer (JEOL, Tokyo, Japan) at the Center

Molecules 2019, 24, 1231
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of Advanced Instrumental Analysis, Kyushu University. Chemical shifts in the 1H-NMR spectra are
reported in parts per million relative to the peak of tetramethylsilane (TMS, 0.00 ppm), used as an
δ
internal standard. The 1H-NMR data are reported, as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13C-NMR
spectra were recorded with complete proton decoupling, and chemical shifts are reported in parts per
million relative to the solvent resonance (CDCl3, δ 77.0 ppm), used as an internal standard.
3.2. Preparation of TOCNs with Low Carboxylate Content
Wet-state cellulose nanofibers (3.0 g dry weight of cellulose) were suspended in deionized water
(300 mL) containing TEMPO (48 mg) and NaBr (300 mg). TEMPO-mediated oxidation was started by
adding sodium hypochlorite (2.0 mmol/g of cellulose) to the suspension. The mixture was stirred at
room temperature for 30 min, while the suspension was maintained at pH 10 while using a pH titrator
(GT-200 Automatic Titrator, Mitsubishi Chemical Analytech, Yamato, Japan) that was loaded with
NaOH (0.5 M). The oxidation was quenched with ethanol (10 mL) and the suspension was washed
thoroughly with deionized water by successive centrifugation at 22,540
×
g for 10 min (TOMMY
Suprema 21 High-Speed Refrigerated Centrifuge, TOMMY Seiko, Tokyo, Japan). Nanofibrillation was
conducted by aqueous counter collision with a high-pressure water jet system at 245 MPa (0.1-mm
diameter dual-nozzle chamber; Star Burst Labo, Sugino Machine Limited, Uozu, Japan) [43]. The
obtained mixture was then centrifuged to separate the cellulose nanofiber as supernatant (0.6 wt%)
from the unfibrillized fibers (10 min, 22,540
carboxylate content of the TOCNs [41].
×
g). Electrical conductivity titration confirmed the
3.3. Water Removal Process from Nanocellulose Samples
Each nanocellulose was subjected to solvent exchange to remove water prior to use, because water
inhibited the reaction, except for that in entry 4 in Table 1, which was then freeze-dried. To obtain
freeze-dried samples, TOCN water suspension (10 mL, 1.04 wt%) was mixed with tertiary butanol
(30 mL), frozen in liquid nitrogen, and dried under vacuum (Scanvac CoolSafe LaboGene, Sakuma
Seisakusho, Co. Ltd., Tokyo, Japan). Washing the TOCN water suspension (10 mL, 1.04 wt%) with
MeOH (30 mL) by centrifugation (9200
exchange process.
×
g, 5 min) five times was undertaken to perform the solvent
3.4. Representative Procedure for the Proline-Catalyzed Michael Addition of Cyclohexanone to trans-
in the Presence of TOCNs
β-Nitrostyrene
Cyclohexanone (1a) (4.0 mL, excess) and trans-β-nitrostyrene (2a) (74.6 mg, 0.50 mmol) were
added to the reaction medium, followed by a solution of (S)-proline (4.4 mg, 7.5 mol% with respect to 2a
)
in MeOH (2.0 mL). The resulting mixture was stirred at room temperature and TLC monitored progress.
Upon completion, the reaction was quenched by adding aq. NH4Cl, extracted with dichloromethane
(30 mL
×
3), and dried over Na2SO4. Purification of the concentrated organic layer by column
chromatography (hexane and ethyl acetate as eluents) rendered product 3aa as a white solid (108.8 mg,
88%). The enantiomeric and diastereomeric ratios of the reactions were measured by supercritical fluid
chromatography (SFC) while using a chiral stationary phase (ACQUITY UPC2, Waters, Tokyo, Japan).
The spectroscopic data of each product were in agreement with previously reported data [39,44].
Spectroscopic Data
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (3aa) [44]. White solid (108.8 mg, 88%); 1H-NMR
(400 MHz, CDCl3) syn-3aa
(dd, J = 12.4, 10.0 Hz, 1H), 3.76 (dd, J = 10.0, 4.8 Hz, 1H), 2.73–2.66 (m, 1H), 2.51–2.35 (m, 2H), 2.12–2.04
(m, 1H), 1.82–1.51 (m, 4H), 1.29–1.19 (m, 1H); detectable peaks of anti-3aa 4.89–4.81 (m, 0.1H),
4.04–3.99 (m, 0.05H), 2.76–2.75 (m, overlapped with syn-3aa, 0.04H), 2.30–2.24 (m, overlapped with
syn-3aa, 0.02H), 1.92–1.84 (m, 0.04H), 1.43–1.34 (m, 0.05H); 13C-NMR (100.5 MHz, CDCl3) syn-3aa
: δ 7.34–7.28 (m, 3H), 7.18–7.15 (m, 2H), 4.94 (dd, J = 12.4, 4.4 Hz, 1H), 4.64
:
δ
:

Molecules 2019, 24, 1231
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δ
δ
211.9, 137.7, 128.8, 128.1, 127.6, 78.8, 52.4, 43.8, 42.6, 33.1, 28.4, 24.9; detectable peaks of anti-3aa
:
210.4, 138.3, 128.6, 128.2, 127.4, 76.4, 53.7, 42.9, 42.2, 29.8, 27.3; SFC: Daicel Chiralpak IC-3 ( = 210 nm,
λ
CO2/2-propanol, 93:7, 1.0 mL/min, 30 ◦C), tr (major) = 3.56 min, tr (minor) = 4.70 min.
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone (3ab) [44]. Yellow solid (94.6 mg, 68%);
1H-NMR (400 MHz, CDCl3) syn-3ab
7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.91 (dd,
J = 12.4, 4.8 Hz, 1H), 4.58 (dd, J = 12.4, 10.0 Hz, 1H), 3.78 (s, 3H), 3.74–3.68 (m, 1H), 2.68–2.61 (m, 1H),
2.50–2.34 (m, 2H), 2.11–2.04 (m, 1H), 1.82–1.52 (m, 4H), 1.28–1.18 (m, 1H); detectable peaks of anti-3ab
7.20–7.16 (m, 0.09H), 4.87–4.71 (m, 0.13H), 3.96–3.88 (m, 0.06H); 13C-NMR (100.5 MHz, CDCl3)
syn-3ab 212.0, 158.8, 129.4, 129.0, 114.1, 79.0, 55.1, 52.5, 43.1, 42.6, 33.0, 28.4, 24.9; detectable peaks
of anti-3ab
:
δ
:
δ
:
δ
:
δ 210.6, 158.7, 129.3, 113.9, 76.9, 53.7, 42.4, 42.2, 30.0, 27.2; SFC: Daicel Chiralpak AD-3,
(λ = 220 nm, CO2/methanol, 95:5, 1.0 mL/min, 30 ◦C), tr (minor) = 5.90 min, tr (major) = 8.61 min.
(S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)cyclohexanone (3ac) [44]. White solid (135.7 mg, 83%); 1H-NMR
(400 MHz, CDCl3) syn-3ac: δ 7.48–7.43 (m, 2H), 7.20–7.04 (m, 2H), 4.93 (dd, J = 12.8, 4.6 Hz, 1H),
4.60 (dd, J = 12.8, 10.1 Hz, 1H), 3.75 (td, J = 9.8, 4.4 Hz, 1H), 2.68–2.62 (m, 1H), 2.50–2.45 (m, 1H),
2.42–2.33 (m, 1H), 2.12–2.06 (m, 1H), 1.83–1.55 (m, 4H), 1.23 (qd, J = 12.4, 3.5 Hz, 1H); detectable peaks
of anti-3ac
2.75–2.70 (m, overlapped with syn-3ac, 0.11H), 1.94–1.87 (m, 0.13H), 1.42–1.31 (m, 0.11H); 13C-NMR
(100.5 MHz, CDCl3) syn-3ac 211.4, 136.8, 131.9, 129.8, 121.5, 78.4, 52.1, 43.3, 42.6, 33.0, 28.3, 24.9;
detectable peaks of anti-3ac
IC-3, (
: δ 7.44–7.43 (m, 0.26H), 7.16–7.14 (m, 0.21H), 4.89–4.78 (m, 0.21H), 3.94–3.89 (m, 0.12H),
:
δ
:
δ
210.2, 137.3, 131.7, 130.1, 76.4, 53.4, 42.2, 30.0, 27.2; SFC: Daicel Chiralpak
◦
λ
= 220 nm, CO2/2-propanol, 95:5, 1.0 mL/min, 30 C), tr (major) = 6.22 min, tr (minor) = 9.62 min.
(S)-2-((R)-1-Naphthyl-2-nitroethyl)cyclohexanone (3ad) [44]. Off-white solid (105.1 mg, 71%); 1H-NMR
(400 MHz, CDCl3) syn-3ad 7.82–7.77 (m, 3H), 7.67 (d, J = 26.5 Hz, 1H), 7.49–7.44 (m, 2H), 7.30–7.25
:
δ
(m, 1H), 5.03 (dd, J = 12.6, 4.3 Hz, 1H), 4.72 (dd, J = 12.8, 10.1 Hz, 1H), 3.95 (td, J = 10.1, 4.1 Hz,
1H), 2.76 (td, J = 11.1, 4.6 Hz, 1H), 2.49–2.32 (m, 2H), 2.05–2.00 (m, 1H), 1.71–1.49 (m, 4H), 1.28–1.19
(m, 1H); detectable peaks of anti-3ad
4.20–4.15 (m, 0.08H), 2.24 (m, 0.07H), 1.85–1.76 (m, 0.08H), 1.42–1.29 (m, overlapped with syn-3ad
0.04H); 13C-NMR (100.5 MHz, CDCl3) syn-3ad
211.8, 135.0, 133.2, 132.7, 128.7, 127.7, 127.5, 126.3,
126.0, 125.1, 78.7, 52.3, 44.0, 42.6, 33.2, 28.4, 24.9; detectable peaks of anti-3ad 210.4, 135.8, 133.1,
: δ 7.69 (s, 0.12H), 7.39–7.36 (m, 0.11H), 4.96–4.93 (m, 0.13H),
,
:
δ
:
δ
132.5, 128.4, 127.5, 126.9, 126.4, 126.2, 126.0, 76.4, 53.7, 42.9, 42.2, 29.8, 27.2; SFC: Daicel Chiralpak OD-3,
(λ = 210 nm, CO2/2-propanol, 82:18, 1.0 mL/min, 30 ◦C), tr (major) = 1.34 min, tr (minor) = 1.73 min.
(S)-3-((R)-2-Nitro-1-phenylethyl)tetrahydro-4H-thiopyran-4-one (3ba) [39]. White solid (100.8 mg, 76%);
1H-NMR (400 MHz, CDCl3) syn-3ba
:
δ
7.36–7.17 (m, 5H), 4.73 (dd, J = 12.8, 4.6 Hz, 1H), 4.61 (dd,
J = 12.8, 9.6 Hz, 1H), 3.96 (td, J = 10.3, 4.7 Hz, 1H), 3.06–2.93 (m, 3H), 2.87–2.77 (m, 2H), 2.62–2.41 (m, 2H);
detectable peaks of anti-3ba 4.90–4.81 (m, 0.02H), 4.18–4.13 (m, 0.03H), 2.94–2.92 (m, overlapped
with syn-3ba, 0.06H); 13C-NMR (100.5 MHz, CDCl3) syn-3ba
209.5, 136.4, 129.3, 128.3, 128.1, 78.6,
54.9, 44.5, 43.4, 35.1, 31.6; detectable peak of anti-3ba 129.0; SFC: Daicel Chiralpak IC-3, ( = 210 nm,
CO2/methanol, 96:4, 1.0 mL/min, 30 ◦C), tr (major) = 2.41 min, tr (minor) = 2.75 min.
:
δ
:
δ
:
δ
λ
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclopentan-1-one (3ca) [44]. Off-white solid (13.7 mg, 12%); 1H-NMR
(400 MHz, CDCl3) syn-3ca 7.32 (s, 3H), 7.14 (s, 2H), 5.32 (dd, J = 12.8, 5.5 Hz, 1H), 5.00 (d, J = 7.8 Hz,
:
δ
1H), 4.70 (dd, J = 12.8, 10.1 Hz, 1H), 3.82 (dd, J = 11.9, 7.8 Hz, 1H), 3.71–3.65 (m, 1H), 2.36 (d, J = 43.9 Hz,
1H), 2.12 (d, J = 41.6 Hz, 1H), 1.89 (d, J = 49.4 Hz, 1H), 1.70 (d, J = 34.8 Hz, 1H), 1.47 (d, J = 41.6 Hz,
1H); detectable peaks of anti-3ca
0.34H), 2.29–2.25 (m, overlapped with syn-3ca, 0.16H), 1.41–1.20 (m, 0.17H); 13C-NMR (100.1 MHz,
CDCl3) syn-3ca 218.5, 137.7, 128.9, 128.4, 127.9, 78.2, 50.4, 44.1, 38.6, 28.3, 20.0; detectable peaks of
: δ 7.42–7.41 (m, 0.12H), 7.13–7.05 (m, 0.18H), 3.83 (td, J = 7.8, 4.1 Hz,
:
δ
anti-3ca
Chiralpak IA-3, (
:
δ
219.1, 137.3, 128.9 (overlapped with syn-3ca), 77.1, 51.4, 44.0, 39.2, 27.0, 20.5; SFC: Daicel
◦
λ
= 210 nm, CO2/2-propanol, 95:5, 1.0 mL/min, 30 C), tr (minor) = 1.70 min, tr (major)
= 2.56 min.

Molecules 2019, 24, 1231
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(R)-5-Nitro-4-phenylpentan-2-one (3da) [39]. White solid (72.3 mg, 70%); 1H-NMR (400 MHz, CDCl3):
7.33–7.19 (m, 5H), 4.62 (ddd, J = 40.0, 12.3, 7.5 Hz, 2H), 4.03–3.95 (m, 1H), 2.89 (d, J = 7.3 Hz, 2H),
2.09 (s, 3H); 13C-NMR (100.5 MHz, CDCl3):
205.4, 138.8, 128.9, 127.7, 127.3, 79.3, 46.0, 38.9, 30.2; SFC:
= 210 nm, CO2/2-propanol, 93:7, 1.0 mL/min, 30 ◦C), tr (major) = 3.05 min,
δ
δ
Daicel Chiralpak IC-3, (
λ
tr (minor) = 3.50 min.
4. Conclusions
We have developed a novel method that substantially enhanced the proline-catalyzed Michael
additions of ketones to nitroalkenes through the simple incorporation of nanocellulose, TOCNs,
in the reaction medium at room temperature. We assumed that crystalline TOCNs with densely
packed surface carboxylate groups played a significant role in increasing the catalytic activity,
because TOCNs with low carboxylate content only gave a small yield enhancement. In addition,
molecular carboxylates that originated from sodium acetate gave a modestly improved yield, while
the amorphous carboxylated cellulose derivative was not effective. Furthermore, the efficiency of the
catalytic system was directly related to the amount of nanocellulose used. The method was successfully
applied to different ketones and nitroalkene substrates. Concerted catalysis using nanocelluloses and
organocatalysts provides new research avenues for both emerging applications of nanocellulose and
green sustainable chemistry.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: N.J.R. conducted all experiments and analysis. N.J.R. and K.K. wrote the manuscript.
T.K. conceived the present idea, and K.K. and T.K. designed the research. All authors reviewed and approved
the manuscript.
Funding: This research was supported by Advanced Low Carbon Technology Research and Development
Program from Japan Science and Technology Agency (T.K.), by Research Scholarships from the Ministry of
Education, Culture, Sports, Science and Technology, Japan (N.J.R.), and by Research Fellowships for Young
Scientists from Japan Society for the Promotion of Science (K.K.).
Acknowledgments: The authors thank Nippon Paper Industries Co. Ltd. for kindly supplying TEMPO-oxidized
cellulose nanofibers.
Conflicts of Interest: The authors declare no conflicts of interest. The funding sources had no role in the design of
the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision
to publish the results.
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Sample Availability: All data generated and/or compound samples analyzed during this study are included in
this article and are available from the corresponding author on reasonable request.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).