Asymmetric conjugate additions of carbonyl compounds to nitroalkenes under solvent-free conditions using fluorous diaminomethylenemalononitrile organocatalyst

Article abstract of DOI:10.1248/cpb.c17-00596

The novel fluorous organocatalyst bearing a diaminomethylenemalononitrile motif is prepared. The fluorous organocatalyst efficiently promotes asymmetric conjugate additions of ketones to nitroalkenes and results in high yields of these addition products w

Full text of DOI:10.1248/cpb.c17-00596

Vol. 65, No. 12
Chem. Pharm. Bull. 65, 1185–1190 (2017)
1185
Note
Asymmetric Conjugate Additions of Carbonyl Compounds to
Nitroalkenes under Solvent-Free Conditions Using Fluorous
Diaminomethylenemalononitrile Organocatalyst
Shin-ichi Hirashima, Takafumi Narushima, Masahiro Kawada, Kosuke Nakashima, Kaori Hanai,
Yuji Koseki, and Tsuyoshi Miura*
Tokyo University of Pharmacy and Life Sciences; 1432–1 Horinouchi, Hachioji, Tokyo 192–0392, Japan.
Received July 24, 2017; accepted September 8, 2017
The novel fluorous organocatalyst bearing a diaminomethylenemalononitrile motif is prepared. The
fluorous organocatalyst efficiently promotes asymmetric conjugate additions of ketones to nitroalkenes and
results in high yields of these addition products with excellent enantioselectivities under solvent-free condi-
tions.
Key words organocatalyst; fluorous; conjugate addition; solvent-free
4
4–50)
Chiral γ-nitro carbonyl compounds are significant synthons asymmetric reactions.
Organocatalyst 1 bearing a DMM
in organic and medicinal chemistry owing to their easy ac- motif and a cyclic secondary amine unit is a good catalyst
1–9)
cess to biologically active molecules.
Among several for both asymmetric conjugate additions of cyclic ketones to
synthetic methods to obtain enantiomer-enriched, γ-nitro car- nitroalkenes and direct aldol reactions of aromatic aldehydes
45,48)
bonyl compounds, asymmetric conjugate addition of carbonyl with cyclic ketones under solvent-free conditions
compounds to nitroalkenes using organocatalysts is one of On the contrary, asymmetric reactions using organocata-
the most convenient and environmentally benign methodolo- lysts with fluorous tags have been reported by several research
(Fig. 1).
10–17)
51–72)
gies.
Organocatalysis between carbonyl compounds and groups.
Almost all of these reports utilize the benefits
nitro alkenes has been reported by several research groups; of fluorous molecules; the recycling of fluorous organocata-
however, due to obstacles faced by most previously reported lysts was achieved via the fluorous solid-phase extraction
73–75)
organocatalysis, such as high catalyst loading or long reaction (FSPE) technique using fluorous silica gel.
We have also
times, the development of organocatalysts for highly efficient reported some fluorous organocatalysts and demonstrated
76–80)
asymmetric conjugate additions of carbonyl compounds to their recyclability.
It was found that modifying original
nitroalkenes still remains an area of research interest. Thio- organocatalysts via addition of a fluorous tag improved their
urea organocatalysts, which are represented by Takemoto catalytic activity compared to the activity of the original cata-
7
9,80)
catalysts, are excellent catalysts and are applied to remarkably lysts.
important asymmetric reactions.
We attempted the development of organocatalyst 2
18–26)
Good organocatalytic by introducing a perfluorooctyl group to 1, to develop novel
activity is seen when a thiourea motif functions as a double fluorous organocatalysts with improved catalytic activity that
hydrogen-bond donor for a nucleophilic substrate. In addition, could also be recycled. Herein we describe the efficient con-
a squaramide motif as a further double hydrogen-bond donor jugate additions of carbonyl compounds to nitroalkenes using
was reported by Rawal and colleagues, and the squaramide fluorous organocatalyst 2 with a DMM skeleton and a chiral
organocatalyst effectively promotes the asymmetric conjugate
2
7)
additions of 1,3-diketones to nitroalkenes. Since the Rawal’s
report, it has been reported that various organocatalysts with
squaramide motifs are useful for several important asymmet-
2
8–43)
ric reactions.
We recently reported the diaminomethylene-
malononitrile (DMM) motif as another type of double hydro-
gen-bond donor, and the DMM-type organocatalysts exhibited
excellent asymmetric catalytic activity for several significant
Fig. 1. Structure of Organocatalysts
Chart 1. Preparation of Organocatalyst 2
*
To whom correspondence should be addressed. e-mail: tmiura@toyaku.ac.jp
©
2017 The Pharmaceutical Society of Japan

1
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Chem. Pharm. Bull.
Vol. 65, No. 12 (2017)
Table 1. Conjugate Additions Using Organocatalyst 2
1
a) Isolated yield. b) Determined by H-NMR spectroscopic analysis. c) Determined by HPLC analysis. d)
Cyclohexanone (10 equiv) was used. e) The reaction was conducted with acetone (5 equiv) instead of cyclo-
hexanone. f) The reaction was conducted with isobutylaldehyde (5 equiv) instead of cyclohexanone.

Vol. 65, No. 12 (2017)
Chem. Pharm. Bull.
1187
Table 2. Reuse of Fluorous Organocatalyst 2
a)
b)
c)
Reuse
st
nd
Time (h)
% Yield
syn/anti
% ee
Cat. recovery
1
40
86
1
91
22
94:6
94:6
98
90
quant
77
2
a) Isolated yield. b) Determined by H-NMR spectroscopic analysis. c) Determined by HPLC analysis.
pyrrolidine unit under solvent-free conditions.
Results and Discussion
Fluorous organocatalyst 2 was prepared, as shown in Chart
8
1)
1
. Coupling of (4-(perfluorooctyl)phenyl)methanamine (3)
8
2,83)
with 2-(bis(methylthio)methylene)malononitrile (4)
in
tetrahydrofuran (THF) resulted in the fluorous intermediate
63,84,85)
5
at 84% yield. Chiral pyrrolidine derivative 6,
which
can be easily prepared from L-prolinol, reacted with 5, result-
ing in the coupling product 7 at 89% yield. Finally, the tert-
butoxycarbonyl (Boc) protecting group of 7 was removed by
treatment with trifluoroacetic acid (TFA) in CH Cl to give the
desired fluorous organocatalyst 2.
The optimal conditions in the reaction of nitroalkene 8a
2
2
Fig. 2. Plausible Transition State Model
with cyclohexanone using organocatalyst 1 were under sol- dehyde is a poor substrate that gave low yield, although good
vent-free conditions in the presence of acetic acid (0.1 equiv) enantioselectivity was observed (entry 11). Compared with
45)
at room temperature. A solvent-free reaction condition is the results using original catalyst 1, enantioselectivities, when
desirable because it is environmentally benign and suitable using organocatalyst 2, are improved in entries 1, 2, 5, 6, and
8
6–88)
45)
for large-scale synthesis.
The optimal reaction condi- 7. The products shown in Table 1 are known compounds,
tions were applied to the asymmetric conjugate addition using and their relative and absolute configurations were determined
1
13
fluorous organocatalyst 2, giving high yield and excellent by comparison with the literature H-NMR and C-NMR
stereoselectivity (Table 1, entry 1). Percent yield, diastereose- data, as well as by chiral HPLC.
lectivity, and enantioselectivity were all improved for the reac-
We examined the recyclability of fluorous organocatalyst 2
tion with fluorous organocatalyst 2 compared to the reaction via the FSPE technique using fluorous silica gel. After the use
45)
using original organocatalyst 1. The conjugate additions of of 2 in the conjugate addition of cyclohexanone to 8a under
nitroalkene 8b and 8c bearing representative electron-donating the optimal conditions (Table 1, entry 1), catalyst 2 was easily
groups such as methyl or methoxy groups with cyclohexanone recovered via the FSPE technique. The recovered organocata-
resulted in the corresponding adducts 10b and 10c in high lyst 2 could be reused without further purification and both its
yields with high stereoselectivities, respectively (entries 2 and high yield and excellent stereoselectivity were retained for the
3). The nitroalkenes 8d and 8e bearing electron-withdrawing first reuse, although a longer reaction time (40h) was required
groups such as chloro or bromo groups are good substrates, (Table 2). Unfortunately, the catalytic activity of the recovered
resulting in adducts 10d and 10e in high enantioselectivities catalyst 2 decreased significantly for the second reuse. Most
(entries 4 and 5). The reaction between nitroalkene 8f with likely organocatalyst 2 was deactivated because the secondary
a naphthyl skeleton and cyclohexanone resulted in the syn- amine group of 2 directly attacks the β-carbon of nitroalkenes
addition product 10f with high yield and high stereoselectivity to afford the adduct, which could not be detected.
(entry 6). The reaciton of nitroalkene 8g with an acetal motif
By considering the stereochemistry of addition products
as an acid-labile functional group afforded 10g in moderate 10, we infer that the conjugate addition of cyclohexanone to
yield under standard conditions; however, high yield and high nitroalkenes involving fluorous organocatalyst 2 progresses
enantioselectivity were obtained when 10eq of cyclohexanone through the transition state shown in Fig. 2. The secondary
were used. (entry 7). Nitroalkenes 8h and 8i bearing het- amine group of 2 condenses with cyclohexanone to convert
erocyclic motifs such as thiophene or a furan ring smoothly the corresponding enamine intermediate. Then, the two amine
coupled with cyclohexanone, resulting in the addition products protons of the DMM motif act as a hydrogen-bond donor to
10h and 10i in high yields with good enantioselectivities, activate the nitro groups of 8. These interactions control the
respectively (entries 8 and 9). Acetone, as the other type of attack of enamine to the Re face of nitroalkenes. This ulti-
ketone, reacted with 8a to make the adduct 10j at good yield; mately affords the corresponding adducts 10 with excellent
however, the enantioselectivity was low (entry 10). Isobutyral- enantioselectivities.

1
188
Chem. Pharm. Bull.
Vol. 65, No. 12 (2017)
In conclusion, the novel fluorous organocatalyst 2 bearing (m, 1H), 1.83–1.90 (m, 2H), 2.00–2.10 (m, 1H), 3.31–3.34 (m,
DMM motif efficiently catalyzes the conjugate additions of 3H), 3.32 (dd, J=6.8, 13.6Hz, 2H), 3.34 (brs, 1H), 3.45–3.51
various nitroalkenes with ketones under solvent-free condi- (m, 1H), 3.80–3.81 (m, 1H), 4.64 (dddd, J=5.6, 15.8, 15.8,
tions, affording the corresponding addition products with high 15.8Hz, 2H), 7.48 (d, J=8.3Hz, 2H), 7.59 (d, J=8.3Hz, 2H);
1
3
to excellent enantioselectivity. Fluorous organocatalyst 2 is a
superior catalyst compared to the original organocatalyst 1
C-NMR (100MHz, CDCl ) δ: 23.8, 28.2, 29.9, 32.9, 46.4,
3
45)
47.1, 57.3, 81.0, 119.0, 127.3, 127.4, 127.4, 127.9, 128.5, 140.8,
in the some reactions. The excellent performance of fluorous 163.3; F-NMR (376MHz, CDCl ) δ: −80.7 (3F), −110.7 (2F),
19
3
organocatalyst 2 is probably due to the ability of the fluorous −121.3 (2F), −121.7 (2F), −121.9 (4F), −122.7 (2F), −126.1
+
tag (–C F ) on 2 to function as a preferable reaction field. (2F); HR-MS ESI-TOF: Calcd for C H N O F Na (M+Na) :
8
17
29 26
5
2 17
Fluorous organocatalyst 2 was readily recovered by simple 822.1713. Found: 822.1718.
solid-phase extraction using fluorous silica gel and was reus- (S)-2-(((4-(Perfluorooctyl)benzyl)amino)((pyrrolidin-2-
able without purification for the first cycle. Application of ylmethyl)amino)methylene)malononitrile 2
fluorous organocatalysts to other types of asymmetric reac-
To a stirred solution of compound 7 (1.93g, 2.41mmol) in
tions and the development of additional novel organocatalysts CH Cl (14mL) was added TFA (14mL) at room temperature.
2
2
are currently underway in our laboratory.
The mixture was stirred at room temperature for 3h. The
solvent was removed under reduced pressure. The residue was
purified by flash column chromatography on silica gel with a
Experimental
1
13
General Methods H-NMR and C-NMR spectra were 50:1–20:1 mixture of CHCl and MeOH to afford the pure
3
2
6
recorded on a Bruker Avance III Nanobay 400MHz spec- 2 (1.26g, 75%). White powder; mp 152–154°C; [α] =−26.3°
D
1
13
1
trometer (400MHz for H-NMR, 100MHz for C-NMR (c 1.00, CHCl ); H-NMR (400MHz, CDCl ) δ: 1.34 (ddd,
3
3
19
and 376MHz for F-NMR). The chemical shifts were re- J=7.5, 13.6, 20.8Hz, 1H), 1.52–1.74 (m, 4H), 1.86–1.94 (m,
ported in ppm on the δ scale relative to Me Si (δ=0.00 1H), 2.20–2.30 (m, 1H), 2.70 (ddd, J=4.8, 6.8, 11.3Hz, 1H),
4
1
13
for H-NMR), CDCl3 (δ=77.0 for
C-NMR), α,α,α- 3.05–3.12 (m, 1H), 3.19–3.25 (m, 1H), 3.33–3.39 (m, 1H),
trifluorotoluene (δ=−63.72 for F-NMR). Mass spectra were 4.67 (s, 2H), 5.81 (brs, 1H), 7.47 (d, J=8.3Hz, 2H), 7.62 (d,
recorded by an electrospray ionization-time of flight (ESI- J=8.3Hz, 2H), 10.96 (brs, 1H); C-NMR (100MHz, CDCl3)
TOF) mass spectrometer (Micromass LCT). For thin layer δ: 26.9, 28.4, 33.5, 45.6, 48.0, 50.0, 58.9, 127.4, 127.5, 128.3,
chromatographic (TLC) analyses, Merck precoated TLC plates 141.4, 165.2; F-NMR (376MHz, CDCl ) δ: −80.7 (3F),
19
1
3
19
3
(
silica gel 60F254) were used. Flash column chromatography −110.7 (2F), −121.2 (2F), −121.8 (6F), −122.7 (2F), −126.1
+
was performed on neutral silica gel (40–50µm).
Preparation of the Organocatalyst 2
(2F); HR-MS (ESI-TOF): Calcd for C H N F (M+H) :
700.1369. Found: 700.1362; Anal. Calcd for C H F N : C,
2
4
19
5 17
24 18 17 5
2
-((Methylthio)((4-(perfluorooctyl)benzyl)amino)methylene)- 41.21; H, 2.59; N, 10.01. Found: C, 41.15; H, 2.53; N, 9.96.
malononitrile 5
Typical Procedure for a Conjugate Addition Using
To
malononitrile (4)
added (4-(perfluorooctyl)phenyl)methanamine (3)
.86mmol). The mixture was stirred under reflux for 24h. was added acetic acid (1.1µL, 0.020mmol) at room tempera-
a stirred solution of 2-(bis(methylthio)methylene)- Organocatalyst 2 (Table 1) To a solution of trans-β-
8
2,83)
(487mg, 2.86mmol) in THF (30mL) was nitrostyrene (8a, 29.8mg, 0.200mmol) and organocatalyst 2
81)
(1.51g, (14.0mg, 0.020mmol) in cyclohexanone (105µL, 1.00mmol)
2
The reaction mixture was cool to room temperature. The sol- ture. After stirring at room temperature for 24h, the reaction
vent was removed under reduced pressure. The residue was mixture was directly purified by flash column chromatography
purified by flash column chromatography on silica gel with on silica gel with a 15:1–5:1 mixture of hexane and AcOEt
a 100:1 mixture of CHCl and MeOH to afford the pure 5 to afford the pure 10a (43.4mg, 88%). Colorless powder;
3
1
1
(
1.56g, 84%). Pale yellow powder; mp 123–126°C; H-NMR
H-NMR (400MHz, CDCl ) δ: 1.22–1.29 (m, 1H), 1.56–1.82
3
(
400MHz, CDCl ) δ: 2.69 (s, 3H), 4.82 (d, J=6.0Hz, 2H), (m, 4H), 2.05–2.12 (m, 1H), 2.35–2.51 (m, 2H), 2.66–2.72 (m,
.54 (brs, 1H), 7.42 (d, J=8.3Hz, 2H), 7.65 (d, J=8.3Hz, 2H); 1H), 3.05–3.12 (m, 1H), 3.76 (dt, J=4.5, 10.0Hz, 1H), 4.64 (dd,
3
6
13
C-NMR (100MHz, CDCl ) δ: 17.9, 49.3, 54.1, 114.8, 115.0, J=9.8, 12.6Hz, 1H), 4.94 (dd, J=4.5, 12.6Hz, 1H), 7.16–7.18
3
19
1
27.6, 127.7, 127.8, 129.2, 139.9, 175.5; F-NMR (376MHz, (m, 2H), 7.28–7.34 (m, 3H).
CDCl ) δ: −80.7 (3F), −110.9 (2F), −121.3 (2F), −121.8 (2F),
Procedure for Recycling and Reusing Fluorous Organo-
3
−
121.9 (4F), −122.7 (2F), −126.2 (2F); high resolution (HR)- catalyst 2 (Table 2) To a solution of trans-β-nitrostyrene
+
MS (ESI-TOF): Calcd for C H N F S (M+H) : 648.0402. (8a, 74.6mg, 0.500mmol) and organocatalyst 2 (35.0mg,
2
0
11
3 17
Found: 648.0399.
tert-Butyl (S)-2-(((2,2-Dicyano-1-((4-(perfluorooctyl)benzyl)- acetic acid (2.9µL, 0.050mmol) at room temperature. The re-
amino)vinyl)amino)methyl)pyrrolidine-1-carboxylate 7
action mixture was stirred at room temperature for 40h. The
0.050mmol) in cyclohexanone (518µL, 5.00mmol) was added
To a stirred solution of compound 5 (1.56g, 2.40mmol) reaction mixture was chromatographed on fluorous silica gel
in THF (24mL) was added tert-butyl (S)-2-(aminomethyl)- with a 7:3 mixture of methanol and water. Next, the fluorous
63,84,85)
pyrrolidine-1-carboxylate (6)
(480.7mg, 2.40mmol). silica gel was eluted with methanol, and the methanol frac-
The mixture was stirred under reflux for 24h. The reaction tion was evaporated to recover the fluorous organocatalyst 2
mixture was cool to room temperature. The solvent was (35.6mg, 100%). The 70% methanol fractions were evaporated
removed under reduced pressure. The residue was purified to a one-third to original volume. The residue was extracted
by flash column chromatography on silica gel with a 10:1 three times with AcOEt. The AcOEt layers were combined,
mixture of hexane and AcOEt to afford the pure 7 (1.93g, washed with brine, dried over anhydrous MgSO , and evapo-
4
2
9
8
9%). White powder; mp 136–141°C; [α] =−29.8° (c 1.00, rated. The residue was purified by flash column chromatog-
D
1
CHCl ); H-NMR (400MHz, CDCl ) δ: 1.34 (s, 9H), 1.70–1.76 raphy on silica gel with a 15:1–5:1 mixture of hexane and
3
3

Vol. 65, No. 12 (2017)
Chem. Pharm. Bull.
1189
9
3)
AcOEt to afford the pure 10a (112.7mg, 91%) as a colorless
(R)-2,2-Dimethyl-4-nitro-3-phenylbutanal (10k)
2
5
powder.
Yellow oil, 3.2mg (7% yield), 81% ee; [α] =+5.1 (c 0.16,
CHCl ). Enantiomeric excess was determined by HPLC with
D
8
9)
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexan-1-one (10a)
3
43.4mg (88% yield), 97% ee; Enantiomeric excess was ChiralCel OD-H column (hexane–2-propanol=92:8), flow
determined by HPLC with ChiralPak AS-H column (hex- rate=1.0mL/min; λ=210nm; tmajor=19.4min, tminor=30.9min.
ane–2-propanol=85:15), flow rate=1.0mL/min; λ=230nm;
tminor=13.8min, tmajor=20.8min.
S)-2-((R)-2-Nitro-1-(p-tolyl)ethyl)cyclohexan-1-one (10b)
Acknowledgments This work was supported by the Japan
Society for the Promotion of Science (JSPS) KAKENHI Grant
8
9)
(
45.9mg (88% yield), 98% ee; Enantiomeric excess was Number 16K08178. The authors would like to thank Enago
determined by HPLC with ChiralPak AS-H column (hex- (www.enago.jp) for the English language review.
ane–2-propanol=80:20), flow rate=1.0mL/min; λ=206nm;
tminor=8.0min, tmajor=13.2 min.
Conflict of Interest The authors declare no conflict of
(
S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexan-1- interest.
9
0)
one (10c)
4
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(
10f)
1
55.6mg (93% yield), 93% ee; Enantiomeric excess was
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0.2mg (86% yield), 91% ee; Enantiomeric excess was
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(
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1
(S)-2-((S)-2-Nitro-1-(thiophen-2-yl)ethyl)cyclohexan-1-one
1
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(
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8
9)
(10i)
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