Catalytic Activity of epi -Quinine-Derived 3,5-Bis(trifluoromethyl)benzamide in Asymmetric Nitro-Michael Reaction of Furanones

Article abstract of DOI:10.1021/acs.orglett.5b01224

High catalytic activity of novel epi-quinine-derived 3,5-bis(CF₃)benzamide in the asymmetric nitro-Michael reaction is described. With 0.1-5 mol % loadings of this catalyst, the addition of 5-substituted 2(3-H)-furanones to a wide range of nitr

Full text of DOI:10.1021/acs.orglett.5b01224

Letter
pubs.acs.org/OrgLett
Catalytic Activity of epi-Quinine-Derived 3,5-
Bis(trifluoromethyl)benzamide in Asymmetric Nitro-Michael Reaction
of Furanones
Tohru Sekikawa, Takayuki Kitaguchi, Hayato Kitaura, Tatsuya Minami, and Yasuo Hatanaka*
Department of Applied Chemistry, Graduate School of Engineering, Osaka City University, Sumiyoshi, Osaka 558-8585, Japan
*
S Supporting Information
ABSTRACT: High catalytic activity of novel epi-quinine-derived
,5-bis(CF )benzamide in the asymmetric nitro-Michael reaction is
3
3
described. With 0.1−5 mol % loadings of this catalyst, the addition
of 5-substituted 2(3-H)-furanones to a wide range of nitroalkenes
involving challenging substrates, β-alkylnitroalkenes, smoothly
proceeded, giving the Michael adducts in high yields (>90%)
with excellent diastereo- and enantioselectivity (>98:2 dr, syn major; 88−98% ee). DFT calculation was carried out to account
for the high catalytic activity.
mong a large variety of the Michael reactions, nitroalkens
have been one of the most widely used Michael acceptors
alkylnitroalkenes, which have been traditionally challenging
substrates in the organocatalytic nitro-Michael reactions.
2,3a
A
because of the versatility of nitro groups in numerous
As shown in Table 1, we have found that bifunctional epi-
quinine-derived catalysts are capable of promoting the Michael
addition of angelica lactone 1 to (E)-β-nitrostyrene 2 with 10
mol % of catalyst loading, affording the Michael adduct 3 (entries
1−6). Thus, with 10 mol % of 4a, 3 was obtained in 56% yield
with moderate diastereo- and enantioselectivity (70:30 =
syn:anti; 71% ee (syn) (entry 4)). THF is the solvent of choice
1
transformations. Organocatalysts employed in the asymmetric
nitro-Michael reaction have been mainly bifunctional enamine
1
a,d,g
catalysts,
although on use of the enamine catalysts the
1f
substrates are restricted to aldehydes and ketones. This
limitation can be largely overcome by bifunctional hydrogen-
bonding catalysts such as thiourea derivatives. However, weak,
2
noncovalent H-bonding activation of nitro groups often leads to
moderate enantioselectivity (<90% ee), severely limited
substrate scope, and the need for substoichiometric amounts of
(
entry 4). Next, we explored the effect of catalysts on the
5a
reaction. More effective catalyst (4b) was synthesized by
replacing the 9-OH and 6′-OH of 4a with 9-benzamide and 6′-
OMe (entry 7). Although the enantioselectivity dropped
considerably (58% ee), catalyst 4b significantly improved the
2b−j
catalysts (≥10 mol %).
Recently, organocatalytic diastereo- and enantioselective
vinylogous Michael additions of furanone-derived dienolates to
nitroalkenes have been reported as a straightforward route to
diastereoselectivity (syn:anti > 98:2) as well as the yield of 3
5b
(
80%). Interestingly, diastereomeric catalyst 4c exhibited
3
highly functionalized chiral β-butenolides (Scheme 1). β-
astonishingly reduced stereoselectivity (entry 8). A significant
improvement of the catalytic performance has been attained
Scheme 1. Michael Addition of Furanones to Nitroalkenes
upon the employment of epi-quinine-derived 3,5-bis(CF )-
3
5c
benzamide 4d. A 5 mol % loading of 4d successfully catalyzed
the Michael addition of 1 to 2, affording the Michael adduct 3 in
9
8% yield with high diastereo- and enantioselectivity (≥98:2 dr,
syn major; 90% ee) (entry 9). Furthermore, the practicability of
the 4d catalyzed nitro-Michael reaction was demonstrated by the
large-scale reaction of 1 (7.5 mmol) and 2 (5 mmol) at only 1
mol % loading of 4d to give 3 in 98% yield with high diastereo-
and enantioselectivity (94% ee) (entry 10). Catalysts 4e and 4f
showed no improvement of the catalytic effectiveness (entries 11
and 12). With the purpose of achieving further improvement of
Butenolides are often subunits of natural products and
biologically active compounds. Given the great number of
natural products containing chiral β-butenolides, the application
of reactive 2(3H)-furanones as a direct vinylogous nucleophile is
highly promising.
4
5d
catalytic activity, we examined catalyst 4g having pentafluor-
obenzamide, which is a stronger electron-withdrawing group
Herein, we report the remarkable activity of epi-quinine-
than 3,5-bis(CF )benzamide. To our surprise, with a 5 mol %
3
derived 3,5-bis(CF )benzamide catalyst in the asymmetric
3
Michael addition of 2(3-H)-furanones to nitroalkenes. In
particular, this catalyst has proved to be extremely effective in
promoting the nitro-Michael reaction of low reactive β-
Received: May 4, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01224
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
,b
Table 1. Catalytic Nitro-Michael Addition of 1 to 2
Table 2. Nitro-Michael Addition Catalyzed by 4d
c
d
time
(h)
yield
(%)
ee
entry furanone
9: Ar2
product
(%)
1
2
3
4
5
6
7
8
9
1
1
9a: 2-naphthyl
9b: 1-naphthyl
55
60
55
18
37
48
48
18
33
33
24
48
10aa
10ab
95
90
98
97
97
98
98
97
96
92
95
95
93
94
92
96
97
94
92
96
94
96
95
91
1
e
1
9c: 4-ClC H4
10ac
6
8a
8a
8a
8a
8a
8a
8a
8a
8b
9d: 4-MeOC H4
10ba
10bb
10bc
10bd
10be
10bf
10bg
10bh
10ca
6
9e: 4-MeC H4
6
9f: 4-NCC H4
6
9g:4-(F C)C H
4
3
6
9h: 4-ClC H4
6
9i: 3-ClC H4
6
b
c
d
e
0
9j: 2-ClC H4
entry catalyst
solvent
CH Cl
t [h] yield (%) syn/anti
ee (%) (syn)
6
f
e
11
12
9c: 2-furyl
1
2
3
4
5
6
7
8
9
1
1
1
1
4a
4a
4a
4a
4a
4a
4b
4c
4d
4d
4e
4f
36
36
36
20
73
33
24
96
24
48
24
24
24
55
48
33
56
42
56
80
50
98
98
98
82
78
70/30
2
2
2
f
f
e
2: C H
6 5
PhMe
31/69
32/68
70/30
52/48
45/55
>98/2
87/13
>98/2
>98/2
>98/2
>98/2
>98/2
5
a
b
e
All reactions exhibited >2:98 dr. Absolute configuration was
assigned by analogy with compound 10ac. Isolated yield. Obtained
by chiral HPLC analysis. Absolute configuration of 10ac was
determined by X-ray crystallographic analysis.
Et O
2
8
c
d
THF
71
41
63
58
4
e
MeCN
dioxane
THF
f
THF
There remains a severely critical problem with the organo-
catalyst-promoted asymmetric nitro-Michael reaction, that is,
very low reactivity of β-alkylnitroalkenes. Thus far, reports of the
Michael reaction of β-alkylnitroalkenes catalyzed by H-bonding
catalysts or enamine catalysts have been rare.
sporadic examples of this reaction have been reported,
most of them seem to be impractical in view of the requirement
of the substoichiometric amount of the catalysts (≥10 mol %)
and the low to moderate stereoselectivity (<90% ee). Moreover,
the structures of carbon nucleophiles, which can smoothly react
THF
90
94
88
−50
0
g
0
1
2
3
CHCl3
THF
THF
1f,g,2
While a few
4g
THF
2b−j,3a
a
Absolute configuration was assigned by analogy with compound 10ac
Table 2, entry 3). Reaction with 10 mol % loading of catalyst unless
otherwise noted. Isolated yield. Diastereomer ratio was determined
by H NMR analysis. Obtained by chiral HPLC analysis. Reaction
was conducted at room temperature. The reaction was conducted
with 1 mol % loading of 4d on a large scale (1: 7.5 mmol; 2: 5 mmol)
b
(
c d
1
e
f
g
6
with β-alkylnitroalkenes, are severely limited. The low reactivity
of β-alkylnitroalkenes is attributable to the high LUMO energy
level induced by electoron-donating alkyl groups, which leads to
a large HOMO−LUMO gap.
in CHCl3.
We were pleased to find that 0.1−5 mol % loadings of catalyst
4d are extremely effective in promoting the asymmetric nitro-
Michael addition of various 5-substituted furanones to β-
alkylnitroalkenes at 0 °C (Table 3). Generally, the 4d-catalyzed
reaction of β-alkylnitroalkenes exhibited high yields (>90%) with
high diastereo- and enantioselectivity (>98:2 dr syn; 88−96% ee)
(entries 1−10). For example, the Michael addition of furanone 1
to sterically demanding β-cyclohexylnitroalkene 9m, which has
loading of 4g the reaction afforded the racemic product 3 in 78%
yield (entry 13).
We then turned our attention to the substrate scope of the
nitro-Michael reaction in chloroform (Table 2). After solvent
screening shown in Table 1, we have noticed chloroform
bringing about higher diastereo- and enantioselectivity. Table 2
shows that 1−5 mol % loadings of catalyst 4d allowed complete
conversion of the β-arylnitroalkenes in chloroform, giving the
corresponding Michael adducts in excellent yields (90−98%)
with high levels of diastereo- and enantioselectivity (>98:2 dr;
syn; 92−97% ee) (entries 1−12). A series of β-arylnitroalkenes
bearing electron-withdrawing and electron-releasing substituents
on the aromatic rings smoothyl reacted with various 5-
substituted furanones in high yields (>97%) with high diastereo-
and enantioslectivity (>98:2 dr; 92−97% ee) (entries 4−7).
Thus, electronic properties of substituents on the aromatic rings
of β-arylnitroalkenes had no effect on the reaction. Furthermore,
the substitution pattern on the aromatic rings (entries 8−10) and
sterically demanding aromatic ring of β-arylnitroalkenes had no
deleterious effect on the stereoselectivity as well as the yields
2a
been a challenging substrate, successfully took place, giving rise
to the Michael adduct 11ac with 91% ee (entry 3). Despite the
3a
low reactivities of 9m and β-isobutylnitroalkene 9l, the Michael
addition of sterically demanding 5-phenylfuranone 8a to 9l and
9m smoothyl proceeded, affording the adducts 11ba (96% ee)
and 11bb (94% ee) (entries 5 and 6). Thus, the present method
is especially useful for constructing the sterically congested
oxygen-containing quaternary stereogenic centers adjacent to
7
ternary stereogenic centers. To evaluate the potential of catalyst
4d, the Michael additions of sterically demanding 5-isobutylfur-
anone 8b to 9k, 9l, and β-alkenylnitroalkenes 9n were carried
out, giving the corresponding Michael adducts 11ca (94% ee),
11cb (93% ee), and 11cc (92% ee) in high yields (entries 8−10).
The addition of 8b to sterically hindered nitroalkenes 9m needed
(entries 1 and 2).
B
DOI: 10.1021/acs.orglett.5b01224
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Organic Letters
Letter
Table 3. Catalytic Nitro-Michael Addition of Furanones to
a,b
(E)-β-Alkyl- and β-Alkenylnitroalkenes
c
d
yield
(%)
ee
entry furanone
9: R2
product
(%)
1
2
3
4
5
6
7
8
9
1
1
1
9k: CH CH Ph
11aa
11ab
11ac
11ad
11ba
11bb
11bc
11ca
11cb
11cc
11cd
99
99
98
98
84
90
95
98
98
94
99
88
90
91
94
96
94
97
94
93
92
91
2
2
1
9l: i-Bu
9m: Cy
1
1
9n: CHCHPh
8a
8a
8a
8b
8b
8b
8b
9m: Cy
Figure 1. Optimized structures of benzamide-β-isobutylnitroalkene 9l
adduct (A) and thiourea-9l adduct (B). Hydrogen bond lengths in
angstroms.
9l: i-Bu
9k: CH CH Ph
2
2
e
e
9n: (E)-CHCHPh
9k: CH CH Ph
significant decrease in the LUMO energies of 9l (B, −27 kcal
2
2
−1
0
1
9l: i-Bu
9m: Cy
mol ), while a decrease in the LUMO energy of 9l induced by
f
−1
benzamide is considerally smaller (A, −18 kcal mol ), but it
a
b
All reactions exhibited >2:98 dr. Absolute configuration was
assigned by analogy with compound 10ac. Isolated yield. Obtained
by chiral HPLC analysis. Reaction was conducted at −40 °C.
Reaction was conducted with 10 mol % loading of 4d.
suffices for the smooth reaction of 9l with furanones (entries 2, 6,
c
d
and 10 in Table 3); (2) despite the stronger H-bonding
e
activation of 9l, most thiourea catalysts give unsatisfactory results
f
2b−n,3a
of the Michael addition to β-alkylnitroalkenes;
(3)
thiourea-9l adduct B has a conformationally rigid structure due
1
0 mol % catalyst loading for complete substrate conversion
to the strong double H-bondings (H-bonding energy: 9.03 kcal
−1
1d,e
(entry 11). However, the corresponding adduct 11cd (91% ee)
mol ). In contrast, benzamide−9l adduct A, where 9l binds
was obtained in 99% yield. We examined the large-scale reaction
to establish the practical reaction conditions (Scheme 2). When
to the benzamide by single H-bonding, seems to be conforma-
−1
tionally flexible (H-bonding energy: 5.38 kcal mol ).
In general, the energy of transition state strongly depends on
Scheme 2. Practical Reaction Conditions
the angular geometry between HOMO and LUMO of reactants
9
(
i.e., angles between HOMO and LUMO). The calculations
strongly suggest that the thiourea−9l adduct B would hinder the
muximum overlap of the HOMO and LUMO, since the
conformationally rigid adduct B would distort the angular
geometry of the HOMO and LUMO from the ideal angle in
sterically congested chiral environment. In contrast, conforma-
tional flexibility of benzamide−9l adduct A would permit the
nearly maximum HOMO−LUMO overlap in the transition state,
allowing a smoother reaction via a transition state of lower
energy. The DFT calculations sufficiently explain the higher
catalytic activity of 4d compared to thiourea-based catalysts.
Figure 2 displays the simplified pre-transition-state assembly
model optimized at the B3LYP/6-31G(d) level. The quinucli-
the reaction of 8a (35.5 mmol) and 9k (25.0 mmol) was
conducted at room temperature, we found that catalyst loading
could be reduced to only 0.1−1 mol % without affecting the high
diastereo- and enantioselectivity as well as the high yields of the
Michael adduct 11bc (>2:98 dr, 93−97% ee, 93−95% yields).
8
The reaction achieved a TON of 9300. Single recrystallization of
the crude product from ethanol gave enantiomerically pure 11bc
in 83% yield.
To shed light on the mechanism accounting for the remarkable
catalytic activity of 4d in the asymmetric nitiro-Michael reaction,
DFT calculations of the catalyst-β-alkylnitroalkene adducts were
carried out (Figure 1). The structure of 3,5-bis(CF )benzamide-
3
β-isobutylnitroalkene 9l adduct A as a simplified model for 4d−
Figure 2. Simplified pre-transition-state assembly model optimized at
B3LYP/6-31(G). Atomic distances in angstroms.
1d
9
l adduct and the structure of thiourea−9l adduct B as a
simplified model for thiourea catalyst−9l adduct were optimized
at the B3LYP/6-311++G(d,p) level at theory. Thioureas are the
most frequently used H-bonding catalysts in asymmetric nitro-
dine moiety shields the si-face of the nitroalkene bound to the
amide hygrogen. To avoid the steric repulsion between the 5-
substituent of the dienolate and the aromatic ring of the
benzamide, the dienolate bound to the quinuclidinium hydrogen
exposes the si-face to the nitroalkene. The addition of the
1
a,d,f
Michel reactions.
Thus, to explain the high catalytic activity
of 4d, a comparison with thiourea-based catalysts should be
helpful. The results of the calculations have revealed that (1)
activation of 9l by the double H-bondings of thioerea provides a
C
DOI: 10.1021/acs.orglett.5b01224
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dienolate from the si-face to the exposed re-face of the
nitroalkene predicts the sense of the asymmetric induction.
In summary, we have developed a highly enantioselective
nitro-Michael reaction of furanones with very low reactive β-
alkylnitroalkenes catalyzed by a novel epi-quinine-amide 4d. The
DFT calculations revealed that the conformational flexibility of
the catalyst 4d−nitroalkene adducts play a critical role in the high
asymmetric induction. This result is entirely unexpected, since in
general, asymmetric organocatalysts are designed to achieve the
conformational rigidity (e.g., a series of iminium catalysts and
T.; Kitagawa, M.; Minami, T. 92nd Annual Meeting of the Chemical
Society of Japan, March 2012, Yokohama; Abstract (1K5-50A) is
available from The Chemical Society of Japan as a CD (http://www.
chemistry.or.jp). The reaction using chiral Zn catalyst was reported.
However, the substrates are restricted to unsubstituted furanones:
(
e) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572.
4) (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
04. (b) Casiraghi, G.; Rassu, G. Synthesis 1995, 609.
5) (a) Huang, Y.; Yang, L.; Shao, P.; Zhao, Y. Chem. Sci. 2013, 4, 3275.
(
5
(
(b) Brunner, H.; Buegler, J. Bull. Soc. Chim. Belg. 1997, 106, 77. (c) For
similar H-bonding catalysts bearing the CF group, see: Shao, Q.; Chen,
3
2
thiourea-based catalysts).
J.; Tu, M.; Piotorawski, D. V.; Huang, Y. Chem. Commun. 2013, 49,
1
7
1098. (d) Rana, N. K.; Selvokumar, S.; Singh, V. D. J. Org. Chem. 2010,
5, 2089.
ASSOCIATED CONTENT
Supporting Information
■
(
6) Compounds with very low pKa values such as cyclohexyl
*
S
Meldrum’s acid (pK in DMSO = 7−8) and α-nitroacetates (pK in
a
a
Experimental procedure and compound characterization data
including CIF. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01224.
DMSO = ∼9) can react with β-alkylnitroalkenes at 1−3 mol % loadings
of bifunctional H-bonding catalysts: (a) Kimmel, K. L.; Weaver, J. D.;
Ellman, J. A. Chem. Sci. 2012, 3, 121. (b) Li, Y.-Z.; Li, F.; Tian, P.; Lin, G.-
Q. Eur. J. Org. Chem. 2013, 1558.
(7) For a review, see: Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(
8) Development of low-loading asymmetric organocatalysts (≤ 3 mol
AUTHOR INFORMATION
Corresponding Author
■
*
%
) has received considerable attention. Review: Giacolone, F.;
Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406.
(9) Houk, K. N.; Paddon-Row, M. N.; Rondon, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Richard, Y. L.; Loncharich,
R. J. Science 1986, 231, 1108.
E-mail: hatanaka@a-chem.eng.osaka-cu.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work has been supported by a Grant-in-Aid for Scientific
Research (C) (20550101) from JSPS.
■
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DOI: 10.1021/acs.orglett.5b01224
Org. Lett. XXXX, XXX, XXX−XXX