Catalytic intermolecular aldol reactions of transient amide enolates in domino Michael/aldol reactions of nitroalkanes, acrylamides, and aldehydes

Article abstract of DOI:10.1039/d0gc04111d

Three-component reactions of nitroalkanes, acrylamides, and aldehydes by using a catalytic amount of KOH in DMSO gave β′-hydroxy-γ-nitro amides. Mechanistic studies suggested that the reactions proceeded by domino Michael/aldol reactions. The highly nucle

Full text of DOI:10.1039/d0gc04111d

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Catalytic intermolecular aldol reactions of
transient amide enolates in domino Michael/aldol
reactions of nitroalkanes, acrylamides, and
aldehydes†
Cite this: Green Chem., 2021, 23,
1160
Received 4th December 2020,
Accepted 22nd January 2021
DOI: 10.1039/d0gc04111d
Shunya Morita, Tomoyuki Yoshimura
and Jun-ichi Matsuo
*
rsc.li/greenchem
Three-component reactions of nitroalkanes, acrylamides, and lytic intermolecular aldol reactions in DNMA reactions.8 We
aldehydes by using a catalytic amount of KOH in DMSO gave report here catalytic intermolecular aldol reactions coupled
β’-hydroxy-γ-nitro amides. Mechanistic studies suggested that the with Michael addition of nitroalkanes with poor Michael
reactions proceeded by domino Michael/aldol reactions. The acceptors, acrylamides, by using a catalytic amount of KOH in
highly nucleophilic nature of transient amide enolates that were DMSO. Also, very high nucleophilicity rather than Brønsted
formed by Michael addition of nitronate anions to acrylamides in basicity of transient amide enolates in DMSO is disclosed here.
DMSO enabled the realization of catalytic intermolecular aldol
Appropriate bases and solvents were screened for a catalytic
three-component reaction by adding nitroalkane 1a (2.0 equiv.)
and acrylamide 2a (2.0 equiv.) in turn to a mixture of
8.5–10 mol% of a base and aldehyde 3a (1.0 equiv.) (Table 1).
In the case of using THF as a solvent, 10 mol% of LHMDS,
t-BuOK, and t-BuOK/18-crown-6 did not effectively catalyze the
DNMA reaction even after prolonged reaction time (entries
1–3). In these cases, Henry (nitro-aldol) adduct 5a was
obtained in 24–39% yields. Surprisingly, the use of DMSO as a
solvent greatly improved the efficiency of the three-component
reaction and the desired adduct 4a was obtained in 84–87%
yields as a mixture of diastereomers (syn/anti = 57 : 43–62 : 38)
under catalysis of 10 mol% of LHMDS and t-BuOK (entries 4
and 5). A suitable base was then screened using DMSO as a
solvent (entries 6–10). A catalytic amount (8.5 mol%) of pow-
dered KOH and KHMDS worked effectively as in the case of as
in the case of tBuOK (entries 6 and 7).9 Freshly powdered KOH
(85%, purchased from Kanto Chemical Co., Inc.) was used.
Catalysis of Cs2CO3 was also effective, but that of CsOH
afforded 4a in a moderate yield (63% yield) (entries 8 and 9).
The reaction with 10 mol% of Barton’s base provided 4a in
73% yield (entry 10). On the other hand, KOH-catalyzed reac-
tion in DMSO containing 1% H2O gave the desired product 4a
reactions of amide enolates in the presence of acidic nitroalkanes.
Aldol reactions are one of the most fundamental carbon–
carbon bond forming reactions in organic synthesis.1 The
difficulty of intermolecular direct aldol reactions of amides
with a catalytic amount of a base has been well recognized2
since the α-acidity of amides is quite low.3 Recently, direct
aldol reactions of amides using a catalytic amount of a base
have been achieved by introduction of an electron-withdrawing
group to amides4 and/or by chelation of a Lewis acid to
amides.2h,i We were interested in aldol reactions of transient
enolates that were catalytically formed in situ by Michael
addition of nitronate anions to acrylamides, though acryl-
amides are poor Michael acceptors. Domino nitroalkane-
Michael/aldol (DNMA) reactions are powerful synthetic tools
for construction of various β′-hydroxy-γ-nitro carbonyl com-
pounds 4 from three different kinds of functionalized com-
pounds including nitroalkanes 1, electron-deficient alkenes 2,
and aldehydes or ketones 3 (Scheme 1).5 However, inter-
molecular aldol reactions have never been incorporated in the
known DNMA reactions with catalytic amounts of catalysts.6,7
Since amide enolates cannot be formed in equilibrium in the
presence of relatively acidic nitroalkanes by using a catalytic
amount of a base, extremely high nucleophilicity of transient
enolates toward aldehydes is required to realize efficient cata-
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
E-mail: jimatsuo@p.kanazawa-u.ac.jp
†Electronic supplementary information (ESI) available. CCDC 2055717. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0gc04111d
Scheme 1 Intermolecular base-catalyzed three-component reaction
to 4.
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Table 1 Optimization of reaction conditions
Table 2 Various aromatic aldehydes
Timea
(h)
Yieldb (%) of
Yieldc
(%) of 5
Timea 4a b (%)
Base (mol%) (h)
(syn/anti)c
5a d
(%)
Entry
X (3)
4 (syn/anti)c
Entry Solvent
1
2
3
4
5
6
7
8
9
4-CN (3b)
2-CF3 (3c)
4-CF3 (3d)
2-Cl (3e)
2-Br (3f)
2-Pyridiyl (3g)
4-Br (3h)
4-Cl (3i)
1.5
24
24
1.5
24
24
24
24
3
74 (51 : 49)
76 (61 : 39)
69 (60 : 40)
61(59 : 41)
54 (58 : 42)
46 (46 : 54)
64 (67 : 33)
64(64 : 36)
42 (60 : 40)
71 (75 : 25),
73 (72 : 28)d
65 (79 : 21)
63 (78 : 22)
60 (73 : 27)
38 (65 : 35)
43 (70 : 30)
9
6
9
<2
15
2
1
2
3
THF
THF
THF
LHMDS (10)
t-BuOK (10)
t-BuOK/
24
26
26
34 (64 : 36) 24
5 (56 : 44)
3 (56 : 44)
33
39
18-c-6 (10)
LHMDS (10)
t-BuOK (10)
KOH (8.5)
KHMDS (10)
CsOH (10)
Cs2CO3 (10)
Barton’s
4
5
6
7
8
9
10
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
2.0
1.0
2.0
1.0
24
2.0
1.0
84 (62 : 38)
87 (57 : 43)
91 (56 : 44)
86 (62 : 38)
4
0
6
4
16
15
0
4-F (3j)
H (3k)
63 (58 : 42) 17
84 (57 : 43) 7
73 (54 : 46) 11
10
2
0, 4d
basee (10)
11
12
13
14
15e
1-Naphthyl (3l)
2-Me (3m)
4-Me (3n)
2-MeO (3o)
4-MeO (3p)
3
0
0
2
0
0
15
24
1
11
12
13
14
1% H2O–DMSO KOH (8.5)
DMF
DMPU
HMPA
24
24
4
17 (61 : 39) 54
66 (56 : 44) 11
KOH (8.5)
KOH (8.5)
KOH (8.5)
74 (52 : 48)
87 (55 : 45)
2
0
3
6.5
a Reactions were performed until arylamide 2a was not detected by
TLC analysis. In the case of long reaction times (>23 h), acrylamide 2a
was still detected. b Isolated yield. c Determined by 1H NMR analysis.
d Compound 3k (10 mmol) was used. e Barton’s base (10 mol%) was
used instead of KOH.
a Reactions were performed until either arylamide 2a or aldehyde 3a
was not detected by TLC analysis. In the case of long reaction times
(>23 h), acrylamide 2a was still detected. b Isolated yield based on 3a.
For details, see ESI.† c Syn/anti ratios were determined by isolation of
each diastereomer or 1H NMR analysis of a mixture of diastereomers.
d Yields were determined by 1H NMR analysis. e Barton’s base: 2-t-
butyl-1,1,3,3-tetramethylguanidine.
The reactions of various halogenated benzaldehydes afforded
the corresponding three-component adducts 4e–f and 4h–j in
in 17% yield and a substantial amount of Henry adduct 5a moderate yields (entries 4–5 and 7–9). The reactions of
(54%) was obtained (entry 11). Compared with DMSO, polar benzaldehyde, 1-naphthylaldehyde, and tolaldehydes also pro-
aprotic solvents including DMF and DMPU were not effective vided the desired products 4k–n in good yields (entries 10–13),
solvents for the KOH-catalyzed reaction (entries 12 and 13 vs. while the reaction of 2-pyridinecarboxaldehyde 3g gave 4g in a
entry 6), whereas HMPA showed effectiveness equivalent to low (46%) yield (entry 6). Gram-scale synthesis of 4k was per-
that of DMSO (entry 14). In all cases described above, for- formed by using 10 mmol of benzaldehyde 3k, and 2.14 g of
mation of the Michael adduct 6a by reaction between 1a and 4k was obtained (entry 10). The stereochemistry of anti-4k was
2a was detected.10 For example, the Michael adduct 6a was unambiguously determined by its X-ray crystallography.10
obtained in 82% yield under the reaction conditions of entry Moderate diastereoselectivities were observed in the case of
11 (see Table S1†).10 Thus, excess amounts of acrylamide 1a 1-naphthylaldehyde and 2-tolaldehyde (entries 11 and 12). It
and 2-nitropropane 2a that were not incorporated into 4a were was revealed that the Michael addition/protonation sequence
mainly converted to the Michael adduct 6a. Considering the took place preferentially in the case of methoxy-substituted
costs and readily availability of reagents, KOH in DMSO was benzladehydes (entries 14 and 15). Interestingly, the KOH-cata-
selected for the three-component reactions.
lyzed reaction of 4-methoxybenzaldehyde (3p) did not give the
The scope and limitations of the three-component reactions desired compound 4p, while the use of 10 mol% of Barton’s
with 2-nitropropane 1a and acrylamide 2a were investigated by base instead of KOH afforded 4p in 43%. However, the KOH-
using various aromatic aldehydes with the assumption that catalyzed three-component reactions with aliphatic aldehydes
the intermolecular aldol reactions would be influenced by elec- including pivalaldehyde and 3-phenylpropanal did not give the
trophilicity of aldehydes (Table 2). The three-component reac- three-component adducts.10
tions of benzaldehyde derivatives bearing electron-withdrawing
The scope and limitations of nitroalkanes and acrylamides
groups on the aromatic ring gave the desired products 4b–d in in the KOH-catalyzed three-component reactions with 2-nitro-
good yields along with 6–9% of Henry adducts 5 (entries 1–3). benzaldehyde 3a are shown in Fig. 1. The reactions of nitro-
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Fig. 1 Various nitroalkanes and acrylamides.a a Reaction conditions:
aldehyde (1.0 equiv.), α,β-unsaturated amide (2.0 equiv.), nitroalkane
(2.0 equiv.), KOH (8.5 mol%), DMSO, rt. Isolated combined yields of two
diastereomers. b The relative configuration was not assigned. c Barton’s
base (10 mol%) was used instead of KOH.
cyclopentane and nitrocyclohexane proceeded smoothly to afford
the desired products 4q and 4r in excellent yields. The reaction
of nitromethane also provided 4s in 65% yield. The diastereo-
selectivity was slightly improved by using a less hindered
nitroalkane. The reactions of 7-azaindoline amide11 and
Weinreb amide12 gave the corresponding adducts 4t and 4v in
good yields, whereas the reaction of α,β-unsaturated amides
having an N–H group provided the desired product 4u in 18%
yield under catalysis of Barton’s base. The catalysis of KOH did
not afford 4u. The use of N,N-dimethyl-2-butenamide and N,N-
dimethyl methacrylamide did not afford the corresponding
three-component adducts, and only the Henry adduct was
detected (see Table S3†).10
Nucleophiles other than nitroalkanes, including benze-
nethiol, benzyl mercaptan, phthalimide and diethyl methyl-
malonate, did not afford the desired products by the reaction
with 2-nitrobenzaldehyde (3a) and N,N-dimethyl acrylamide
(2a) in the presence of 10 mol% of Barton’s base in DMSO at
room temperature, presumably due to the low electrophilicity
of N,N-dimethyl acrylamide (2a)13 for such nucleophiles.
Some reactions were conducted to clarify the reaction
mechanism (Scheme 2). The catalytic reaction of N,N-dimethyl
α-D-acrylamide 2a-D (>99%D) with 2-nitrobenzaldehyde (3a)
and 2-nitropropane (1a) gave the desired product 4a-D with
high D-contents in both syn- and anti-isomers (Scheme 2a). It
was expected that the D-content of the product 4a would
decrease if the present three-component reaction proceeded by
tandem Baylis–Hillman/Michael reaction.14 In addition,
Baylis–Hillman reaction of 2-nitrobenzaldehyde 3a and N,N-
dimethyl acrylamide 2a did not proceed by using a catalytic
amount of KOH in DMSO (Scheme 2b).15 These results and
isolation of the Michael adduct 6 suggest that the present
three-component reaction did not proceed by tandem Baylis–
Hillman/Michael reaction but proceeded by domino nitroalk-
ane-Michael/aldol reaction. Attempted aldol reaction of the
Michael adduct 6a with 2-nitrobenzaldehyde 3a with 8.5 mol%
Scheme 2 Studies for the reaction mechanism.
was recovered (Scheme 2c). Consequently, the desired product
4a was not formed from an amide enolate that was formed in
equilibrium from 6a, and an aldol reaction of a transient
amide enolate that was formed by Michael addition of a nitro-
nate anion of 1a to acrylamide 2a proceeded.16 Retro-Henry
reaction of 5a followed by Michael/aldol reaction with acryl-
amide 2a took place to provide 4a in 47% yield (Scheme 2d).
Thus, both Henry and retro-Henry reactions proceeded along
with the KOH-catalyzed DNMA reactions. Epimerization of
each isolated diastereomer of 4a did not take place by the treat-
ment with 8.5 mol% of KOH in DMSO at room temperature for
2 h (Scheme S1†).10 Thus, the observed diastereoselectivities of
the DNMA reactions did not result from α-deprotonation/pro-
tonation or retro-aldol/aldol reaction of the products 4, but
they were determined in the domino Michael/aldol process.
In order to confirm the roles of DMSO, we studied aldol
reactions of a potassium enolate of amide 8 with aldehyde 3a
in the presence of a proton donor, 2-nitropropane (1a), by
using THF and DMSO as a solvent (Scheme 3). Addition of a
mixture of aldehyde 3a and 2-nitropropane (1a) to a potassium
enolate of amide 8 in THF and DMSO gave an aldol product 9
Scheme 3 Effect of solvents in a competitive aldol reaction or protona-
of KOH in DMSO did not proceed and 92% of the amide 6a tion of a potassium enolate of 8.
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and amide 8 in ratios of 1 : 9 and 4 : 6, respectively. These
results show that higher nucleophilicity of amide enolate
emerged in DMSO.17,18
The real-time monitoring of the KOH-catalyzed three-com-
ponent reaction of nitroalkane 1a, acrylamide 2a, and alde-
hyde 3a in DMSO-d6 was conducted by 1H NMR at room temp-
erature (Fig. 2). In the initial stage, the Henry adduct 5a
formed more rapidly than the three-component adduct 4a and
the Michael product 6a. Then, 4a and 6a formed gradually
with the disappearance of the Henry adduct 5a. This result
suggested that Henry/retro–Henry reaction of 1a and 3a readily
took place with accompanying the DNMA reaction giving 4a.
This monitoring also confirmed that the three-component
adduct 4a formed more smoothly than the Michael adduct 6a.
Based on the above-described experimental results, a reac-
tion mechanism of the three-component reaction is proposed
in Fig. 3. The Michael addition of a nitronate anion 10, which
is formed by deprotonation of nitroalkane 1a with a base or by
the retro-Henry reaction of 5a, to acrylamide 2a gives a transi-
ent amide enolate 11. Intermolecular aldol reaction of the cata-
lytically formed transient amide enolate 11 with aldehyde 3a
provides an aldolate anion 12. Protonation of the transient
amide enolate 11 with a relatively acidic nitroalkane 1a com-
petes with the intermolecular aldol reaction. High nucleophili-
city of the transient amide enolate 11 for the aldol reaction
rather than Brønsted basicity for the protonation to 6a
emerges by using DMSO as a solvent. It is thought that the
high nucleophilicity came from less aggregated amide enolates
in DMSO.19,20 Less aggregated enolates that have a more
C-anionic character than an O-anionic one21 attack the soft
carbonyl carbon of aldehydes. The catalytic cycle is established
by generation of the nitronate anion 10 and the three-com-
ponent adduct 4a by protonation of the aldolate anion 12 with
nitroalkane 1a.
Fig. 3 A proposed catalytic cycle.
The synthetic utility of β′-hydroxy-γ-nitro amides is shown
in Scheme 4. The nitro group of 4k was reductively removed to
13 by combined use of Bu3SnH and AIBN,22 and 13 was
obtained in 77% yield. The nitro group of 4k was selectively
Scheme 4 Synthetic utility of the three-component adduct 4k.
hydrogenated to a primary amine 14 in 67% yield with H2 and
Pd/C. Chemoselective reduction of the anti-isomer of mesy-
lated 4k with Pd/C and H2 gave γ-nitro amide 15 in 75% yield,
whereas reduction of the syn-mesylate did not proceed.
Conclusions
We have developed catalytic intermolecular DNMA reactions of
acrylamides, nitroalkanes, and aldehydes by using a catalytic
amount of KOH in DMSO. It was found that the use of DMSO
as a solvent was critical for generation of highly nucleophilic
transient amide enolates by Michael addition of nitronates to
acrylamides. Amide enolates generated in DMSO showed very
high nucleophilicity toward aldehydes rather than Brønsted
basicity to nitroalkanes. The profound nature of transient eno-
Fig. 2 Monitoring of KOH (8.5 mol%)-catalyzed DNMA reaction of 1a,
2a, and 3a in DMSO-d6.
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lates in DMSO and the use of a catalytic amount of KOH, a
common base, will offer a new possibility in the development
of other multi-component reactions under environmentally
friendly reaction conditions.
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Conflicts of interest
9 For more than stoichiometric amounts of KOH in DMSO in
enolate chemistry, see: T. Kawabata, K. Moriyama,
S. Kawakami and K. Tsubaki, J. Am. Chem. Soc., 2008, 130,
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There are no conflicts to declare.
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