Catalytic enantioselective desymmetrization of cyclobutane-1,3diones by carbonyl-amine condensation

Article abstract of DOI:10.1021/acs.orglett.1c00067

A chiral phosphoric acid-catalyzed enantioselective condensation of 2,2-disubstituted cyclobutane-1,3-diones with a primary amine is described. This reaction offered a mild and efficient protocol for constructing quaternary carbon-containing cyclobutanes

Full text of DOI:10.1021/acs.orglett.1c00067

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Letter
Catalytic Enantioselective Desymmetrization of Cyclobutane-1,3-
diones by Carbonyl-Amine Condensation
Kai-Ge Wen, Chao Liu, Dong-Hui Wei, Yan-Fei Niu,* Yi-Yuan Peng,* and Xing-Ping Zeng*
Cite This: Org. Lett. 2021, 23, 1118−1122
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ABSTRACT: A chiral phosphoric acid-catalyzed enantioselective
condensation of 2,2-disubstituted cyclobutane-1,3-diones with a
primary amine is described. This reaction offered a mild and
efficient protocol for constructing quaternary carbon-containing
cyclobutanes in good to high yields and enantioselectivities. This
reaction is the first catalytic desymmetrizing carbonyl-amine
condensation reaction and also represents the first catalytic desymmetrizing reaction of prochiral cyclobutane-1,3-dione.
Scheme 1. Catalytic Asymmetric Carbonyl-Amine
Condensation
s a fundamental organic reaction, the dehydration
condensation of carbonyl compounds with amines played
A
a significant role in chemical synthesis.1 Very interestingly,
however, the enantioselective version of this reaction was
largely unexplored. Because the condensation reaction itself
does not create a new chiral center, an asymmetric version of
this reaction could be realized by only either kinetic resolution
of racemic substrates or desymmetrization of prochiral
substrates. Pioneering contributions to this field were made
by List and co-workers in 2017. They reported that the kinetic
resolution of primary amines could be achieved via catalytic
asymmetric carbonyl-amine condensation using a chiral
Brønsted acid catalyst and a 1,3-diketone as the reaction
counterpart (Scheme 1a).2 Unfortunately, such groundbreak-
ing progress did not attract enough attention, as no follow-up
report was found, to the best of our knowledge.
Chiral quaternary carbon-containing cyclobutanes and their
derivatives are important structural units that exist in bioactive
natural products and pharmaceutically relevant small molecules
(Scheme 1c).3 Moreover, they also served as useful precursors
for the synthesis of other value-added organic compounds.4
Therefore, much effort has been devoted to developing
efficient and enantioselective methods for the construction of
functionalized chiral quaternary carbon-containing cyclo-
butanes.5 Despite these significant advances, the development
of mild and efficient protocols remains highly desirable.
On the contrary, the desymmetrization of cyclic 1,3-
diketones has been identified as a powerful synthesis of cyclic
chiral molecules. Previously, the catalytic desymmetrizing
reactions of prochiral cyclopentane-1,3-diones and cyclo-
hexane-1,3-diones have been well established and applied to
the total synthesis of natural products and bioactive
compounds.6 Nevertheless, the catalytic desymmetrization of
prochiral cyclobutane-1,3-dione to construct quaternary
carbon-containing cyclobutane has never been documented,
although several catalytic desymmetrizations of other prochiral
four-membered cyclic substrates have been reported.7
Inspired by List’s seminal research work, together with our
interest in catalytic asymmetric desymmetrizing reactions, we
report herein a chiral phosphoric acid-catalyzed enantioselec-
tive condensation reaction of quaternary cyclobutane-1,3-
Received: January 8, 2021
Published: January 26, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00067
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1118−1122
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diones with a primary amine, which offered an alternative
access to quaternary carbon-containing chiral cyclobutanones
in good to high yields and enantioselectivities (Scheme 1b).
This reaction is the first catalytic desymmetrizing carbonyl-
amine condensation reaction and also represents the first
catalytic desymmetrizing reaction of prochiral cyclobutane-1,3-
dione.
An inherent problem in the development of the catalytic
carbonyl-amine condensation reaction is the identification of
an amine with suitable basicity and nucleophilicity. In other
words, a good amine counterpart should not quench the chiral
Brønsted acid catalysts or cause serious noncatalytic back-
ground reaction. We commenced our reaction development by
reacting prochiral cyclobutane-1,3-dione 1a with various
amines in DCE using (R)-TRIP as the catalyst at 25 °C
(Table 1).8
Solvent effect optimization revealed toluene as the optimal
choice, in which the reaction could give the highest yield of
89% (entries 11−14). Considering that the current reaction is
a dehydration process, we tried to add activated molecular
sieves (MS) to remove the byproduct H2O from the organic
phase and, thus, accelerate the reaction. After several trials
(entries 15−17), we found the addition of 5 Å MS could afford
the best results, in terms of both yield and enantioselectivity
(entry 16). When the reaction temperature was decreased to 0
°C, the reaction became rather sluggish and no significant
improvement in the ee value was observed (entry 18). Further
optimization revealed that decreasing the amount of 5 Å MS to
50 mg could promote the reaction to reach completion within
24 h and afford the desired product in 97% yield and 90%
enantioselectivity (entry 19).
The scope of this catalytic desymmetrizing carbonyl-amine
condensation reaction was then examined using the optimized
reaction conditions described above (Scheme 2). The effect of
the substituents on the benzene ring of the benzyl group was
first evaluated. In general, the introduction of both an electron-
a
Table 1. Reaction Development
Scheme 2. Substrate Scope
entry
R
solvent
t (h)
yield (%)
ee (%)
1
2
3
4
Bn (2a)
Ph (2b)
p-Ts (2c)
DCE
DCE
DCE
DCE
24
2
24
2
no reaction
97
no reaction
97
−
9
−
4-MeO-C6H4 (2d)
6
5
6
7
8
3,5-Me2-C6H3 (2e)
2,4,6-Me3-C6H2 (2f)
2,6-(iPr)2-C6H3 (2g)
4-NO2-C6H4 (2h)
C6F5- (2i)
3,5-(CF3)2-C6H3 (2j)
2f
2f
2f
2f
2f
2f
2f
2f
2f
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
toluene
PhCF3
n-C6H14
toluene
toluene
toluene
toluene
toluene
2
96
81
16
89
−
72
72
12
72
12
72
72
72
72
72
48
48
72
24
no reaction
97
59
94
65
89
88
60
79
97
89
<10
97
24
53
38
90
89
87
89
91
90
89
91
90
9
10
11
12
13
14
15
16
17
18
19
b
c
d
c
,e
f
a
All reactions were conducted using 1a (0.2 mmol), 2 (0.3 mmol),
and (R)-TRIP (10 mol %) in 2 mL of solvent at 25 °C, unless noted
b
c
d
otherwise. With 4 Å MS (100 mg). With 5 Å MS (100 mg). With
e
f
13 X MS (100 mg). At 0 °C. With 5 Å MS (50 mg).
Initially, we tried to use benzyl amine (2a), but no reaction
took place, possibly because of its high basicity (entry 1). To
our delight, when the less basic aniline (2b) was subjected to
the conditions described above, the reaction proceeded
smoothly to give the desired chiral quaternary cyclobutenone
in 97% yield, albeit with only 9% ee values (entry 2). The more
electron-deficient amines, such as p-TsNH2 and H2NBoc,
showed no reactivity (entry 3). In the following, we examined
the steric and electronic effects of anilines on the reaction
outcome, aiming to improve the enantioselectivity (entries 4−
10). It was found that when 2,4,6-trimethyl aniline (2f), which
is moderate in both nucleophilicity and steric hindrance, was
used as the amine nucleophile, the desired condensation
products could be obtained in 89% ee and 81% yield (entry 6).
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donating and an electron-withdrawing group on the ortho and
meta position of the benzene ring did not have a significant
effect on the enantioselectivities of the reaction, as is shown by
86−90% ee values for products 3a−c, 3e−h, 3j, and 3k,
whereas the existence of steric substituents at the para position
could slightly improve the ee, as exemplified by the 91% and
92% ee values for 3d and 3i, respectively. The condensation of
naphthalen-1-ylmethyl-substituted cyclobutane-1,3-dione 1l
with aniline 2f also proceeded well to deliver a 97% yield
and an 86% ee for product 3l, the absolute configuration of
which has been determined by X-ray crystallography analysis
(see the Supporting Information for details). Besides benzyl
groups, allyl and other linear aliphatic substituents were also
well tolerated, giving products 3m−o in 84−89% enantiose-
lectivities. Additionally, when the more steric substrates 1p and
1q were subjected to the conditions described above, the
corresponding products 3p and 3q could be obtained in 89−
94% yields with 92% ee.
Scheme 4. Product Elaboration
shown in Scheme 5, reaction of 1a and 2f became rather
sluggish when the potassium salt of (R)-TRIP [prepared from
Scheme 5. Control Experiment and Proposed Transition
State
It should be mentioned that the ee values of the product
could be further improved by using more steric (R)-TRIP
analogues as the catalyst or recrystallization (Scheme 3). When
Scheme 3. Further Efforts to Improve the ee Value of
Products 3
(R)-TRIP and t-BuOK] was used as the catalyst and the
corresponding product 3a was obtained in only 35% yield even
after 72 h. This result indicates that the hydroxyl group in the
phosphoric acid catalyst played a vital in the success of the
current reaction. On the basis of this observation and literature
reports, a transition state for the enantio-determining step was
proposed, in which the phosphoric acid serves as a bifunctional
catalyst to activate both reactants via hydrogen-bonding
interactions.
In conclusion, the first catalytic desymmetrizing carbonyl-
amine condensation reaction of 2,2-disubstituted cyclobutane-
1,3-diones with a primary amine has been developed using
chiral phosphoric acid catalysis. The current reaction offered a
mild and efficient protocol for obtaining quaternary carbon-
containing cyclobutanes in good to high yields and
enantioselectivities. The enamine nature of the obtained
products enabled it to undergo various elaborations to give a
series of fully substituted cyclobutenone derivatives. Notice-
ably, this reaction also represents the first catalytic desymme-
trizing reaction of prochiral 2,2-disubstituted cyclobutane-1,3-
diones.
chiral phosphoric acid PA14 was used instead of (R)-TRIP,
the reaction of 1a and 2f could give product 3a in 96% yield
with 94% ee. To demonstrate the practicability of the current
method, we conducted a gram-scale reaction of cyclobutane-
1,3-dione 1a and 2,4,6- trimethyl aniline 2f (Scheme 3). In the
presence of only 5 mol % (R)-TRIP, the reaction of 1a (4.0
mmol) with 2f (1.25 equiv) could deliver product 3a in 91%
yield (1.11 g) with 90% ee. The ee value of 3a could be
improved from 90% to 99% via a single recrystallization from
acetone and petroleum ether in 78% yield.
The thus obtained chiral cyclobutenone could undergo
various elaborations to give a series of fully substituted
cyclobutenone derivatives. Upon treatment with NBS and
KSCN, 3a could be transformed into 4 in 97% yield without a
loss of enantiopurity.9 In addition, the enamine nature of 3a
enabled it to participate in nucleophilic addition reactions, as
exemplified by the synthesis of 2-ethoxymethyl cyclobutenone
5 and 2-aminomethyl cyclobutenone 6 in 91% and 80% yields,
respectively.10 We also tried the reaction of 3a with α,β-
unsaturated ketones and nitroalkenes, but no reaction was
observed in the presence of either Brønsted acid or base
catalyst (Scheme 4).
ASSOCIATED CONTENT
* Supporting Information
■
sı
To gain preliminary insight into the mechanism of the
current reaction, a control experiment was conducted. As
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00067.
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REFERENCES
General procedures and experimental details for all
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3 (PDF)
■
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AUTHOR INFORMATION
■
Corresponding Authors
Xing-Ping Zeng − Key Laboratory of Small Functional
Organic Molecule, Ministry of Education and Jiangxi Key
Laboratory of Green Chemistry, College of Chemistry and
Chemical Engineering, Jiangxi Normal University, Nanchang,
Jiangxi 330022, China; orcid.org/0000-0002-8643-
8091; Email: 005173@ jxnu.edu.cn
Yi-Yuan Peng − Key Laboratory of Small Functional Organic
Molecule, Ministry of Education and Jiangxi Key Laboratory
of Green Chemistry, College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang, Jiangxi
330022, China; Email: yypeng@ jxnu.edu.cn
̈
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Yan-Fei Niu − Shanghai Key Laboratory of Green Chemistry
and Chemical Process, East China Normal University,
Shanghai 200062, China; Email: yfniu@chem.ecnu.edu.cn
Authors
Kai-Ge Wen − Key Laboratory of Small Functional Organic
Molecule, Ministry of Education and Jiangxi Key Laboratory
of Green Chemistry, College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang, Jiangxi
330022, China
Chao Liu − Key Laboratory of Small Functional Organic
Molecule, Ministry of Education and Jiangxi Key Laboratory
of Green Chemistry, College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang, Jiangxi
330022, China
Dong-Hui Wei − Key Laboratory of Small Functional Organic
Molecule, Ministry of Education and Jiangxi Key Laboratory
of Green Chemistry, College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang, Jiangxi
330022, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00067
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful for the financial support from the
National Natural Science Foundation of China (21702080),
the Natural Science Foundation of Jiangxi Province of China
(20181BAB213003), the Open Project Program of Key
Laboratory of Functional Small Organic Molecule, Ministry
of Education, Jiangxi Normal University (KLFS-KF-201603),
and the foundation of Jiangxi Educational Committee
(170223).
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