Enantioselective electrophilic cyanation of β-keto amides catalysed by a cinchona organocatalyst

Article abstract of DOI:10.1039/c7ob01782k

An operationally simple protocol for the enantioselective electrophilic α-cyanation of β-keto amides catalyzed by cinchona-derived catalysts has been demonstrated. The resulting products could be obtained with good to high enantioselectivities (up to 88% ee) and with excellent yields (up to 94%) by employing the mild active 4-acetylphenyl cyanate as the cationic cyano source in the catalytic asymmetric α-cyanation reaction.

Full text of DOI:10.1039/c7ob01782k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C7OB01782K
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Enantioselective Electrophilic Cyanation of β-keto Amides
Catalysed by Cinchona Organocatalyst
Received 00th January 20xx,
Accepted 00th January 20xx
Pran Gopal Karmaker, Jiashen Qiu, Di Wu, Mengmeng Reng, Zhuo Yang, Hongquan Yin and Fu-Xue
Chen*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An operationally simple protocol for the enantioselective disclosed the racemic α- cyanation of β-keto carbonyls with
electrophilic α-cyanation of β-keto amides catalyzed by cinchona- cyanohyperiodine reagent.14a Subsequently in the same year,
derived catalysts has been demonstrated. The resulting products Waser15a and Zheng15b individually reported their asymmetric
could be obtained with good to high enantioselectivities (up to 88% versions with moderate to good ee values using alkaloid-based
ee) and with excellent yields (up to 94%) by employing the gentle organocatalysts. A third interesting example came from Feng
active 4-acetylphenyl cyanate as the cationic cyano source in the and Liu’s group by an amazing hydrogen-bond network using
catalytic asymmetric α-cyanation reaction.
their featuring N,N'
-dioxide organocatalysts.15c-d They all used
synthesized hypervalent iodine(III) reagents which have been
vastly used in many organic transformations (Scheme 1a).6c,16
Considering the activity of hypervalent iodine(III) reagent, we
selected mild aromatic cyanate as the cyano source affording
excellent enantioselectivities using Lewis acid catalysis.14b
However, β-keto amides are still the problematic substrates
suffering either high catalyst loading, or low enantioselectivity
or even no conversion. Compared with the β-keto esters,15e
the α-functionalization of β-keto amides has been much less
investigated,7f,14b,17a-b possibly due to the lower acidity of the
α-hydrogen, although the amide group is useful for further
manipulation.17 Inspired by these above literature survey as
well as our illimitable interest in the asymmetric synthesis, we
became interested in developing a novel protocol for the
The enantioselective introduction of a cyano group into
various substrates has received considerable research interest
because it was discovered to be an important functional group
among natural products, pharmaceuticals, materials,
agrochemicals as well as multipurpose intermediate with
diverse transformations.1 There are several successful
examples of asymmetric nucleophilic addition of cyano
reagents to sp2-hybridized electrophiles bearing C=O, C=N, and
C=C bonds.2
In the last decade, significant achievements have been made
in nucleophilic addition of cyanide to electrophiles in which,
e.g., preparations of chiral nitriles and cyanohydrins are
realized by the extensively studied enantioselective 1,2-
addition of imines, ketones and aldehydes,2 and conjugated
hydrocyanation of α,β-unsaturated carbonyls3 with diverse
nucleophilic cyanide precursors.4 However, as an alternative
method, electrophilic cyanation reaction of sp3 carbon has
been less explored in previously studied reports compared to
nucleophilic ones.5 On the other hand, α-functionalization of
carbonyl compounds have been developed a large numbers of
interesting synthetic building blocks and molecules.6 A variety
of transformations, specifically through the electrophilic
reaction corridor, such as α-fluorination,7 halogenation,8
hydroxylation,9 arylation,10 trifluoromethylation,7b,11 trifluoro-
methylthiolation,12 and azidation.13 Recently, our group
asymmetric α-cyanation reaction of β-keto amides (1) using
mild active 4-acetylphenyl cyanate (2b) as the electrophilic
cyano transfer reagent (Scheme 1b).
Scheme 1 Asymmetric electrophilic α-cyanation reaction of β-keto amides
School of Chemistry & Chemical Engineering, Beijing Institute of
Technology, 5 South Zhongguancun street, Haidian district, Beijing
100081, China. Fax: (+86)10-68918296. E-mail: fuxue.chen@bit.edu.cn
a.Electronic Supplementary Information (ESI) available: experimental procedure,
characteristics of compounds, copies of spectra, CCDC 1563576. See
DOI: 10.1039/x0xx00000x
Results and Discussion
To optimize the catalyst performance, initially the model
substrate of racemic β-ketoamide (1a) was selected to be
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treated with 4-acetylphenyl cyanate (2b) in the presence of 4 Å yield but the same ee value (entry 19). Further decreasing the
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molecular sieve (MS) in CH2Cl2 at 0 oC under an argon catalyst loading to 1 mol% eroded the catalyst capacity
DOI: 10.1039/C7OB01782K
atmosphere, using a variety of easily accessible cinchona significantly (entry 20). To retain the catalyst efficiency,
derived organocatalysts of different nature (Figure 1). Table 1 increasing the amount of cyano reagent 2b from 1.2 equiv. to
presents an outline of the most significant results obtained in a 5 equiv. improved the enantioselectivity from 73% ee to 82%
detailed screening of the catalysts and reaction parameters.
ee at 5 mol% of catalyst loading (entry 21 vs 19). Interestingly,
prolongation of reaction time from 12 h to 36 h increased both
the enantioselectivity of 3a from 82% to 88% ee and yield from
58% to 94% (entry 22 vs 21, for more details, see Figure S1 and
Table S1 in ESI).
Therefore, the natural occurring A4 is the suitable catalyst.
And the optimal catalyst efficiency was achieved in CH2Cl2 at
o
‒40 C at 5 mol% of catalyst loading with excellent 94% yield
and high enantioselectivity (88% ee) for the model substrate.
The chemical yield of 3a is a simple factor of reaction time and
equivalence of the cationic cyano reagent 2b. However, other
three cationic cyano reagents (2a, 2c and 2d) were also
screened but unfortunately found giving no desired product
under this condition. In addition, 4 Å MS (5 mg) is essential as
either absence or higher or lower of it was unbeneficial to this
protocol.
Figure 1 Cinchona-derived catalysts evaluated in this study.
Table 1 Identification of the optimal organocatalyst and the reaction conditions for the
asymmetric α-cyanation of 1a.a
We were pleased to observe the formation of the desired
product 3a with 41% ee albeit 27% yield (Table 1, entry 1)
when using a simple chinchona alkaloid A1 as the catalyst
bearing a free-OH group. This result suggested that the basic
moiety and H-bond donating group in the natural cinchona
organocatalyst could work cordially in this electrophilic
cyanation reaction. Next, we examined other naturally existed
pseudo-isomers A2, cinchonine A4, quinidine (A5), and the
symmetric dimmer A3. To our delight, A4 gave the promising
highest 54% ee of 3a and comparable low yield of 32% (entry 4
vs entries 2-3 and 5). Subsequently, some structurally modified
cinchona derivatives were screened as the catalyst but
affording inferior results. Either blocking the 9-OH groups by
Entry
Cat.
Solvent
Temp
(oC)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
-20
-40
-78
‒40
‒40
‒40
‒40
‒40
Time
(h)
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
36
Yield
(%)b
27
23
31
32
39
49
52
42
38
43
24
27
27
21
30
40
37
30
25
18
58
94
ee
(%)c
‒41
‒9
7
54
0
‒15
0
‒3
‒9
‒7
39
41
39
51
57
74
65
73
73
63
82
88
(mol%)
A1 (20)
A2 (20)
A3 (20)
A4 (20)
A5 (20)
A6 (20)
A7 (20)
A8 (20)
A9 (20)
A10 (20)
A4 (20)
A4 (20)
A4 (20)
A4 (20)
A4 (20)
A4 (20)
A4 (20)
A4 (10)
A4 (5)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21d
22d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
benzyl in A6, A7 and A9 or free 6-OH in A8 resulted in bad
catalyst performance (entries 6-9), whereas use of A10 as the
PTC catalyst produced 3a with negligible enantioselectivity and
lower yield with opposite configuration (entry 10). These data
indicate a possible H-bond raised by free 9-OH is the key for
good enantioselectivity for cinchonine in this reaction.
Prompted by this result, then the effect of solvent was
investigated. However, other solvents such as toluene, THF,
acetonitrile and chloroform are not suitable for this reaction
because of their inferior enantioselectivity and or low yield
(Table 1, entries 11-14). CH2Cl2 is the suitable solvent for this
catalytic reaction. Subsequently, decreasing the reaction
temperature to ‒20 oC furnished the product with a little
better result 57% ee (entry 15). Further lowering the reaction
temperature to ‒40 °C, the product 3a was isolated in 74% ee
(entry 16). However, performing the reaction at ‒78 oC led to a
slight drop in the both yield and ee value (entry 17).
CH3CN
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
A4 (1)
A4 (5)
A4 (5)
Decreasing the catalyst loading to 10 mol% in the model
reaction, 3a was yielded in comparable enantioselectivity and
a little lower yield (entry 18 vs 16). Continuously lowering the
amount of catalyst loading to 5 mol% gave a step-wise lowered
a Reaction Conditions: 1a (0.1 mmol), 2b (0.12 mmol, 1.2 equiv.), catalyst (20
mol%), 4Å MS (5 mg), solvent (1.0 mL) at 0 oC, 12 h under argon atmosphere,
unless otherwise indicated; Isolated yield; Enantiomeric excess (ee) was
determined by chiral HPLC analysis on Chiralpak AD-H. d 2b (0.5 mmol, 5.0 equiv.).
b
c
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Table 2 Substrate scope and limitation of the asymmetric α-cyanation.a
The absolute configuration (S) of the stereogenic
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carboncenter in the cyanated product 3cDwOaI:s1d0e.1t0e3r9m/Ci7nOeBd01b7y82XK-
ray structure analysis of the single crystal 3c with 98% ee after
simple recrystallization (Figure 2). Other products’ absolute
configurations were established by analogue.
Based on the absolute configuration of product 3c and the
above experimental observations, a plausible mechanism was
proposed in Figure 3. On one hand, the catalyst acts as a
Bronsted base to activate the substrate through enolate in
which a larger planar moiety is consolidated by H-bond around
the prochiral C=C bond by restricting free rotation of exocyclic
Cα-C single bond. On the other hand, C9-OH of cinchonine
connects the acetyl group of the cyano reagent by a second H-
bond thus activating the O-CN bond. This two hydrogen bonds
network warranted the arrangement of the most stable
conformation in the transition state, governing the Si face
attack in favour of the formation of (S)-enantiomers.
Figure 2 The X-ray structure of product 3c.
a All reactions were performed on the scale of 0.1 mmol of the substrate with 4Å
MS (5 mg) in CH2Cl2 (1 mL) at ‒40 oC for 36 h under argon atmosphere. The
results are listed with isolated yields and ee values determined by Chiral HPLC
analysis on Chiralpak AD-H.
Under the optimized reaction conditions of 1a, the substrate
scope of this protocol with some differently substituted β-keto
amides 1b-1r was subsequently explored. As shown in Table 2,
good yields and moderate to high enantioselectivities were
obtained in the α-cyanation of indanone-derived β-keto
amides. The electron-withdrawing substituent such as Cl, F and
Br in the benzene ring at 4,5,6-positions affected the yield and
enantioselectivity slightly by affording the products with a little
Figure 3 Possible model of the reaction transition-state.
lower but almost the same ee values (3b
hand, electron-donating substituent such as 6-Me, 6-MeO and
6-Ph gave higher enantioselectivity with good yield (3h 3i 3j
while β-keto amides 3k and 3l bearing 4- and 5-Ph had no
conversion indicating that the nature of substituent and its
position had complex and ambient influence on the catalyst
performance.
Moreover, substituent at the amide side also affected the
catalytic outcomes. Aniline-derived substrates containing 4'-
MeO, 4'-F, 4'-Br, 4'-CF3, 4'-H groups could be converted into
-3g). On the other
Conclusion
,
,
)
In summary, we have developed a facile enantioselective α-
cyanation of β-keto amides. The readily available of catalyst,
mild reaction conditions, and the highly functionalized nitrile
products with a chiral quaternary carbon center, all make this
transformation more practical. The corresponding products
could be obtained with good to excellent enantioselectivities
(up to 88% ee) and high yields (up to 94%) using the mild
active 4-acetylphenyl cyanate as the cationic cyano source.
the corresponding products 3m-3q in good yields (60-84%) and
moderate 61-77% ee while substrate bearing six-membered
ring (1r) was not suitable for this protocol.15a-b
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473, 470; (e) G. Valero, X. Companyó and R. Rios, Chem. Eur.
Acknowledgment
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J., 2011, 17, 2018; (f) L.-S. Zheng, Y.-L. Wei, K.-Z. Jiang, Y.
Deng, Z.-J. Zheng and L.-W. Xu, Adv. Synth. Catal., 2014,
DOI: 10.1039/C7OB01378526K
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The authors are grateful of financial support from NSFC
(21572020).
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01782K
Abstract
Enantioselective Electrophilic Cyanation of β-keto Amides Catalysed by Cinchona Organocatalysts