Catalytic Asymmetric Addition Reactions of Formaldehyde N, N-Dialkylhydrazone to Synthesize Chiral Nitrile Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c01857

A number of nitrile-containing chiral molecules were synthesized via asymmetric nucleophilic addition of formaldehyde N,N-dialkylhydrazone as the nitrile equivalent. Chiral N,N′-dioxide/metal salt complexes enabled the asymmetric addition reactions to both isatin-derived imines and α,β-unsaturated ketones, generating amino nitriles and 4-oxobutanenitrile derivatives in good yields with high enantioselectivities. This protocol was highlighted by avoiding the use of toxic nitrile reagents, wide substrate scope, and versatile transformations of chiral hydrazone adducts into other valuable molecules.

Full text of DOI:10.1021/acs.orglett.0c01857

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Letter
Catalytic Asymmetric Addition Reactions of Formaldehyde
N,N‑Dialkylhydrazone to Synthesize Chiral Nitrile Derivatives
Hang Zhang, Yao Luo, Chenhao Zhu, Shunxi Dong, Xiaohua Liu,* and Xiaoming Feng*
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ABSTRACT: A number of nitrile-containing chiral molecules were synthesized via asymmetric nucleophilic addition of
formaldehyde N,N-dialkylhydrazone as the nitrile equivalent. Chiral N,N′-dioxide/metal salt complexes enabled the asymmetric
addition reactions to both isatin-derived imines and α,β-unsaturated ketones, generating amino nitriles and 4-oxobutanenitrile
derivatives in good yields with high enantioselectivities. This protocol was highlighted by avoiding the use of toxic nitrile reagents,
wide substrate scope, and versatile transformations of chiral hydrazone adducts into other valuable molecules.
Scheme 1. Catalytic Asymmetric Additions of FDAH
hiral nitrile-containing molecules play a significant role in
Casymmetric synthesis since they can be readily converted
into other valuable optically active functionalized compounds,
such as carboxylic acids derivatives, amines, aldehydes, ketones,
and heterocycles.1 Moreover, an array of enantioenriched
nitriles have been found in pharmaceutical molecules.2 During
the past several decades, tremendous endeavors have been
devoted to the rapid construction of chiral nitriles from both
academics and industry researchers.3,4 Among of various
methods established, the addition of cyano reagents to
prochiral carbonyl compounds, imines, and alkenes represents
one of the most efficient and prevailing strategies.4 However,
most of these methods suffered from the use of highly toxic
cyanide reagents as the nitrile source.4 In light of safety and
environmental constraints, the search for low toxic5 and/or
cyanide-free6 nitrile sources has become a much sought after
goal among synthetic chemists. Until now, several well-
designed nitrile equivalents have been successfully utilized in
a few of organic transformations,6 including sporadic
asymmetric variants.6b−f,8,9 Nevertheless, there still leaves
much room for improvement in terms of type of catalyst,
efficiency, and substrate scope.
Benefitting from ready availability and ease of trans-
formation into formyl and cyanide functional groups, form-
aldehyde N,N-dialkylhydrazone (FDAH) has been extensively
studied as a distinct and useful neutral synthon by the groups
of Enders, Lassaletta, and others.7−9 Notably, the asymmetric
addition of such hydrazone to imines (Scheme 1a-1) and
electron-deficient olefins provides an alternative route to
enantiomerically enriched Strecker adducts and related
Received: June 2, 2020
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© XXXX American Chemical Society
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a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope for Isatin-Derived Imines
b
c
entry
ligand
yield (%)
ee (%)
1
2
3
4
L-PrPr2
97
52
98
98
98
90
98
98
98
96
30
20
49
70
75
74
79
83
92
92
L-RaPr2
L-PiPr2
L-PiEt2
5
L-PiEt2Me
L-PiMe3
6
d
7
L-PiEt2Me
L-PiEt2Me
L-PiEt2Me
L-PiEt2Me
de
,
8
d f
−
9
d g
−
10
a
Reactions were performed with 1a (0.10 mmol), 2a (1.5 equiv), 4 Å
MS (20 mg), and Zn(OTf)2/ligand (1:1, 10 mol %) in CH2Cl2 (0.5
a
Reactions were performed with 1 (0.20 mmol), 2b (1.5 equiv), and
b
c
Zn(OTf)2/L-PiEt2Me (1:1, 5 mol %) in CHCl3 (0.4 mL) at −20 °C
for 24 h; after column separation, m-CPBA (85 wt %, 3 equiv) was
added to the products 3 in CH2Cl2 (2.0 mL).
mL) at 30 °C for 24 h. Yield of the isolated product. Determined by
chiral HPLC analysis on a chiral stationary phase. CHCl3 (0.5 mL)
was used without 4 Å MS. Substrate 2b was used. At −20 °C. 5 mol
% catalyst in CHCl3 (0.2 mL).
d
e
f
g
with high enantiomeric excess by subsequent oxidization of the
adducts under mild conditions.
nitriles.8 Generally, chiral organocatalysts were found to be
particularly appropriate for accelerating foregoing reactions.7d,8
In contrast, asymmetric variants with chiral Lewis acid
complexes were rare.9 In this respect, the group of Lassaletta
described the first example wherein Zn(OTf)2/tBuBOX was
employed as an efficient promoter in asymmetric conjugate
addition of FDAH to alkyl-substituted α-hydroxy enones
(Scheme 1a-2).9a Recently, Carreira and co-workers developed
an elegant Iridium-mediated asymmetric allylic substitution
with FDAH as a neutral C1-nucleophile (Scheme 1a-3).9b As
part of our interest in synthesis of chiral nitriles,10 we
envisioned that chiral N,N’-dioxide−metal complexes11
developed by our group have potential to be efficient catalysts
in the asymmetic additions of FDAH to imines and electron-
deficient olefins for two reasons: (1) The well-defined chiral
N,N′-dioxide−metal Lewis acid catalysts prefer to coordinate
with electrophiles in a bidentate fashion rather than nitrogen
atom of FDAH, which was crucial for maintaining the high
activity of catalyst and avoiding the decomposition of
FDAH.10e (2) Outstanding performance has been shown for
chiral N,N′-dioxide−metal complexes in discriminating
prochiral face of various electrophiles.11c Herein, we report
our achievement in this area. Highly enantioselective addition
reactions of formaldehyde N,N-dialkylhydrazone with isatin-
derived imines and α,β-unsaturated ketones were achieved in
the presence of chiral N,N′-dioxide complexes of ZnII, MgII, or
NiII salts. Various enantioenriched nitriles, including amino
nitriles and 4-oxobutanenitriles, were afforded in good yields
First, the addition of formaldehyde N,N-dialkylhydrazone 2a
to isatin-derived imine 1a was selected as the model reaction to
optimize the reaction conditions (Table 1). On the basis of the
initial investigation,10e Zn(OTf)2 was employed as the central
metal to examine chiral N,N′-dioxide ligands. It was found that
L-pipecolic acid derived L-PiPr2 was superior than L-PrPr2
derived from L-proline and L-RaPr2 derived from L-ramipril in
terms of enantioselectivity (98% yield, 49% ee, entry 3 vs
entries 1 and 2). The substituents at the amide moiety in the
ligand displayed an important role on the chiral control, the
use of the ligand L-PiEt2Me bearing 2,6-diethyl-4-methyl
substituent delivered the highest ee value (entry 5 vs entries 4
and 6, 75% ee). When CHCl3 was used as the solvent and no 4
Å MS was added, the product 3aa was obtained in 98% yield
with a slightly higher ee value (entry 7 vs entry 5; 79% ee).
Fortunately, switching substrate 2a having piperidine ring to
2b with pyrrolidine ring resulted in an increased enantiomeric
excess (entry 8, 83% vs 79% ee). In addition, performing the
reaction at −20 °C provided a significant improvement for the
enantioselectivity of 3ab (entry 9, 92% ee). Finally, adjustment
of the reaction concentration supplied the optimal conditions,
and the product 3ab was isolated in 96% yield, 92% ee at 5 mol
% catalyst loading (entry 10). As expected, treatment of adduct
3ab with m-CPBA (3 equiv) delivered the corresponding chiral
amino nitrile 4ab in 90% yield with 91% ee.
With these optimized reaction conditions in hand, various
substituted isatin imines 1 were examined. As shown in
B
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a
Scheme 3. Substrate Scope for Ketones
a
These reactions were performed with 5 (0.20 mmol), 2b (1.5 equiv), and Mg(OTf)2/L-PrPr2 (1:1, 10 mol %) in EtOAc (1.0 mL) at 30 °C for the
b
indicated time. Then MMPP·6H2O (80 wt %, 204 mg, 1.6 equiv) was used to oxidize isolated product 6 into nitriles 7. Carried out with 9 (0.20
c
mmol), 2b (1.5 equiv), and Ni(OTf)2/L-PrPr3 (1:1, 10 mol %) in EtOAc (1.0 mL) at 30 °C. Then m-CPBA (85 wt %, 80 mg, 2 equiv) was used
d
in the following oxidation process. Performed with 13a (0.10 mmol), 2b (1.5 equiv), and Co(OTf)2/L -PrPr3 (1:1, 10 mol %) in DCM (0.5 mL)
2
e
at 35 °C for 24 h. Carried out with 13b−13d (0.10 mmol), 2b (1.5 equiv), and Ni(OTf)2/L -PrPr3 (1:1, 10 mol %) in DCM (0.5 mL) at 35 °C
for 48 h.
2
Scheme 2, the reaction of FDAH 2b with N-Boc imines 1
prepared from different N-protected isatin derivatives, such as
methyl, −CH2CO2 Bu, propargyl, and allyl groups, occurred
the reaction was carried out with Mg(OTf)2/L-PrPr2 in EtOAc
at 30 °C, following an oxidation reaction of the addition
product 6ab by MMPP·6H2O (magnesium monoperoxyph-
thalate), the corresponding chiral β-cyano substituted ketone
7ab was isolated in 98% yield and 93% ee along with a minute
amount of β-formyl-substituted ketone 8ab. Next, different
unsaturated acylpyridines 5 were tested (Scheme 3a). It is
important to note that the addition products 6, especially with
electron-donating substituents at the β-aryl group, were
unstable at room temperature. Thus, these adducts were
immediately converted into the stable nitrile adducts 7. As
summarized in Scheme 3a, subjecting β-aromatic substituted
enones 5a−5g into the above conditions afforded the desired
products 7ab−7hb in high yields and moderate to high
enantioselectivities (90−98% yields and 81−94% ee). In
addition, the absolute configuration of the product 7hb was
determined to be R by X-ray crystal diffraction analysis. In
comparison, the reaction of the substrate 5i with a tert-butyl
group provided the adduct 7ib in moderate ee value (64% ee).
Encouraged by these results, we attempted to displace
unsaturated acylpyridines 5 with α,β-unsaturated 2-acylimida-
t
well, yielding the corresponding chiral amino nitriles 4bb−4gb
in good to high yields (78−95%) with excellent enantiose-
lectivities (92−97% ee). It was worth noting that the product
4gb (94% yield and 93% ee) could be easily transformed into
the spirohydantoin I according to a previous report,12a which
was potentially useful in the treatment of pain.12b The
substituents on the phenyl ring of isatin backbones were also
investigated. Regardless of the substituent pattern and the
electronic property of the aryl moiety, the products 4hb−4rb
could be furnished in good results (81−95% yield, 84−93%
ee). In addition, the absolute configuration of the product 4eb
was determined to be S by X-ray crystal diffraction analysis.
Subsequently, we turned our attention to extend the
substrate scope to the α,β-unsaturated carbonyl compounds.
Unsaturated acylpyridine 5a and FDAH 2b were selected as
model reactants, and only moderate ee value was given under
the above optimized conditions. Therefore, the reaction
parameters were modulated (for details, see the SI). When
C
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chiral β-formyl substituted carbonyl derivative, which was
difficult to access by conventional catalytic Stetter reaction.15
Moreover, following by a well-established Wittig reaction, the
1,6-dicarbonyl compound 16 was afforded in 76% yield (three
steps), 6/94 Z/E, and 93% ee. With the same procedure shown
in Scheme 4a, compound 16 could be transformed into the
corresponding ester 17 in 90% yield and 92% ee (Scheme 4b).
In addition, the β-cyano-substituted ketone 12bb was also
obtained in 90% yield and 94% ee after a subsequent oxidative
transformation. Treatment of product 12bb with MeOTf in
acetonitrile, followed by a catalytic amount of DMAP in
methanol, could furnish synthetic useful intermediate chiral β-
cyano ester 18 in 85% yield and 90% ee (Scheme 4c), which
could be easily transformed into the drug R-Baclofen according
to a previous report.14
Scheme 4. Gram-Scale Experiment and Product
Derivatizations
In summary, the catalytic asymmetric addition reactions of
formaldehyde N,N-dialkylhydrazone with isatin imines or α,β-
unsaturated ketones were achieved by using chiral N,N′-
dioxide/metal salt complexes as the catalysts. The correspond-
ing chiral adducts were readily converted into enantioenriched
nitrile compounds. This addition/oxidation sequence provided
an efficient and practical access to diverse chiral nitriles
without having to resort to the use of highly toxic nitrile
reagents. In addition, it also gave a convenient way to
synthesize the formaldehyde Stetter adduct. Further studies on
the exploration of the current method in organic synthesis and
extension to other substrates are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01857.
■
zoles 9, which could be readily transformed into esters.13 To
our delight, in the presence of Ni(OTf)2/L-PrPr3 complex,
substrates 9a−9i bearing either β-aryl or β-alkyl groups led to
the addition products 10ab−10ib in high yields with excellent
enantioselectivities (Scheme 3b, 85−99% yields, 94−96% ee).
When the ketone 9j bearing a chiral substituent was used in
this catalytic system, the addition product 10jb was isolated in
excellent diastereoselectivity (>19:1 dr) with 54% yield along
with 39% yield of the intramolecular Diels−Alder adduct 11
(>19:1 dr). Since the products 10 with electron-rich aromatic
groups or alkyl substituents were not stable, they were readily
oxidized into chiral nitriles 12 by using m-CPBA as the
oxidant. As depicted in Scheme 3b, all of the nitrile products
12 were obtained in moderate to good yields (12ab, 12kb−
12sb, 65−89% yield) with excellent enantioselectivities (93−
98% ee). In addition, sterically congested β,β-disubstituted
α,β-unsaturated ketones 13a−d were also well tolerated in
modified catalytic system, generating the all-carbon quaternary
nitrile products 14 in high yields with moderate enantiose-
lectivities (Scheme 3c, 14ab−14db, 87−99% yields, 45−80%
ee).
To evaluate the synthetic potential of the catalytic system, a
gram-scale synthesis of 4-oxobutanenitrile 12rb was carried
out. As shown in Scheme 4a, 5.0 mmol of 9r reacted smoothly
with 7.5 mmol of 2b with 5 mol % of the catalyst Ni(OTf)2/L-
PrPr3, delivering the product 12rb in 95% yield and 94% ee
after a subsequent oxidative transformation. Furthermore,
treatment of product 12rb with MeOTf, followed by DMAP in
methanol could furnish synthetic useful intermediate chiral β-
cyano ester1c,d,10a 15 in 95% yield and 93% ee (Scheme 4a).
The absolute configuration of 15 was assigned to be R by
comparing the optical rotation data in reported literature.14
Additionally, in the presence of copper salt and HCl(1.5 M)/
Et2O, the addition product 10rb smoothly converted into
sı
Experimental details, characterization data (copies of 1H,
13C{1H}, 19F{1H} NMR, HPLC, and HRMS data)
(PDF)
Accession Codes
CCDC 1982495 and 2007078 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Xiaohua Liu − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0001-9555-0555; Email: xhliu@scu.edu.cn
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478; Email: xmfeng@scu.edu.cn
Authors
Hang Zhang − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Yao Luo − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
D
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140, 16353. (g) Orecchia, P.; Yuan, W. M.; Oestreich, M. Transfer
Hydrocyanation of α- and α,β-Substituted Styrenes Catalyzed by
Boron Lewis Acids. Angew. Chem., Int. Ed. 2019, 58, 3579.
Chenhao Zhu − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
(6) (a) Fier, P. S.; Maloney, K. M. NHC-Catalyzed Deamination of
Primary Sulfonamides: A Platform for Late-Stage Functionalization. J.
Am. Chem. Soc. 2019, 141, 1441. (b) Schuppe, A. W.; Borrajo-Calleja,
G. M.; Buchwald, S. L. Enantioselective Olefin Hydrocyanation
without Cyanide. J. Am. Chem. Soc. 2019, 141, 18668. (c) Li, X. X.;
You, C.; Yang, J. X.; Li, S. L.; Zhang, D. Q.; Lv, H.; Zhang, X. M.
Asymmetric Hydrocyanation of Alkenes without HCN. Angew. Chem.,
Int. Ed. 2019, 58, 10928. (d) Betke, T.; Rommelmann, P.; Oike, K.;
Shunxi Dong − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0002-3018-3085
Complete contact information is available at:
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̈
Asano, Y.; Groger, H. Cyanide-Free and Broadly Applicable
Notes
Enantioselective Synthetic Platform for Chiral Nitriles through a
Biocatalytic Approach. Angew. Chem., Int. Ed. 2017, 56, 12361.
(e) Guin, J.; Varseev, G.; List, B. Catalytic Asymmetric Protonation of
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Plant, A.; Backhaus, D.; Reinhold, U. Asymmetric Synthesis of α-
Substituted Nitriles and Cyanohydrins by Oxidative Cleavage of
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21801175 and U19A2014) for financial support.
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