Preparation of O-Protected Cyanohydrins by Aerobic Oxidation of α-Substituted Malononitriles in the Presence of Diarylphosphine Oxides

Article abstract of DOI:10.1021/acs.orglett.9b00569

A mild, reagent-cyanide-free, and efficient synthesis of O-phosphinoyl-protected cyanohydrins from readily available α-substituted malononitriles was realized using diarylphosphine oxides in the presence of O₂. Mechanistic studies indicated that in addition to the initial aerobic oxidation of the malononitrile derivative notable features of this process include the formation of a tetrahedral intermediate and a subsequent intramolecular rearrangement. The phosphinoyl-protecting group can be removed by alcoholysis or by reduction with DIBAL-H.

Full text of DOI:10.1021/acs.orglett.9b00569

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Preparation of O‑Protected Cyanohydrins by Aerobic Oxidation of
α‑Substituted Malononitriles in the Presence of Diarylphosphine
Oxides
Dapeng Zhang,† Mingming Lian,*,† Jia Liu,† Shukun Tang,† Guangzhi Liu,‡ Cunfei Ma,§
Qingwei Meng,§ Haisheng Peng,*,† and Daling Zhu†
†Department of Pharmaceutics, Harbin Medical University (Daqing), Daqing 163319, China
‡Irradiation Technology Application Factory of Changshu, Changshu 215557, China
§State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology Department, Dalian University of
Technology, Dalian 116024, China
S
* Supporting Information
ABSTRACT: A mild, reagent-cyanide-free, and efficient synthesis
of O-phosphinoyl-protected cyanohydrins from readily available α-
substituted malononitriles was realized using diarylphosphine
oxides in the presence of O2. Mechanistic studies indicated that
in addition to the initial aerobic oxidation of the malononitrile
derivative notable features of this process include the formation of a
tetrahedral intermediate and a subsequent intramolecular rear-
rangement. The phosphinoyl-protecting group can be removed by
alcoholysis or by reduction with DIBAL-H.
Scheme 1. Synthetic Strategies toward Cyanohydrins or
Their O-Protected Derivatives
yanohydrins or O-protected cyanohydrins are important
Csynthons because nitrile- and alcohol-containing mole-
cules can be easily converted into a diverse range of 1,2-
difunctional compounds, such as α-hydroxy aldehydes, α-
hydroxy acids, and β-hydroxy amines.1 Recently, it has been
reported that highly functionalized compounds can be
prepared from cyanohydrins,2 and O-acetyl cyanohydrins can
also act as a derivatizable directing group for Pd-catalyzed
regioselective olefination reactions.3 Cyanohydrins are also
present in a number of natural products,4 and these
compounds show high insecticidal,5 antiviral,6 and anticancer
activities.7 Numerous strategies for accessing cyanohydrins or
the more stable O-protected derivatives generally rely on
highly toxic cyanide sources such as HCN, metal cyanides, and
TMSCN.1a,d,4e,8 Until recently, only Ruijter and Orru had
documented a Brønsted-acid-catalyzed cyanide-free method,
and they utilized trityl isocyanide as a pseudocyanide source to
prepare O-trityl cyanohydrin (Scheme 1).9
Based on our previous work on environmentally benign
methods for the α-hydroxylation of β-ketoesters,10 we
hypothesized that O2 could be used to generate a C−O
bond at the α-position of a nitrile group. Based on this
assumption, malononitrile derivatives, which contain two
nitrile groups, attracted our attention.11 Although α-position
derivatization reactions of malononitriles have become
common,12 a method for α-C−O bond formation via the
oxidation of malononitrile, yielding the corresponding
cyanohydrin or its derivative, has not been reported. In
2016, the Hayashi group reported an oxidative amidation of α-
substituted malononitriles with amines, but both nitrile groups
were lost in the reaction.13 During the aerobic process, the
oxidation state of the carbon atom in the α-position of
malononitrile was increased from −1 to +2; however, the
required oxidation state of the α-carbon in cyanohydrin is 0.14
We speculate that reducing agents, especially those containing
nonmetallic elements at lower oxidation states, may reduce the
Received: February 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00569
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Letter
oxidation state of acyl cyanide from +2 to 0, facilitating the
formation of cyanohydrin or its O-protected derivative.
Based on this hypothesis, we explored some commercially
available organophosphorus reagents as reductants in the
proposed aerobic preparation of cyanohydrin derivatives from
α-benzyl malononitrile (1a, Table 1). To our delight, the
Table 2. Oxidation of α-Substituted Malononitriles in the
Presence of Diphenylphosphine Oxide 2a
a,b
Table 1. Optimization of Organophosphorus and Reaction
a
Conditions
b
entry organophosphorus
base
solvent
time (h) yield (%)
c
1
2
3
4
5
6
7
8
P(Ph)3
(EtO)2P(O)H
P(OEt)3
Ph2P(O)H 2a
K2CO3
K2CO3
K2CO3
K2CO3
DIEA
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
DMF
MeOH
DCM
toluene
MeCN
MeCN
MeCN
24
24
24
12
24
24
4
-
-
-
c
c
3aa, 54%
3aa, 56%
3aa, 49%
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
DMAP
LiOH
c
-
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
6
3aa, 19%
3aa, 67%
3aa, 59%
9
10
11
12
13
14
15
16
20
7
24
24
3
c
-
3aa, 44%
NR
3aa, 50%
NR
d
e
f
g
24
24
h
3aa, 54%
a
Reaction conditions: 1a (1.25 mmol), organophosphorus (2.0
equiv), and base (2.0 equiv) in solvent (5 mL) were stirred under a
constant flow (bubbling) of O2 at room temperature. NR = No
b
c
reaction. Isolated yield based on 1a. Complex reaction mixture with
d
e
1a consumed. 55% of 1a was recovered. Reaction was performed at
50 °C. Reaction was performed at −10 °C. 72% of 1a was recovered.
0.5 equiv of K2CO3 was used. DIEA = N,N-diisopropylethylamine,
f
g
h
DMAP = dimethylaminopyridine.
a
Reaction conditions: 1a−z, 1a′ (1.25 mmol), and Ph2P(O)H (2.0
equiv) in MeCN (5 mL) were stirred under a constant flow
(bubbling) of O2. Conditions A: K2CO3 (2.0 equiv), room
treatment of 1a and diphenylphosphine oxide (2a) with O2 in
the presence of K2CO3 gave O-phosphinoyl-protected
cyanohydrin 3aa in 54% yield. Encouraged by this result, we
further optimized the reaction conditions. Screening inorganic
and organic bases in different solvents at room temperature
demonstrated that the mixture of MeCN and K2CO3 gave the
highest reaction yield (Table 1, entry 9). A diminished yield
was obtained when the reaction was carried out at a lower
temperature (Table 1, entry 15), while a modestly reduced
yield was achieved at a higher temperature (Table 1, entry 14).
With the optimized reaction conditions in hand (Conditions
A), we turned our attention to the scope of the reaction with
respect to the α-substituted malononitrile substrates. As shown
in Table 2, the scope of substrates with different substituents
on the benzyl ring (1b−1k, 1v) was investigated first. Electron-
donating or electron-withdrawing groups at the ortho, meta, or
para positions slightly affected the reactivity, giving desired
products 3ba−3ka in moderate to good yields. Sterically
hindered substrates, such as mesityl- or naphthalene-containing
compounds 1v or 1u, afforded O-diphenylphosphinoyl
cyanohydrins 3va and 3ua in 85% and 75% yields, respectively.
b
temperature. Conditions B: DIEA (2.0 equiv), 50 °C. Isolated yield.
Next, our intent was to apply this oxidative process to more
challenging α-phenyl malononitriles 2l−2t, as the previous
conditions were not effective for the synthesis of these
cyanohydrins. The choice of the appropriate base was crucial,
and 3la was formed in 54% yield once the base was switched
from K2CO3 to DIEA (Conditions B). The following
examinations showed that substrates 2m and 2o, bearing
electron-donating substituents at the ortho position, were well
tolerated, while 2n, with electron-withdrawing substituents,
was not suitable for the reaction. However, aromatic
malononitriles with substituents with different electronic
demands at the meta or para positions showed similar
reactivities and gave corresponding products 3pa−3ta in
41% to 59% yields. To our delight, α-naphthol substrate 2a′
with greater steric hindrance afforded corresponding cyanohy-
drin derivative 3a′a in 76% yield. In addition, the
B
DOI: 10.1021/acs.orglett.9b00569
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Letter
incorporation of heteroarene and alkane moieties is tolerated,
and 2w−2z underwent the transformation to produce 3wa−
3za in up to 81% yield.
Scheme 3. Proposed Reaction Mechanism
Having established the scope of α-substituted malononitriles
1, we next screened the scope of diarylphosphine oxides 2b−
2m and other organophosphorus compounds 2n−2p (Scheme
2). Only diarylphosphine oxides with an electron-withdrawing
Scheme 2. Oxidation of α-Benzyl Malononitrile 1a in the
a b
,
Presence of Diarylphosphine Oxide 2
P−C−O−H system results in the formation of the O-
phosphinoyl cyanohydrin.
Experiments were then carried out to clarify and evaluate the
proposed reaction mechanism. First, commercially available
benzoyl cyanide 8 was subjected to the standard conditions,
and corresponding product 3la was obtained in 98% yield after
30 min (Scheme 4A). Strikingly, when the amount of benzoyl
Scheme 4. Mechanism Studies
a
Reaction conditions: 1a (1.25 mmol), 2b−p (2.0 equiv), and K2CO3
(2.0 equiv) in MeCN (5 mL) were stirred under a constant flow
b
(bubbling) of O2 at room temperature. Isolated yield based on 1a.
group at the para position (2c, 2d, 2f) or limited group at the
meta position (2g, 2i) were tolerated in the reaction and gave
moderate to good yields. Similarly, compared with unreactive
di-α-naphthylphosphine oxide (2m), β-naphthyl derivative 2l
gave the desired product in high yield. Unfortunately, 2n−2p
were not suitable for the reaction, probably due to inhibition of
the p−π conjugation between the phosphorus atom and the
benzene ring, which may be critical for the nucleophilicity of
the organophosphorus reagent (see Supporting Information
for details).
Based on literature reports and our previous work on the α-
hydroxylation of β-keto esters, a plausible mechanism for the
process is proposed as shown in Scheme 3.10a−c,13a Initially,
radical insertion of O2 into an α-C−H bond of malononitrile 1
under basic conditions affords α-hydroperoxide 4, which can
be reduced by another equivalent of 1 to form two equivalents
of α-hydroxy malononitrile 5. Consequently, acyl cyanide
intermediate 6 is produced by the elimination of HCN from 5
in the presence of base. For diarylphosphine oxide 2 to
tautomerize to the P−OH form (2′), the in situ formation of a
quaternary carbon center must be accomplished through the
nucleophilic addition of phosphinous acid 2′ to acyl cyanide 6.
Finally, an intramolecular exchange through a four-centered
cyanide 8 was increased to 2.5 equiv, benzoyl-protected
compound 9 was isolated in 80% yield, and this compound
could be readily converted to 3la under basic conditions in the
presence of stoichiometric water. Second, two peaks with a
mass-to-charge ratio (m/z) of 348.11 were detected in the LC/
MS spectrum (see the Supporting Information). One of the
peaks was presumed to be the intermediate 7 (R = Bn).
Although the intermediates were not isolated, the proposed
mechanism can suitably explain the experimental results.
Finally, a series of control experiments were also designed to
probe the oxidation process, and the decreased yield of 3aa in
the presence of radical scavenger implied that a radical species
might be involved (Scheme 4B).
A multigram-scale reaction of 1a with 2a afforded product
3aa (6.9 g, 20 mmol) in 70% yield, highlighting the good
reliability of the bubbling process. To demonstrate the
synthetic utility of this transformation, we further elaborated
C
DOI: 10.1021/acs.orglett.9b00569
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Letter
product 3aa (Scheme 5A). The nitrile group could be
selectively hydrolyzed in the presence of hydrochloric acid or
nitrile derivatization product 10, and deprotection of the
diphenylphosphinoyl group was performed with LiOH in a
THF/MeOH solution to give compound 20 in a total yield of
64% from 3aa (Scheme 5C).15 To our delight, we also
established a straightforward method of accessing the free
hydroxyl group by breaking the P−O bond. The partial
reduction of a nitrile group with diisobutylaluminum hydride
(DIBAL-H) at a low temperature (∼40 °C) affords an
aldehyde. However, the treatment of 3aa or 3la with excess
DIBAL-H at −78 °C resulted in the formation of cyanohydrins
17 and 21 in high yields with the nitrile functionality intact
(Scheme 5D).
Scheme 5. Elaboration of Product 3aa and Deprotection of
the O-Phosphinoyl Cyanohydrins
In conclusion, we have developed an aerobic redox strategy
for the synthesis of O-phosphinoyl cyanohydrins under mild
reaction conditions using α-substituted malononitriles as the
nitrile source and diarylphosphine oxides as the reducing
agents. Importantly, this approach is different from conven-
tional cyanohydrin syntheses. Mechanistic studies supported
that the mild process involves a radical oxidation, the
generation of a quaternary carbon center, and an intra-
molecular rearrangement. Finally, the phosphinoyl substituent
is demonstrated to be a convenient protecting group. Given
the utility of O-protected cyanohydrins, we anticipate that this
approach will facilitate the construction of this important and
challenging moiety in synthetic applications. Further studies on
an asymmetric catalyst system are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00569.
1
Experimental details, analytical data, and H, 13C, and
31P NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lotuseeds@gmail.com.
*E-mail: fisher1688@163.com.
ORCID
Mingming Lian: 0000-0001-7737-5036
Qingwei Meng: 0000-0002-1743-2518
Notes
The authors declare no competing financial interest.
sulfuric acid, producing carboxylic acid 10 or amide 11 in
excellent yields. Pinner reactions between 3aa and an alcohol
or a thiol to yield ester 12 or thioether 13 were successfully
conducted. In addition, 3aa reacted well with a tertiary alcohol
in a Ritter reaction, resulting in the formation of N-tert-
alkylamide 14 in 56% yield. In addition, 3aa was readily
reduced to afford primary amine 15 in 56% yield upon
exposure to LiAlH4, and the phosphinoyl group was not
affected by this reaction.
Finally, we focused on developing an efficient method to
cleave the diphenylphosphinoyl group. The base-catalyzed
alcoholysis of 3aa in THF/methanol afforded methyl
diphenylphosphinate 16 in high yield, but the expected
cyanohydrin 17 was not detected (Scheme 5B). We speculated
that base-accelerated elimination of HCN led to the failure of
the alcoholysis. With respect to the alcoholysis strategy,
carboxyl-protected amino acid 18 was initially coupled with
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No.
21506044, 81671814), the China Postdoctoral Science
Foundation (No. 2014M561369), the Natural Science
Foundation of Heilongjiang Province (No. QC2015016),
and Seed Fund of Harbin Medical University (Daqing) (No.
DQ2013-04, DQXN201703, and DQXN201705).
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