Cyano-borrowing reaction: Nickel-catalyzed direct conversion of cyanohydrins and aldehydes/ketones to β-cyano ketone

Article abstract of DOI:10.1039/c9sc00640k

A direct nickel-catalyzed, high atom- and step-economical reaction of cyanohydrins with aldehydes or ketones via an unprecedented "cyano-borrowing reaction" has been developed. Cleavage of the C-CN bond of cyanohydrins followed by aldol condensation and conjugate addition of cyanide to α,β-unsaturated ketones proceeded to deliver a range of racemic β-cyano ketones with good to high yields. The practical procedure with the use of a commercial and less-toxic CN source bodes well for wide application of this protocol.

Full text of DOI:10.1039/c9sc00640k

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ARTICLE
Cyano-Borrowing Reaction: Nickel-Catalyzed Direct Conversion of
Cyanohydrins and Aldehydes/Ketones to -Cyano Ketone
Zhao-Feng Li, Qian Li, Li-Qing Ren, Qing-Hua Li, Yun-Gui Peng*, Tang-Lin Liu*
Received 00th January 20xx,
Accepted 00th January 20xx
A direct nickel-catalyzed, high atom- and step-economical reaction of cyanohydrins with aldehydes or ketones via an
unprecedented “cyano-borrowing reaction” has been developed. Cleavage of the C-CN bond of cyanohydrins, aldol
condensation followed by conjugate addition of cyanide to ,-unsaturated ketones proceeded to deliver a range of racemic
-cyano ketones with good to high yields. The practical procedure with the use of commercial and lower-toxic CN source
bodes well for wide application of this protocol.
DOI: 10.1039/x0xx00000x
a) Hydrocyanation
Catalyst
Hydrocyanation
Introduction
O
CN
O
HCN Source
+
R
R'
R
+
R'
The nitriles are important synthesis intermediates in
transformation1 and are key components in various natural
products, medicinal pharmacophores and drugs,2 and in organic
synthesis, cyano group is equivalent to amine or carbonyl
group. The catalytic addition of cyano group to C=C bond has
been established as one of the most direct pathways for the
synthesis of nitriles.3,4 Among the important nitriles, -cyano-
ketonesare commonly utilized in organic synthesis.5 One of the
classical approaches to deliver these compounds is the
catalyzed conjugate addition of cyanide to ,-unsaturated
carbonyl compounds (Hydrocyanation procedure, Scheme 1a),6
which utilizes the highly toxicity and explosive HCN gas as the
cyano source. An alternative strategy is the transfer
hydrocyanation which involves the commercially available,
lower-toxicity and lower-explosive cyanohydrin to deliver
nitriles (Scheme 1b), but with low atom economy.7 Recently,
Morandi developed a nickel-catalyzed transfer hydrocyanation
reaction between alkyl nitriles and alkenes or aryl chlorides,
which utilizes none toxicity alkyl nitriles as the cyanide source.8
Although the catalyzed hydrocyanation and transfer
hydrocyanation reactions have been well developed,6-7 it
remains an important challenge to bypass the usage of toxic
HCN gas as the cyano source and overcome the issue of atom-
economy. To mitigate these concerns and inspired by the atom-
and step-economical procedure of -alkylation of secondary
toxic reagents
b) Transfer Hydrocyanation
O
O
Catalyst
CN
O
HO CN
R'' Me
+
Transfer
R
R'
R''
Me
R
R'
Hydrocyanation
waste
commercially
available;
Lower-toxic
Our Hypothesis
c)
: Cyano-Borrowing Reaction
CN
HO
O
[M]
CN
+
R'
O
R
Me
R
R'
[M]n
Cyano-Borrowing Reaction
NC
[M]n
O
O
+
R'
O
R
R'
R
Me
H2O
This work
d)
: Nickel-Catalyzed Cyano-Borrowing Reaction
O
CN
R3
O
HO
R1
NiCl
NiCl
2 (5 mol%)
2 (5 mol%)
CN
R2
O
R1 Me
+
n-BuPAd2 (5 mol%)
n-BuPAd2 (5 mol%)
R1
LiOH, dioxane
100 oC, 18 h
LiOH, dioxane
100 oC, 18 h
R3
CN
+
R2
HO
R2
R1, R2 = (Hetero)Ar, Alkyl
R3 = H or Alkyl
alcohols with aldehydes via borrowing hydrogen reactions9-10
,
up to 90%
up to 83%
we postulated that the cyano group could be tolerated in the
reaction with analogous mechanism as the borrowing hydrogen
reactions. Guided by these considerations, we envisioned that,
as shown in Scheme 1c, under the catalysis of transition metal,
34 examples
9 examples
High atom-economy: H2O as the sole side product
C-CN bond cleavage and formation Commercial, non-toxic CN source
Scheme 1 Development of Cyano-Borrowing.
cleavage of the C-CN bond11,12 of the cyanohydrin and deliver
the corresponding ketones and metal-cyano intermediate
([M]n-CN), followed by Aldol condensation of ketones with
aldehydes, subsequently conjugate addition of cyanide to
School of Chemistry and Chemical Engineering, Southwest University, Chongqing
400715, China.
Email: liuschop@swu.edu.cn, pyg@swu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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chalcones and utilizes the [M]n+1-CN as the cyano donor to
deliver the desired products (Scheme 1c). This hypothesis is
notable in that cyanohydrin plays a dual role both as the source
of ketone and the cyanide donor with high atom- and step-
economy. Herein, we report the first catalytic process of the
direct transformation of cyanohydrins with aldehydes to deliver
-cyano ketones as the sole product via nickel catalyzed cyano-
borrowing reactions.13
extensive array of parameters. By varying the anion of the nickel
salt (i.e., NiCl2, Ni(OAc)2, Ni(OTf)2 and Ni(acac)2) as precatalysts,
View Article Online
DOI: 10.1039/C9SC00640K
NiCl2 exhibited the best yield (Table 1, entries 3-5 vs 2). The
screening of different phosphines revealed that this
t-
transformation requires a bulky, electron rich ligand, and
BuPAd2 showed the highest reactivity with 82% yield (table 1,
entry 11 vs 2 and 6-10). Stronger base such as NaOH and KOt-Bu
shows low reactivity. Meanwhile, Cs2CO3 and organic base (i.e.,
DMAP and DBU), failed to provide the target products (table 1,
entries 14-16). Optimization of the solvent led to no
improvement (table 1, entries 17-19). Lowering the
Results and discussion
To test our hypothesis, we initiated the cyano-borrowing
reaction using commercially available acetophenone
cyanohydrin 1a which could be prepared from acetophenone
and TMSCN and benzaldehyde 2a for the optimization of the
reaction conditions. After screening an array of the transition
metal catalyst, we found that nickel complex showed better
performance. To our delight, a cocktail consisting of NiBr2, PPh3,
and LiOH as base in dioxane at 100 oC could deliver the desired
racemic -cyano ketone 3aa in 52% yield (table 1, entry 1).
Notably, determined by the crude 1H NMR of the reaction
mixture, not even trace of 1,2-addition products were
observed.14 As shown in Table 1, we then examined an
o
temperature to 80 C gives a lower yield (table 1, entry 20).
Control experiments verified that the presence of Ni-complex
was necessary to achieve high yield in cyano-borrowing reaction
(table 1, entry 21). No reaction occurred in the absence of LiOH
(table 1, entry 22). After the screening of the reaction
parameters, we found that NiCl2 and n-BuPAd2 as the precatalyst
and LiOH as the base in dioxane at 100 °C for 20 h (82% yield)
was the optimal conditions.
Having identified the optimized reaction conditions, we further
explored the substrate scope of this reaction. Various
commercially available ketones cyanohydrins were examined
with benzaldehyde (2a) and the results are summarized in
Scheme 2. The electron-deficient substrate with varying
substituent patterns at p-position did not dramatically influence
yields (3ba-3da). Substituting the cyanohydrin with p-methyl
also shows high reactivity and 72% of desire product was
obtained (Scheme 2, 3ea). However, substituting the para
position with a more electron-rich functionality (i.e., p-MeO) led
to diminished yields, but the desired product could be delivered
with 86% yield while increasing the reaction temperature to 120
oC (Scheme 2, 3fa). Reactions of cyanohydrin with ortho- and
meta-substituted on aryl groups gave excellent yields (Scheme
2, 3ga-3ja). The reaction proceeds smoothly in the case of the
Table 1 Screening studies of -alkylation of cyanohydrin 1a
with benzaldehyde 2aa
[Ni] (5 mol%)
O
CN
HO
CN
L (10 mol%)
CHO
+
Base (3.0 equiv.)
Solvent, 4A MS
100 o
C
1a
2a
3aa
entry
1
[Ni]
NiBr2
NiCl2
L
base
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
NaOH
KOt-Bu
Cs2CO3
DMAP
DBU
Solvent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
TBME
Yield (%)b
52
PPh3
PPh3
2
76
3
Ni(OAc)2
Ni(OTf)2
Ni(acac)2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
--
PPh3
66
4
PPh3
62
5
PPh3
71
NiCl2 (5 mol%)
n-BuPAd2 (10 mol%)
O
CN
6
PCy3
76
CHO
HO CN
R1
+
R1
7
dppe
72
LiOH (3.0 equiv.)
Me
1,4-dioxane, 4A MS
8
dppp
78
1
2a
3
100 o
C
9
dppb
37
O
CN
Ph
MeO
O
CN
Ph
O
CN
Ph
10
11
12
13
14
15
16
17
18
19
20c
21
22
BINAP
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
--
44
O
CN
Ph
82
Me
(X = Cl) 70% yield
(X = Br) 90% yield
(X = F) 85% yield
X
28
b
3aa
3ba
3ca
3da
,
,
3ea
3fa
, 86% yield
, 82% yield
, 72% yield
trace
0
,
0
O
CN
Ph
O
CN
Ph
O
CN
Ph
O
CN
Ph
0
LiOH
LiOH
LiOH
LiOH
LiOH
--
22
Cl
Me
OMe
3ja
Cl
3ia
23
, 85% yield
3ha
, 72% yield
CN
Ph
, 65% yield
CN
Ph
3ga
, 65% yield
O
THF
72
CN
Ph
O
O
O
CN
Ph
Dioxane
Dioxane
Dioxane
59
Et
<10
S
NiCl2
n-BuPAd2
0
3na
, 57% yield
3ka
3la
3ma
, 40% yield
, 53% yield
, 82% yield
aThe reaction was carried out with 0.4 mmol of 1a, 0.4 mmol of 2a, 5 mol% [Ni],
aThe reaction was carried out with 0.4 mmol of 1a, 0.4 mmol of 2, 5 mol% NiCl2,
10 mol% n-BuPAd2 and 300 mol% LiOH in 0.5 mL of dioxane at 100 oC for 18 h. The
yields are isolated yield. bThe reaction was carried out at 120 oC.
10 mol% ligand (L) and 300 mol% base in 0.5 mL of solvent at 100 oC for 18 h.
bIsolated yield. cThe reaction was carried out at 80 oC. dppm
=
Bis(diphenylphosphino)methane; dppe = Bis(diphenylphosphino)ethane; dppp =
n-
Bis(diphenylphosphino)-propane; dppb
= Bis(diphenylphosphino)butane;
Scheme 2 Reaction Scope of ketone cyanohydrins.
BuPAd2 = Di(1-adamantyl)-n-butylphosphine; TBME = Methyl tert-butyl ether.
2 | J. Name., 2012, 00, 1-3
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cyanohydrin bearing
a
thienyl group, affording the Inspired by the success with nickel-catalyzed cyano-borrowing
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corresponding product 3la in 82% isolated yield. In terms of reaction of cyanohydrins derived froDmOI: 1k0e.1t0o3n9/eCs9SC00640K
1
with
thealkyl substituents, cyanohydrin derived from butanone aldehydes, we further demonstrate the cyano-borrowing
proceeded smoothly to afford the desired product with 40% protocol to the more challenging substrates such as aldehyde
yield (Scheme 2, 3ma). Substrate bearing a cyclopropyl group cyanohydrin 5. To our delight, benzaldehyde cyanohydrin 5a
was well tolerated, leading to the cyclopropyl substituted reacted with acetophenone 4a smoothly under standard
product with 57% yield (Scheme 2, 3na). Importantly, the condition, yielded the corresponding product 3aa with full
cyclopropyl group remains untouched, which indicates that this conversion and 83% isolated yield. To indicate the generality of
nickel-catalyzed protocol does not go thought radical pathway. this protocol, we then examined the scope of benzaldehyde
Next, various aldehydes were investigated with acetophenone cyanohydrins and ketones. In addition to the phenyl group, it
cyanohydrin (1a) using the optimized reaction conditions, and was found that substrates bearing electron-rich or electron–
representative results are summarized in Scheme 3. deficient on the benzene ring were well tolerated to give the -
Benzaldehydes bearing various electron-deficient (3ab-3ad and cyano ketones in moderate to good yields (3ba, 3ea, 3ad and
3ag-3ah), electron-neutral (3al and 3am) and electron-rich 3af in Scheme 4). Moreover, heteroaryl and alkyl substitutes
(3ae-3af and 3ai-3ak) substituent reacted with 1a to deliver the also participated in this protocol very well (Scheme 4, 3la, 3ma,
desired products in moderate to excellent yields (58-90%). 3ao and 3ar).
Furthermore, the reaction is also compatible with heteroaryl
NiCl2 (5 mol%)
rings, such as 2-furanyl (3an), 2-thiophenyl (3ao) and
unprotected 3-indolyl (3ap), providing diverse -cyano ketones
in 51-77% yield. Remarkably, compared with the aryl aldehydes,
the alkyl substituted aldehydes (e.g., 2-phenylacetaldehyde and
cyclohexanecarbaldehyde) reacted with 1a to afford the
corresponding products 3aq and 3ar in 64% and 80% yields,
respectively. The aldehyde containing a sulfur atom is also
tolerated under the nickel-catalyzed protocol and deliver the
desired product 3as with a slightly lower yield. To demonstrate
the practicality and scalability of our protocol, we proceeded to
carry out a gram-scale reaction with 5.0 mmol 2i reacted with
10.0 mmol 1a catalyzed by 5 mmol% of NiCl2, affording 1.12 g
3ai in 85% yield, suggesting that this procedure is quite reliable
and have practically applicable.
n-BuPAd2 (10 mol%)
O
4
OH
R4
O
CN
R4
+
R3
NC
R3
LiOH (3.0 equiv.)
1,4-dioxane, 4A MS
5
3
100 o
C
O
CN
O
CN
O
CN
Cl
Me
3aa
3ba,
3ea
, 83% yield
75% yield
CN
, 77% yield
CN
O
O
CN
O
S
Br
3la
3ma
3ad
, 80% yield
CN
, 45% yield
, 78% yield
CN
O
O
CN
O
S
NiCl2 (5 mol%)
HO
O
CN
R2
n-BuPAd2 (10 mol%)
CN
Me
R2-CHO
+
OMe
LiOH (3.0 equiv.)
b
3af
3ao
3ar
, 82% yield
, 79% yield
, 69% yield
1,4-dioxane, 4A MS
1a
2
3
100 o
C
aThe reaction was carried out with 0.4 mmol of 1a, 0.4 mmol of 2, 5 mol% NiCl2,
10 mol% n-BuPAd2 and 300 mol% LiOH in 0.5 mL of dioxane at 100 oC for 18 h. The
yields are isolated yield. bThe reaction was carried out at 120 oC.
O
CN
O
CN
O
CN
O
CN
Ph
Ph
Ph
Ph
Me
Scheme 4 Examples of aldehyde cyanohydrin with ketone.a
OMe
F
X
b
3ae
3af
, 66% yield
CN
, 76% yield
CN
3ab
3ac
3ad
, 83% yield
CN
(X = Cl), 77% yield
(X = Br), 73% yield
To illustrate the scope and limitations of the new
transformation, challenging substrates beyond methyl ketones
were further examined, shown in Scheme 5. The
propiophenone cyanohydrin 6 was selected to react with
benzaldehyde 2a under the standard reaction conditions, the
desired product 8 was obtained in 31% isolated yield and high
diasteroselectivity (d.r > 10:1) (Scheme 5a, left). Furthermore,
we also examined benzaldehyde cyanohydrin 5a and
propiophenone 7, with nickel catalyst, the corresponding
product 8 was obtained in 25% yield. (Scheme 5a, right).
Notably, the bioactive ketone, epiandrosterone was tested in
this reaction with the partner of benzaldehyde cyanohydrin 5a,
and the corresponding product 10 was deliver in 57% yields with
5:1 dr (Scheme 5b), which shown the potential of this nickel-
catalyzed cyano borrowing process for the selective
modification of bioactive ketones.
O
O
O
CN
O
O
O
Ph
Ph
Ph
Ph
MeO
X
OMe
, 68% yield
3ag
3ah
(X = Cl), 56% yield
(X = Br), 75% yield
3ai
, 90% yield
3ak
, 70% yield
3aj
(85% on 5 mmol scale)
O
CN
O
CN
O
CN
O
CN
O
S
Ph
Ph
Ph
Ph
3an
3ao
, 77% yield
CN
, 67% yield
CN
3al
3am
, 58% yield
CN
, 89% yield
CN
O
O
O
O
Ph
Ph
Ph
S
Ph
NH
3as
3ar
, 32% yield
3aq
, 83% yield
, 64% yield
3ap
, 51% yield
aThe reaction was carried out with 0.4 mmol of 1a, 0.4 mmol of 2, 5 mol% NiCl2,
10 mol% n-BuPAd2 and 300 mol% LiOH in 0.5 mL of dioxane at 100 oC for 18 h. The
yields are isolated yield. bThe reaction was carried out at 120 oC.
Scheme 3. Reaction Scope of Aldehydes.
To shed light on the mechanism for the nickel-catalyzed cyano-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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mmol) NiCl2 (5 mol%), n-BuPAd2 (5 mol%), LiOH (0.6 mmol), 100 mg
4Å MS and anhydrous dioxane (1 mL) in the glovebox. The reaction
a) Phenyl Ethyl Ketone.
View Article Online
DOI: 10.1039/C9SC00640K
O
CN
HO
Standard
Standard
Ph
Ph
Ph
mixture was taken outside the glovebox and allowed to stir at room
temperature for 30 min. After then, the reaction mixture was
allowed to stir at 100 oC for 18 hours. The crude reaction mixture was
concentrated under reduced pressure and directly purified by silica
gel chromatography to give pure products.
CN
Ph
O
conditions
conditions
Me
Me
6
7
+
Ph
+
31% Yield
d.r > 10:1
25% Yield
d.r > 10:1
CN
Me
O
8
HO
Ph
2a
5a
b) The Bioactive Ketone.
Method B: To a vial equipped with a dried stir bar was added ketones
(0.2 mmol) aldehyde cyanohydrins (0.4 mmol) NiCl2 (5 mol%),
BuPAd2 (5 mol%), LiOH (0.6 mmol), 100 mg 4Å MS and anhydrous
dioxane (1 mL) in the glovebox. The same procedure as Method A.
O
O
n-
CN
1a
(2 equiv.)
H
H
Standard
H
H
H
H
conditions
HO
HO
9
10
epiandrosterone
57% Yield, 5:1 dr.
Conclusions
Scheme 5. Cyano-borrowing beyond methyl ketones.
In conclusion, we have developed an unprecedented nickel-
catalyzed protocol for the direct conversion of cyanohydrins
and aldehydes or ketones into racemic -cyano ketones via
borrowing protocol, a series of control experiments were
conducted. As shown in Scheme 6, acetophenone cyanohydrin
1a reacted smoothly with chalcone 11 and give the
corresponding product 3aa in excellent yields, which indicated
that cyanohydrin are the source of cyano group in the transfer
hydrocyanation under standard reaction condition.
Benzaldehyde cyanohydrin 5a could also reacting with chalcone
11 efficiently, deliver 3aa with 89% yield, and the hydrogen-
borrowing product 12 was not observed, showing that cleavage
the C-CN bond is more easy than the C-H bond in cyanohydrins.
Meanwhile, in the crossover reaction of 1a, 2e and 11 under
standard condition, we got the corresponding products 3aa and
3ae with the ratio of 1.05:1, which shows that the cyano group
from the cleavage of C-CN bond of cyanohydrin was a free anion
in this nickel-catalyzed protocol and has the same opportunity
to conjugate to each chalcone. Together, these experimental
results support our hypothesis on nickel-catalyzed step- and
atom-economical cyano-borrowing reaction of cyanohydrin
with aldehydes or ketones (Scheme 1c) (for more details of the
mechanism studies, please see supporting information).
nickel-catalyzed cyano-borrowing reaction.
A range of
cyanohydrins derived from aldehyde or ketone could be
tolerated and delivered products with high regioselectivity and
good to excellent yields. To the best of our knowledge, catalytic
conversion of cyanohydrins into -cyano ketones by reaction
with aldehydes/ketones has not been reported. Further studies
of catalytic cyano-borrowing reaction of cyanohydrins is in
progress in our reasearch lab and will be reported in due course.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for the financial support provided by National
Natural Science Foundation of China (21801209 and 21801210),
the Fundamental Research Funds for the Central Universities
(SWU118117, XDJK2018C044 and SWU118028) and Venture &
Innovation Support Program for Chongqing Overseas Returnees
(cx2018085).
HO
O
O
CN
Standard Conditions
CN
+
Ph
Ph
O
Ph
Ph
Ph
3aa, 85% yield
1a
11
OH
CN
O
CN
Ph Ph
O
Standard Conditions
Notes and references
+
+
Ph
Ph
Ph
Ph
Ph
1
(a) R. J. H. Gregory, Chem. Rev., 1999, 99, 3649-3682; (b) D.
Enders and J. P. Shilvock, Chem. Soc. Rev., 2000, 29, 359-373;
(c) M.-X. Wang, Top. Catal., 2005, 35, 117-130; (d) Smith, M.
B. March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 6th ed.; Wiley-Interscience,
2007; (e) R. Wang and J. R. Falck, Catal. Rev.: Sci. Eng., 2014,
56, 288-331; (f) M. Tobisu, R. Nakamura, Y. Kita and N.
Chatani, J. Am. Chem. Soc., 2009, 131, 3174-3175; (g) G. A.
Chotana, M. A. Rak and M. R. Smith, J. Am. Chem. Soc., 2005,
127, 10539-10544; (h) T. Patra, S. Agasti, A. Modak and D.
Maiti, Chem. Commun., 2013, 49, 8362-8364; (i) T. Patra, S.
Agasti, Akanksha and D. Maiti, Chem. Commun., 2013, 49, 69-
71; (j) M. Tobisu, H. Kinuta, Y. Kita, E. Rémond and N. Chatani,
J. Am. Chem. Soc., 2012, 134, 115-118; (k) M. Tobisu, Y. Kita
and N. Chatani, J. Am. Chem. Soc., 2006, 128, 8152-8153; (l) E.
C. Keske, T. H. West and G. C. Lloyd-Jones, ACS Catal., 2018,
8932-8940.
12
not observed
3aa
5a
11
89% yield
Standard
O
CN
Ar
HO
O
O
CN
Ph Ph
CN
CHO
Conditions
Ar
+
+
Ph
Ph
Ph
Ph
Ar = p-MeC6H4
1a
2e
11
3aa
3aa 3ae
3ae
= 1.05:1
:
Scheme 6 Mechanism studies.
Experimental
General Procedure: Method A: To a vial equipped with a dried stir
bar was added aldehydes (0.2 mmol) ketone cyanohydrins (0.4
4 | J. Name., 2012, 00, 1-3
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