CO2-Enabled Cyanohydrin Synthesis and Facile Iterative Homologation Reactions**

Article abstract of DOI:10.1002/chem.202003623

Thermodynamic and kinetic control of a chemical process is the key to access desired products and states. Changes are made when a desired product is not accessible; one may manipulate the reaction with additional reagents, catalysts and/or protecting groups. Here we report the use of carbon dioxide to accelerate cyanohydrin synthesis under neutral conditions with an insoluble cyanide source (KCN) without generating toxic HCN. Under inert atmosphere, the reaction is essentially not operative due to the unfavored equilibrium. The utility of CO₂-mediated selective cyanohydrin synthesis was further showcased by broadening Kiliani–Fischer synthesis under neutral conditions. This protocol offers an easy access to a variety of polyols, cyanohydrins, linear alkylnitriles, by simply starting from alkyl- and arylaldehydes, KCN and an atmospheric pressure of CO₂.

Full text of DOI:10.1002/chem.202003623

Accepted Article
Accepted Article
Title: CO2-Enabled Cyanohydrin Synthesis and Facile Iterative
Homologation Reactions
Authors: Ji-Woong Lee, Martin Juhl, and Allan R. Petersen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202003623
Link to VoR: https://doi.org/10.1002/chem.202003623
01/2020

10.1002/chem.202003623
Chemistry - A European Journal
COMMUNICATION
CO2-Enabled Cyanohydrin Synthesis and Facile Iterative
Homologation Reactions
Martin Juhl,[a] Allan R. Petersen,[a] and Ji-Woong Lee*[a]
[a]
Dr. M. Juhl, Dr. A. R. Petersen, Dr. J.-W. Lee
Department of Chemistry
University of Copenhagen
Universitetsparken 5, 2100, Copenhagen, Denmark
E-mail: jiwoong.lee@chem.ku.dk
Supporting information for this article is given via a link at the end of the document.
Abstract: Thermodynamic and kinetic control of a chemical process
is the key to access the desired products and states. Changes are
made when a desired product is not accessible; one may manipulate
the reaction with additional reagents, catalysts and/or protecting
groups. Here we report the use of carbon dioxide to accelerate
cyanohydrin synthesis under neutral conditions with an insoluble
cyanide source (KCN) without generating toxic HCN. Under inert
atmosphere, the reaction is essentially not operative due to the
unfavored equilibrium. The utility of CO2-mediated selective
cyanohydrin synthesis was further showcased by broadening Kiliani-
Fischer synthesis under neutral conditions. This protocol offers an
easy access to variety of polyols, cyanohydrins, linear alkylnitriles, by
simply starting from alkyl- and arylaldehydes, KCN and an
atmospheric pressure of CO2.
TMSCN15] and cyanoformate[16] as a HCN surrogate.[11,12,17] These
reagents suffer from poor atom economy when unprotected
cyanohydrins are desired. Furthermore, the cyanation reactions
with in-situ generated HCN (from a mixture of TMSCN and an
alcohol) are limited by the instability of the cyanide sources
thereby limiting the solvent compatibility.[11,18]
Here we demonstrate our strategy in controlling nucleophilic
1,2-addition reactions, namely the cyanohydrin formation reaction,
promoted and controlled by CO2. Addition reactions commonly
employ nucleophilic reactants which generate anionic
intermediates or transition states. The use of electrophilic CO2
can be beneficial when asymmetric binding is realized with CO2;
weak interactions with nucleophiles (B), and stronger interactions
with anionic intermediate, to accelerate the reaction. We
confirmed this positive effect of CO2 in practical and scalable
cyanohydrin synthesis, which enabled straightforward iterative
homologation of an aldehyde with cyanide.
A chemical reaction is governed by kinetics and thermodynamics,
and a simultaneous control of both parameters is a common
practice in designing and optimizing chemical reactions. The
manipulation of thermodynamic stability of reactants and products
will decide the outcome of a chemical process, while various
reaction pathways can lead to undesired products thus reducing
overall efficiency of the process.[1] To circumvent unwanted
reaction pathways, chemists have developed selective catalysis,
protecting groups (“P” in Figure 1), trapping reagents and
reactivity-altered reactants (A’ and B’), which in turn can limit the
scope and generality of the original reaction. In our ongoing
pursuit to implement CO2 in the core of organic synthesis, we
sought out ways in which equilibria can be controlled by the use
of CO2 – a mild Lewis acid where anionic intermediates can be
stabilized.
Carbon dioxide is an intrinsically stable molecule,[2,3]
however, it can readily and reversibly react with various
nucleophiles.[2,4] Recent applications of carbon dioxide in organic
synthesis showed fruitful success particularly in CO2-
incorporation,[5] CO2 as a temporal protecting group for C-H
activation,[6] CO2 for asymmetric catalysis[7] and oxidation
reactions.[8] We recently investigated the role of CO2 in a
cyanation reaction,[9] where CO2 can be used in catalytic amounts
to facilitate the stereoselective transformation of activated
electrophiles via 1,4-conjugate addition reactions. Cyanohydrin
synthesis - 1,2-cyanide addition reactions to carbonyls - is one of
the oldest C-C bond-forming reactions using HCN as a cyanide
source.[10] Despite the high utility of cyanohydrins in organic
synthesis[11-14] the use of HCN reduces its application potential
due to its volatile nature and health risks. Recent research
activities in cyanohydrin synthesis are mainly performed by using
CO2-Mediated Addition Reactions
Traditional Approaches:
δ-
δ+
δ-
Keq
C
A
+ B
A + B
C
CO2
- CO2
when Keq<1
"C-CO2"
C
1. stabilization: [A - B]‡-CO2
2. ΔGo favored by "C-CO2"
3. traceless, practical, inexpensive
+"P"
C' or D
A' + B'
O
K+
R
O-K+
CN
OH
OH
CN
unfavored
enolizable
RCHO
RCHO
(R=Ar,Alkyl)
R
R
favored
R
OK
R
HO
R
KCN
R'
O
H
R'
H+
CHO
R'
no HCN
formation
-
O
OCO2 K+
OH
CN
RCHO
K
C
favored
CN
+CO2
R
CN
O
R
Scheme 1. Top; A comparison of traditional reaction optimization and CO2-
mediated addition reactions. (P = catalysts, protecting groups or trapping
reagents); Bottom: cyanohydrin synthesis enabled by CO2/KCN without HCN
generation and side reaction pathways.
As summarized in Scheme 1 (bottom), it has been a common
knowledge that cyanohydrin formation can not be “catalyzed” due
to the high nucleophilicity of cyanides, although the reaction
undergoes strong backward reaction (kforward = 1.96 x 10-8 sec-1M-
1, kbackward = 0.87 x 10-10 sec-1, in RCHO +HCN ↔ RC(OH)CN).[19]
Whilst Brønsted acids can generate volatile yet nucleophilic HCN
1
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COMMUNICATION
Table 1. Optimization of CO2-Mediated Cyanation.[a]
from solid cyanide sources (NaCN or KCN), general and specific
acid catalysis can only be operative at exceedingly low
concentration of an acid catalyst.[20] This has been manifested in
total synthesis, where sophisticated cyanide sources and
reagents have been employed. For example, high selectivity
towards cyanohydrin formation was mediated by using an
activated reagent, i.e. Al-based cyanide sources (AlEt2CN,
Nagata’s reagent).[21,22] At this juncture, the lack of a general and
practical method for cyanohydrin formation reaction under
practical and neutral conditions led us to investigate the potential
utility of CO2 in cyanohydrin synthesis, which can generate a
slightly acidic medium. However, another challenge lays on the
side reactions: benzoin- and self-aldol reactions of aldehydes by
nucleophilic and basic cyanide (Scheme 1). This is related to the
Entry
Deviation from standard reaction conditions
No CO2 (under N2)
Yield[b]
7%
1
2
3
4
HCN (2 equiv) instead of KCN
30 min of reaction time
21%
96%
>85%
MeOH/water/n-heptane/CH3CN/DMF/DMSO
instead of EtOH
limited scope of Killiani-Fischer synthesis with carbohydrate
5
6
7
8
9
NaCN instead of KCN, 30 min
NEt4CN, 30 min, under N2
57%
33%
97%
24%
95%
[23]
derivatives.
Therefore, we examined the use of CO2 for
cyanohydrin formation reactions under practical reaction
conditions, to access variety of compounds in a modular fashion.
We have recently shown the applicability cyanohydrins as a
nucleophile via an umpolung strategy to access a-keto acids.[24]
In the absence of Ti(IV) and DBU, we observed facile formation
of cyanohydrin in pseudo first order of the aldehyde with KCN
under CO2 atmosphere (1 atm) in ethanol (k = 2.50 x 10-3). This
is approximately 105-folds rate acceleration compared to the
reported values without CO2.[19] We verified that the solubility of
KCN was increased in the presence of CO2 (Figure S6), owing to
the formation of cyanoformate in solution, thus increasing the
concentration of available cyanide nucleophiles.[25] To further
verify the positive effect of CO2, we performed various control
experiments (Table 1). Under CO2 atmosphere (1 atm), full
conversion of the starting material (4-fluorobenzaldehyde) was
observed to the desired cyanohydrin in quantitative isolated yield
(99% conversion, 97% yield). When performing the cyanation
under a N2 atmosphere, low conversion to cyanohydrin (7%) was
detected within 10 min with no increase in yield of the product
after prolonged reaction time (up to 18 h, entry 1, Figure 1 gray
circles), indicating the reaction reached fast equilibrium in favor of
starting materials with KCN. More importantly, in situ generated
HCN gave inferior result, (entry 2, 21% yield), while quantitative
yield was obtained with KCN/CO2 combination within 30 minutes
(entry 3, 96%, Figure 1 pink circles). A variety of solvents were
found to be compatible to induce the desired product under CO2.
It is noteworthy here that inferior results were obtained under N2
in all tested solvents compared to under CO2, highlighting the
generality of the positive CO2 effect regardless of the choice of
solvents (entry 3, i.e. methanol, n-heptane, acetonitrile and water,
and see Table S1-13 for full optimization). Sodium cyanide is also
effective under the standard reaction conditions (entry 5). The
solubility of cyanide is important – a soluble cyanide source,
ammonium cyanide, showed good conversion to the product with
CO2 however, the reaction was not efficient under inert N2
atmosphere (entries 6 and 7). Therefore, the increased solubility
of KCN under CO2 is not the sole reason for the observed
increase in yield. A common reaction procedure for cyanohydrin
synthesis was not comparable in terms of reaction rate: strong
acid (e.g. HCl) afforded only low yield of the product because
HCN (a “slower” nucleophile) generation is favored (entry 8). The
use of acetic acid[26] showed compatible yield (entry 9) confirming
that weak acids can indeed promote the reaction without complete
protonation of KCN to HCN.
NEt4CN, 30 min under CO2
aq. 5M HCl (4 eq.) instead of CO2
AcOH (4 eq.) instead of CO2
[a] 4-fluorobenzaldehyde (1 mmol) and KCN (2 mmol) were mixed in EtOH (2
mL). The reaction mixture was stirred under CO2 (1 atm) for 18 h. [b] Yield was
determined by 19F nuclear magnetic resonance spectroscopy (NMR) (D1;
relaxation time = 2 s) of the crude mixture.
100
80
60
40
CO2 (1 atm)
CO2 (20 mol%)
N2 (1 atm)
20
0
0
20
40
60
80
100
120
time (min)
Figure 1. Cyanohydrin formation using CO2 (1 atm, pink), sub-stoichiometric
amounts of CO2 (6 x 20 mol%, black circles with a cross mark indicate repected
injection) and under nitrogen atmosphere (1 atm, gray).
The role of CO2 in the cyanohydrin synthesis was further verified
by adding sub-stoichiometric amounts of CO2 (20 mol%) to a
reaction mixture repeatedly (Figure 1, black). A sharp increase of
product formation was immediately observed followed by the
addition of CO2. A near stoichiometric relationship between
product formation and the amounts of added CO2 indicates the
added CO2 was quantitatively consumed as a stoichiometric
reagent.
Having demonstrated the feasibility of the CO2 promoted
cyanohydrin formation, we explored the scope of the reaction with
respect to both aryl and alkyl aldehydes and ketones (Scheme 2).
A variety of aryl aldehydes were tested and provided the
corresponding cyanohydrin in excellent yields regardless of their
substitution in terms of electron donating and withdrawing
2
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10.1002/chem.202003623
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properties. Cyanohydrins of ortho-substituted benzaldehydes
showed increased stability,[27] affording high purity products
without purification. When subjecting the α,β-unsaturated
aldehydes to the reaction conditions the corresponding
cyanohydrins (19 and 20) was isolated in excellent yields, without
the formation of byproduct derived from 1,4-conjugate addition
reactions. Aliphatic aldehydes were tolerated (21-24) when
The cyanohydrin formation reaction was feasible in the presence
of CS2 as a CO2 surrogate. In this case, we expected that the
formation of xanthate would render a synthetic platform to
diversify the product. Both aryl and aliphatic aldehydes were
converted into the corresponding cyano methyl xanthates in
excellent yields under optimized conditions (29-30, See Tables
S15-S17 for more details), demonstrating, to the best of our
knowledge, the first example of an α-aryl cyano xanthate. We
observed that the presence of CO2 is critical for the successful
xanthate formation reaction of aromatic aldehydes with CS2. We
presumed that the carbonate and dithiocarbonate exchange
equilibrium would afford desired products after methylation
reaction. In contrast, aliphatic aldehyde was smoothly
transformed to the corresponding a-cyano xanthate (30) under
nitrogen atmosphere.
With these results in our hands, we sought the developed
cyanohydrin synthesis and xanthate formation reaction can offer
two distinct modes of intuitive homologation strategy: 1) CHO
homologation by preserving the hydroxy group of cyanohydrin,
and 2) CH2 homologation combined with Barton-McCombie
deoxygenation conditions.[28] These would enable selective
elongation via “expanded” Kiliani-Fischer synthesis, which has
been restricted to CHO-elongation of carbohydrate-based
aldehydes. Additionally, to the best of knowledge, previously
reported cyanohydrin formation and elongation sequences are
limited to aliphatic aldehyde substrates, which can not undergo
aldol and benzoin reactions.[29] After extensive optimization, we
confirmed that the cyanohydrin synthesis is highly scalable up to
500 mmol scale (1 and 22, Scheme 2). The obtained cyanohydrin
was smoothly transformed into the corresponding TBDMS
protected cyanohydrin, 31, (CHO elongation, 91%, 2 steps), and
alkyl nitrile, 35, (CH2 elongation, 85%, 2 steps) after protection
and the reductive deoxygenation reaction, respectively. Each
elongation sequence was further iterated to generate a-hydroxy
aldehyde for CHO elongation and CH2 elongation to afford 1,2-
diol, 32, in 71% yield (3 steps) and b-hydroxy nitrile 34 in excellent
isolated yield (93%). Alkyl nitrile 35, the CH2 elongation product,
was further functionalized to TBDMS-protected cyanohydrin, 36,
in 75% yield (3 steps), and two-carbon elongated linear nitrile, 38,
in high isolated yield (92%, Scheme 3). Combinations of CHO and
CH2 elongation display a selective iterative 3-step sequence
homologation, providing straightforward retrosynthetic pathways
for linear hydrocarbons with functional groups and variety of
polyketide-like products under practical and simple reaction
conditions enabled by CO2.
performed under
a CO2 atmosphere, while various aldol
condensation products were observed under N2 atmosphere,
highlighting the importance of the CO2-mediated cyanohydrin
formation
conditions.
For
example,
when
3-
phenylpropionaldehyde (22) was subjected to the reaction
conditions under N2 atmosphere, a complicated reaction mixture
was observed due to aldol-reaction related byproducts.
Furthermore, the cyanation reaction of sterically hindered free
alcohol was achieved (23), which would otherwise not be
straightforward by classical means.[18] Despite the reduced
reactivity of ketones,11 both α-keto acids (27-28) and aliphatic
ketones (25-26) were smoothly transformed into cyanohydrins in
good to excellent yield, with no hemiketal[18] or aldol-reaction
related by-products formation.
OH
OCS2Me
CO2 or CS2
O
or
R
CN
R
CN
conditions
OH
R
R'
R'
R'
OH
CN
OH
CN
R
OH
CN
CN
F
R
Cl
1, 97%, 95%a
under N2: 7%
R = H, 2, 94%
R = Me, 3, 91%
R = I, 4, 93%
R = Br, 7, 86%
R = Cl, 8, 98%
R = OMe, 9, 95%
10, 83%
R = Br, 5, 92%
R = Ph, 6, 92%
OMe OH
OH
CN
OH
O
OH
CN
CN
CN
MeO
11, 99%
12, 86%
16, 97%
13, 96%
14, 97%
HO CN
OH
OH
OH
CN
O
CN
CN
NO2
Me2N
15, 72%
19, 91%
17, 92%
18, 92%
OH
CN
OH
CN
OH
OH
CN
CN
22, 98%b
20, 79%
21, 94%
under N2: 0%
NC
OH
OH
CN
OH
CN
NC OH
HO
(
)
10
23, 95%
24, 90%
HO CN
25, 95%
26, 84%
OCS2Me
CN
To shed some lights on the reaction mechanism, we
attempted to isolate the carbonate species from the CO2-
mediated cyanohydrin formation reaction. We obtained the Cbz
(carboxylbenzyl) protected cyanohydrin, 39 (Scheme 4A),
whereas preformed cyanohydrin (22) afforded no product under
CO2 atmosphere (Scheme 4B), suggesting in-situ cyanoformate
and cyanohydrin formations may be responsible for the
successful CO2 mediated reaction. It is noteworthy here that our
protocol demonstrates the synthesis of Cbz protected
cyanohydrin from carbon dioxide, without the need for reactive
reagents such as benzyl cyanoformate or chloroformates.[30]
HO CN
OCS2Me
CN
OH
OH
O
O
F
27, 95%c
28, 96%c
29, 87%d
30, 96%e
Scheme 2. Substrate scope of carbon dioxide mediated cyanohydrin synthesis
of aromatic and aliphatic aldehydes and ketones. Cyanohydrin formation:
carbonyl (1 mmol), KCN (2 eq), EtOH (0.5 M) and CO2 (1 atm) was stirred at rt
for 18 h. Cyano xanthate formation: aldehyde (1 mmol), KCN (5 eq), CS2 (10
eq), MeI (5 eq) and MeCN (0.5 M) was stirred at 0 °C for 4 h, then rt for 2 h.[a]
Reaction performed on a 100 mmol scale using KCN (1.2 eq). [b] Reaction
performed on a 500 mmol scale using KCN (1.2 eq). [c] KCN (3 eq). [d]
Performed under a CO2 atmosphere. [e] Performed under a N2 atmosphere.
3
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Scheme 3. Kiliani-Fischer homologation and iterative elongation by CO2- and CS2-mediated cyanation with KCN (R = 4-F-C6H4)
substrate scope for cyanohydrins, xanthates, and iterative
homologation reactions. A brief thermodynamic analysis of the
cyanohydrin synthesis confirms that the desired reaction
pathways is not viable with KCN under conventional reaction
conditions (Figure 2A). The obtained equilibrium constant with
KCN and CO2 is an order of magnitude greater than the reported
value with HCN (2.0 x 102) with HCN.[31] We therefore believe that
CO2 is not only changing the polarity of the reaction medium as
an additive, but also affecting the equilibrium by forming stable
adducts with CO2 while acting as a general catalyst. This can be
O
C
KCN (2 equiv.)
CO2 (1 atm)
BnBr (2 equiv)
O
OBn
O
CN
H
DMF, r.t.
18 h, 82% yield
O
C
CO2 (1 atm)
BnBr (2 equiv)
KHCO3 (1 equiv)
O
OBn
OH
CN
CN
DMF, r.t.
full conversion
no desired product
22
a
general method in organic synthesis considering many
reactions are performed with nucleophilic reagents undergoing
anionic or negatively charged intermediates and transition states.
The use of CO2 is highly practical by simplifying work-up
procedures without any remaining protecting groups or reagents
after the removal of CO2, highlighted by large scale reactions.
Further studies in detailed mechanisms of CO2-mediated
cyanohydrin synthesis are under investigation.
Scheme 4. Attempts to access Cbz-protected cyanohydrin from CO2 and (A) an
aldehyde with KCN, and (B) with a preformed cyanohydrin (22).
Acknowledgements
The generous support of the Department of Chemistry, University
of Copenhagen, the Novo Nordisk Fonden (NNF17OC0027598)
and the Villum Fonden (00019062) is gratefully acknowledged.
Figure 2. (A) Reported equilibrium constants for traditional cyanohydrin
synthesis with HCN[31] and (B) CO2-controlled reactions with KCN and (R1 = 4-
F-C6H4, R2 = C6H5, all reactions were in ethanol at room temperature)
Keywords: carbon dioxide • cyanohydrins • homologation •
xanthate • elongation
In conclusion, we have developed a synthetic method to
access cyanohydrins under practical conditions, which enabled a
general method for homologation sequences using a convenient
cyanide source, potassium cyanide, mediated by carbon dioxide.
In the absence of CO2, it was found that aldehydes were prone to
form byproducts related to benzoin reaction and aldol
condensation reactions due to the nucleophilic and basic cyanide.
These side reactions were prohibited by the action of CO2, acting
as a temporary protecting group, thus providing the broad
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10.1002/chem.202003623
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
[A-B]‡
Impossible Chemical Transformations
A
A
B
+
B
C
ΔGo >0
(product)
high activation barrier
strong reverse reaction
A+B
‡
CO2 for Modification of Reaction Coordinate!
CO2
[A-B]-CO2
C-CO2
A
A
B
+
B
ΔGo<0
lower ΔG‡
A+B
C
cyanohydrins
up to 99% yield
up to 500 mmol scale
KCN
RCHO
RCOR
35 example
no reaction without CO2!
Carbon-dioxide promotes cyanohydrins synthesis, enabling facile and iterative homologation reactions for organic synthesis. This
traceless, practical and atom-efficient cyanohydrin synthesis shows a broad substrate scope with high isolated yields of synthetically
versatile cyanohydrins. The use of CO2 can be productive in chemical reactions undergoing anionic intermediates and negatively
charged transitions states, which can be stabilized by Lewis-acidic CO2.
Institute and/or researcher Twitter usernames: @TheLeeLab_Chem
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