Enantioselective cyanoformylation of aldehydes using a recyclable dimeric cinchonidine ammonium salt as an organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2008.01.011

A dimeric anthracenyldimethyl-derived cinchonidine ammonium salt is used as a chiral organocatalyst in the enantioselective addition of alkyl cyanoformates to aldehydes in the presence of substoichiometric amounts of triethylamine. Quantitative yields and

Full text of DOI:10.1016/j.tetasy.2008.01.011

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 265–268
Enantioselective cyanoformylation of aldehydes using a recyclable
dimeric cinchonidine ammonium salt as an organocatalyst
*
*
´
Rafael Chinchilla, Carmen Najera and Francisco J. Ortega
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, and Instituto de Sı´ntesis Orga´nica (ISO),
Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
Received 5 December 2007; accepted 10 January 2008
Abstract—A dimeric anthracenyldimethyl-derived cinchonidine ammonium salt is used as a chiral organocatalyst in the enantioselective
addition of alkyl cyanoformates to aldehydes in the presence of substoichiometric amounts of triethylamine. Quantitative yields and
enantioselectivities up to 88% ee for the corresponding (R)-O-methoxycarbonyl cyanohydrins are obtained using only 1 mol % organo-
catalyst loading and working at 10 °C. The organocatalyst can be almost quantitatively recovered by precipitation and reused.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tion of alkyl cyanoformates (ROCOCN) to aldehydes in
the presence of catalytic amounts of a chiral metal com-
plex. Thus, titanium(salen) bimetallic4 and N,N0-dioxide
titanium5 complexes have been used as chiral catalysts, as
well as self-assembled,6 multicomponent titanium cata-
lysts7 and heterobimetallic titanium–vanadium complexes.8
In addition, the enantioselective cyanoformylation of alde-
hydes has been performed using chiral binaphthyl-contain-
ing monometallic bifunctional aluminium catalysts,2 as
well as a cinchonine-containing heterobimetallic alumin-
ium lithium bis(binaphthoxide) complex.9 Moreover,
a lithium tris(binaphthoxide) yttrium complex has been
used in the asymmetric cyanoethoxycarbonylation of
aldehydes.10
The preparation of optically active cyanohydrins by the
enantioselective cyanation of prochiral carbonyl com-
pounds has aroused great interest in recent years1 because
of the synthetic versatility of cyanohydrins when transfer-
ring their functionality in the preparation of bioactive
and natural products. In particular, procedures allowing
the direct access to O-protected non-racemic cyanohydrins
are interesting to avoid reversibility of the cyanide addition
and therefore a decrease in the final enantioselection. Thus,
methodologies for the direct enantioselective preparation
of O-silylated, O-phosphorylated, O-acylated and O-
formylated cyanohydrins from aldehydes and ketones have
been developed.1 Among these O-protected cyanohydrins,
cyanohydrin carbonates show a series of advantages. They
are configurationally stable and significantly less prone to
decomposition than others, such as the most popular cya-
nohydrin trimethylsilyl ethers, and can be prepared using
inexpensive and less toxic reagents. Cyanocarbonates have
shown excellent configurational stability towards chemio-
selective hydrolysis in acidic media,2 in reduction processes
affording b-aminoalcohols,2 and in palladium-catalyzed
nucleophilic substitutions.1g,3
Although these chiral catalysts have generally achieved a
high enantioselection in the addition of alkyl cyanofor-
mates to aldehydes, there are inherent disadvantages asso-
ciated with the use of these types of metal complexes which
hamper its use on a large scale. Most of them are air and
moisture sensitive, which makes necessary the use of care-
ful and rather strict reaction conditions. They are not
recoverable and large amounts (5–20 mol %) of chiral li-
gands are frequently required as well as the presence of
some additives. Thus, the development of efficient metal-
free enantioselective cyanoformylation of carbonyl com-
pounds would be desirable.
The direct synthesis of enantiomerically enriched O-formy-
lated cyanohydrins has been mainly achieved by the addi-
The organocatalyzed enantioselective addition of alkyl
cyanoformates to carbonyl compounds is a field where
few examples can be found. Thus, Deng used a dimeric
*
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549
(C.N.); e-mail addresses: chinchilla@ua.es; cnajera@ua.es
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.011

266
R. Chinchilla et al. / Tetrahedron: Asymmetry 19 (2008) 265–268
Table 1. Organocatalytic addition of alkyl cyanoformates to benzalde-
hyde
dihydroquinidine derivative to catalyze the asymmetric
addition of ethyl cyanoformate to ketones with up to
97% ee, although the reaction required 10–30 mol % of
the catalyst and long reaction times up to 7 d.11 Recently,
Feng reported the enantioselective formylation of alde-
hydes catalyzed by a chiral quaternary ammonium salt
from quinidine 1 (10 mol %) in the presence of triethyl-
amine, achieving moderate enantioselectivities (61–72%
ee) in reaction times ranging from ca. 1 to 6 d and working
at ꢀ78 °C.12
O
O
O
OR
O
2
, Et3N
+
RO
3a
CN
CH2Cl2
Ph
CN
Ph
H
4aa
, R = Me
4ba
4ca
3b, R = Et
3c, R = Bn
Entry
2
3
Et3N
T
t
No. Yielda eeb
(mol %)
(mol %) (°C) (h)
(%)
(%)
AcO-
OMe
1
2
3
4
5
6
7
8
9
2a (10)
2b (10)
2c (10)
2a (5)
2a (1)
2a (1)
2a (1)
2a (1)
2a (1)
2a (1)
2a (1)
2a (1)
3a 20
3a 20
3a 20
3a 20
3a 20
3b 20
3c 20
3a 20
3a 20
3a 20
3a 10
25
25
25
25
25
25
25
10
0
2
2
2
2
2
3
3
3
6
4aa 99
60
0
F3C
4aa 99
4aa 99
4aa 99
4aa 99
4ba 99
N
+
44
60
69
56
65
80
75
61
74
63
HO
N
F3C
1
4ca
99
4aa 99
4aa 99
4aa 99
4aa 88c
4aa 85c
We have developed a series of dimeric anthracenyldimethyl-
derived ammonium salts from Cinchona alkaloids, such as
the cinchonidine-derived quats 2, as recoverable chiral
phase-transfer catalysts for asymmetric alkylation13 and
Michael addition14 reactions of glycinate Schiff bases for
the enantioselective synthesis of a-amino acids.15 Herein,
we report the behaviour of the dimeric ammonium salts 2
as organocatalysts in the direct enantioselective formyla-
tion of aldehydes.
10
11
12
ꢀ20 15
10
10
8
9
3a
5
Optimization reactions.
a Isolated as pure crude products according to 1H NMR (300 MHz) and
with >95% purity according to GLC.
b Determined by chiral HPLC.
c Determined by 1H NMR (300 MHz).
group in the organocatalyst. In addition, exchanging the
chloride counteranion in 2a by the tetrafluoroborate anion
affording the dimeric salt 2c, something favourable when
dealing with enantioselective PTC reactions using these
dimeric catalysts,13b,14 gave rise to a lower enantioselection
for 4aa (44% ee) (Table 1, entry 3). Therefore, ammonium
salt 2a was used in subsequent reactions.
2 X-
N
+
OR
+
N
N
RO
N
2a, R = H, X = Cl
Once the appropriate organocatalyst was established, the
next step was to determine if the catalyst loading could
be lowered while keeping its asymmetry-inducing proper-
ties. Thus, the amount of 2a was reduced to 5 mol %
observing no influence in the final enantioselectivity for
4aa (Table 1, entry 4). Interestingly, when the loading of
2a was lowered to only 1 mol %, a quantitative yield
of 4aa in 69% ee was obtained in the same reaction time
(Table 1, entry 5). When other alkyl cyanoformates, such
as ethyl cyanoformate 3b and benzyl cyanoformate 3c,
were used as cyanide sources under these reaction condi-
tions and catalyst loading, slightly lower enantioselectivi-
ties for the corresponding formylated products 4ba and
4ca, respectively, were obtained (Table 1, entries 6 and 7).
2b
, R = allyl, X = Br
2c, R = H, X = BF4
2. Results and discussion
The cyanoformylation of benzaldehyde as a model sub-
strate with methyl cyanoformate 3a using cinchonidine-de-
rived salt 2a as organocatalyst was performed under
reaction conditions similar to Feng’s.12 A 10 mol % of
organocatalyst loading was used in the presence of triethyl-
amine (20 mol %) in dichloromethane as solvent at room
temperature. Under these conditions, a 60% ee of the
(R)-O-formylated cyanohydrin 4aa was obtained in quanti-
tative yield after 2 h reaction time (Table 1, entry 1). The
(R)-stereochemistry for 4aa was assigned according to the
relative reported retention times in chiral HPLC.2b,12 This
result was very promising, as only 44% ee of the corre-
sponding protected cyanohydrin was reported using 1 as
organocatalyst and working at ꢀ15 °C.12 However, when
the O-allylated cinchonidine-derived dimeric ammonium
salt 2b was used as an organocatalyst, no enantioselection
for product 4aa was obtained (Table 1, entry 2). This result
showed the importance of the presence of the free OH
We subsequently wondered if the enantioselectivity of the
reaction could be improved by lowering the reaction tem-
perature. Thus, when the temperature was lowered to
10 °C, the reaction took 3 h instead of 2 h and compound
4aa was obtained quantitatively in 80% ee (Table 1, com-
pare entries 5 and 8). This result can be considered quite
good, when compared to the 67% ee reported using ammo-
nium salt 1 as a catalyst working at ꢀ78 °C.12 However,
when the reaction temperature was lowered to 0 °C, a
75% ee for compound 4aa was obtained in 6 h, this

R. Chinchilla et al. / Tetrahedron: Asymmetry 19 (2008) 265–268
267
decrease in the enantioselectivity was even more noticeable
when working at ꢀ20 °C where only a 61% ee was obtained
in 15 h reaction time (Table 1, entries 9 and 10). In addi-
tion, we also lowered the amount of triethylamine present
in the reaction, observing a lower enantioselectivity and
yield, as well as longer reaction times, when using 10 or
5 mol % of triethylamine (Table 1, entries 11 and 12). Other
attempted bases, such as dicyclohexylmethylamine or pyr-
idine gave almost a racemic 4aa.
or heliotropin (benzo[d][1,3]dioxole-5-carbaldehyde), gave
rise to the corresponding products 4ad and 4ae in 80%
and 83% ee, respectively (Table 2, entries 4 and 5).
When the electron-poor 4-chlorobenzaldehyde was cyano-
formylated, the final enantioselectivity was lower, affording
product 4af in only 41% ee (Table 2, entry 6). In this case,
lowering the reaction temperature to ꢀ20 °C was beneficial
and the enantioselectivity improved to 71% ee (Table 2, en-
try 6). However, when a more powerful electron-withdraw-
ing group was present, as in the case of 4-nitro-
benzaldehyde, product 4ag was obtained in 75% ee under
the typical reaction conditions (Table 2, entry 7). This
result is interesting, as this substrate has given rise to low
enantioselections when using chiral aluminium complexes
in the synthesis of other O-protected systems such as
cyanohydrin O-phosphates, probably due to competing
coordination of the nitro group to the metal.19 In addition,
other aromatic aldehydes, such as 1- and 2-naphthalde-
hyde, afforded final enantioselections of 78% and 75% for
4ah and 4ai, respectively (Table 2, entries 8 and 9).
With the optimized reaction conditions for the model reac-
tion (1 mol % loading of 2a, 20 mol % Et3N, CH2Cl2,
10 °C), we investigated the enantioselectivity of the reac-
tion for a series of aldehydes (Table 2, entry 1 included
for comparison).16,17 All the obtained (R)-O-methoxycar-
bonyl cyanohydrins 4a18 were isolated generally as pure
crude products (see footnote in Table 2) after only 2–4 h
reaction times.
Table 2. Enantioselective cyanoformylation of aldehydes using 2a as
organocatalyst (Ref. 16)
O
The use of a heteroaromatic aldehyde with a basic charac-
ter such as nicotinaldehyde gave racemic product 4aj
(Table 2, entry 10). This result was expected, due to the
competing properties of a stoichiometric amount of a pyr-
idine-containing system with the triethylamine when acti-
vating the cyanation reagent. However, when other
heteroaromatic aldehyde such as furfural was employed,
the corresponding cyanoformate 4ak was isolated quantita-
tively in 81% ee (Table 2, entry 11). In addition, a,b-unsat-
urated aldehydes gave lower enantioselectivities than
aromatic aldehydes, as shown in the formylation of
(E)-crotonaldehyde and (E)-oct-2-enal, which gave the
corresponding products 4al and 4am in 60% and 46% ee,
respectively (Table 2, entries 12 and 13). An aliphatic
aldehyde such as cyclohexanecarbaldehyde gave poor
enantioselectivity (Table 2, entry 14).
O
O
O
OMe
CN
4aa 4an
2a ( 1 mol%)
+
MeO
CN Et3N (20 mol%),
CH2Cl2, 10 ºC
R
H
R
3a
-
Entry Aldehyde
t
No. Yielda eeb
(h)
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Benzaldehyde
3
4aa 99
80
83
88
80
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
3,4,5-Trimethoxybenzaldehyde
Heliotropin
4-Chlorobenzaldehyde
4-Nitrobenzaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
Nicotinaldehyde
3
3
3
2
4ab 99
4ac 99
4ad 99
4ae 99
83
3(8)c 4af 99
41(71)c
75
4
3
3
3
3
3
3
3
4ag 99
4ah 99
78
75
0
81
60e
46e
40e
4ai
4aj
99
99
Furfural
4ak 99
As the dimeric cinchonidine ammonium salt 2a has been
previously used as a phase-transfer catalyst recoverable
by precipitation in ether,13 its recuperation was studied
by performing the cyanoformylation reaction of benzalde-
hyde on a 4 mmol scale with a slight change in the final
workup.16 Thus, the dichloromethane was evaporated after
the reaction completion and the crude was dissolved in
ether. Filtering the precipitate allowed the almost quantita-
tive (94%) recovery of the organocatalyst 2a, which could
be reused without any loss of activity. The final yield and
enantioselectivity for 4aa in this scaled reaction resulted
also similar to when performed at smaller scale (Table 2,
entry 1), also proving the scalability of the procedure.
(E)-Crotonaldehyde
(E)-Oct-2-enal
Cyclohexanecarbaldehyde
4al
97d
4am 88d
4an 86d
a Isolated as pure crude products according to 1H NMR (300 MHz) and
with >95% purity according to GLC.
b Determined by chiral HPLC (Ref. 17).
c In parenthesis, result when performed at ꢀ20 °C.
d Determined by 1H NMR (300 MHz).
e Determined by chiral GLC (Ref. 17).
The presence of a 4-methyl group in the aromatic ring of
benzaldehyde produced higher enantioselectivity for the
corresponding formylated cyanohydrin 4ab (Table 2,
compare entry 1 with entry 2). When a more powerful
electron-donating group was present, as in the case of 4-
methoxybenzaldehyde, the corresponding O-protected
cyanohydrin 4ac was isolated in 88% ee (Table 2, entry 3).
This result is remarkable, as only a 65% of 4ac in 70% ee
has been reported after 160 h reaction time at ꢀ78 °C when
a quinidine-derived ammonium salt as been used as an
organocatalyst.12 The presence of other electron rich
groups, as in the case of the 3,4,5-trimethoxybenzaldehyde
The mechanism operating in this enantioselective transfor-
mation is still unclear. As the presence of a free hydroxyl
group in the catalysts is crucial, probably a hydrogen bond
between this group and the carbonyl of the aldehyde is pos-
sibly created in a preliminary substrate-catalyst interaction.
In addition, the higher enantioselectivities obtained using
aromatic aldehydes as substrates would suggest a p-stack-
ing between both species. How the cyanide anion ap-
proaches the carbonyl group in the nucleophilic attack

268
R. Chinchilla et al. / Tetrahedron: Asymmetry 19 (2008) 265–268
Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M.
Tetrahedron 2004, 60, 10433–10447; (c) Belokon’, Y. N.;
Clegg, W.; Harrington, R. W.; Ishibashi, E.; Nomura, H.;
North, M. Tetrahedron 2007, 63, 9724–9740; (d) Chen, S.-K.;
Peng, D.; Zhou, H.; Wang, L.-W.; Chen, F.-X.; Feng, X. Eur.
J. Org. Chem. 2007, 639–644; (e) Lundgren, S.; Wingstrand,
E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc. 2005, 127,
11592–11593; (f) Belokon’, Y. N.; Ishibashi, E.; Nomura, H.;
North, M. Chem. Commun. 2006, 16, 1775–1777.
5. Li, Q.; Chang, L.; Liu, X.; Feng, X. Synlett 2006, 1675–
1678.
remains unknown. Perhaps a preliminary cyanide anion
interaction takes place with the positively charged ammo-
nium cation, leaving the cyanide close to the activated car-
bonyl. This cyanide anion would arise after the formation
of an acyl triethylammonium species by reaction of the
alkylcyanoformate reagent with triethylamine.2,11 In addi-
tion, the (R)-enantioselectivity of this process is unex-
pected, considering that (R)-cyanoformates have also
been obtained when using the quinidine-derived catalyst 1
which contains an apparent pseudoenantiomeric chiral envi-
ronment. Additional investigation would be necessary to
clarify these points.
6. (a) Wang, W.; Gou, S.; Liu, X.; Feng, X. Synlett 2007, 2875–
2878; (b) Gou, S.; Liu, X.; Zhou, X.; Feng, X. Tetrahedron
2007, 63, 7935–7941.
7. Gou, S.; Chen, X.; Xiong, Y.; Feng, X. J. Org. Chem. 2006,
71, 5732–5736.
8. Belokon, Y. N.; Clegg, W.; Harrington, R. W.; Young, C.;
North, M. Tetrahedron 2007, 63, 5287–5299.
3. Conclusion
We can conclude that dimeric cinchonidine-derived ammo-
nium salt 2a can be used as an efficient and recoverable
organocatalyst in the direct enantioselective cyanoformyla-
tion of aldehydes using methyl cyanoformate as the cya-
nide source in the presence of triethylamine. The final
enantiomerically enriched methyl cyanoformates are
obtained quantitatively in short reaction times without
requiring very low temperatures or anhydrous conditions
and with the lowest catalyst loading employed up to date
for this type of reaction. Further experiments are currently
underway in our laboratory order to determine the origin
of the enantioselection of this reaction.
9. Gou, S.; Wang, J.; Liu, X.; Wang, W.; Chen, F.-X.; Feng, X.
Adv. Synth. Catal. 2007, 349, 343–349.
10. (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2002, 41, 3636–3638; (b) Yamagiwa,
N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 3413–3422.
11. (a) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195–
6196; (b) Tian, S.-K.; Deng, L. Tetrahedron 2006, 62, 11320–
11330.
12. Peng, D.; Zhou, H.; Liu, X.; Wang, L.; Chen, S.; Feng, X.
Synlett 2007, 2448–2450.
´
´
13. (a) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron:
´
Asymmetry 2002, 13, 927–931; (b) Chinchilla, R.; Mazon,
´
P.; Najera, C.; Ortega, F. J. Tetrahedron: Asymmetry 2004,
15, 2603–2607.
´
´
14. Chinchilla, R.; Mazon, P.; Najera, C.; Ortega, F. J.; Yus, M.
Acknowledgements
Arkivoc 2005, 222–232.
´
15. Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584–
We thank the financial support from the Spanish Ministe-
4671.
´
rio de Educacion y Ciencia (projects CTQ 2004-00808/
16. Typical cyanoformylation procedure: A solution of the corre-
sponding aldehyde (0.2 mmol), catalyst 2a (0.002 mmol,
1.7 mg) and Et3N (0.04 mmol, 5.5 lL) dissolved in CH2Cl2
(2 mL) was cooled to 10 °C. Methyl cyanoformate (0.3 mmol,
24 lL) was added and the mixture was stirred vigorously.
After the reaction was completed (GLC), the mixture was
diluted with water (20 mL) and extracted with ethyl acetate
(3 ꢁ 5 mL). The combined organics were dried with MgSO4,
filtered and evaporated in vacuo (15 Torr) to afford crude
products, which were analyzed by 1H NMR (300 MHz)
spectroscopy.
17. Chiral HPLC: Chiralcel OD-H, k = 210 nm, hexane–2-pro-
panol 99:1, 1.0 mL/min; Chiralcel OG, k = 210 nm, hexane–
2-propanol 99:1, 1.0 mL/min; Chiralpak AD, k = 210 nm,
hexane–2-propanol 99:1, 1.0 mL/min. Chiral GLC: Cyclosil-
B, initial temperature 105 °C, flow rate 2.0 °C/min, 9 psi.
Racemic samples were prepared in the absence of 2a: Baeza,
BQU and Consolider Ingenio 2010, CSD2007-00006), the
Generalitat Valenciana (projects CTIOIB/2002/320, GRU-
POS03/134 and GV05/144) and the University of Alicante.
F.J.O. thanks the University of Alicante for a pre-doctoral
fellowship.
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