Efficient synthesis in water of mixed carbonates of cyanohydrins from aromatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2019.151414

An efficient preparation of cyanohydrin ethyl carbonates via cyanocarbonation of aromatic and hetero-aromatic aldehydes with sodium cyanide and ethyl chlorocarbonate using commercial surfactants (5 mol %) in aqueous media at low temperature afforded almos

Full text of DOI:10.1016/j.tetlet.2019.151414

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis in water of mixed carbonates of cyanohydrins from
aromatic aldehydes
⇑
Héctor Manuel Torres Domínguez, Luis Ángel Maldonado, Ronan Le Lagadec
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Ciudad de México, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient preparation of cyanohydrin ethyl carbonates via cyanocarbonation of aromatic and hetero-
aromatic aldehydes with sodium cyanide and ethyl chlorocarbonate using commercial surfactants
(5 mol %) in aqueous media at low temperature afforded almost quantitative isolated yields (ꢀ94%) in
30 min. Aromatic aldehydes bearing electron-donating as well as electron-withdrawing groups have been
successfully employed without any significant changes. Centrifugation of the reaction mixture allows
accessible purification without the need of solvent extraction. Reaction conditions can be readily
upscaled to multigrams.
Received 8 September 2019
Revised 10 November 2019
Accepted 17 November 2019
Available online xxxx
Keywords:
Protected cyanohydrins
Aromatic aldehydes
Surfactants
Ó 2019 Published by Elsevier Ltd.
Aqueous media reactions
Introduction
alternative to substitute organic solvents in organic reactions
[12]. In this media the issues linked with the low solubility of
Cyanohydrins are important intermediates in the synthesis of
various biological active compounds [1]. Because of their instabil-
ity, cyanohydrins have been O-protected and the ethoxycarbonyl
protective group has attracted much interest due to the great sta-
bility exhibited by mixed carbonates of cyanohydrins [2]. In addi-
tion, anions of cyanohydrin ethyl carbonates of aromatic aldehydes
have been employed as synthetic equivalents of acyl carbanions in
Michael addition / Claisen condensation tandem reaction type [3].
For the preparation of cyanohydrin ethyl carbonates, ethyl
cyanoformate in the presence of catalyst is frequently used as a
cyanide and simultaneously as the protective hydroxy group
source. Various catalysts, such as salen Ti(IV) complexes [4,5]
and V(V) complexes [6,7], allowed the preparation of asymmetric
cyanohydrin carbonates. On the other hand, 4-dimethylaminopy-
ridine (DMAP) [8], trimethylamine [9], and dimetylsulfoxide
(DMSO) [10] have been shown to be effective activators in the syn-
thesis of racemic cyanohydrin carbonates. Sodium cyanide has also
been used as a cyanide source in combination with ethyl chlorocar-
bonate in phase transfer reaction conditions in the presence of
tetrabutylammonium bromide [11]. All these methods afford high
yields of cyanohydrin carbonates. However, the use of halogenated
solvents in most cases presents unsatisfactory reactions conditions
from an environmental point of view. Recently, organic reactions in
aqueous media have emerged as a powerful and eco-friendly
organic reacting species and products have been partially solved
by the action of surfactants and several well-known reactions have
already been reported in the literature. Some recent examples
include olefin cross metathesis [13], Sonogashira couplings [14],
Suzuki-Miraura cross couplings [15], Prins reaction [16], Diels-
Alder cycloadditions [17], Morita-Baylis-Hillman reaction [18],
and Mannich-type reactions [19]. In the context of the preparation
of carbonated cyanohydrins, due to the solubility of NaCN in water,
we considered that aqueous reaction condition could be used for
the preparation of such compounds using NaCN as a cyanide
source in the presence of ethyl chlorocarbonate, the aldehyde
and a surfactant. A previous synthesis of ethyl carbonates of
cyanohydrins in water from aromatic aldehydes using KCN, ethyl
chlorocarbonate and excess of MgSO4 has been described in 1950
[20]. However, detailed role of MgSO4 was not explained. The pre-
sent article describes our results when NaCN as a cyanide source
was used in the presence of ethyl chlorocarbonate, the aldehyde
and a surfactant in aqueous reaction conditions. Additionally, cen-
trifugation of the final reaction mixture allows to skip the extrac-
tion step, permitting the immediate chromatographic purification
of the cyanocarbonates.
Results and discussion
Initially, in order to assess the reactivity of the method, 4-
methylbenzaldehyde, a deactivated aldehyde towards nucleophilic
additions, was considered as a convenient model compound.
⇑
Corresponding author.
E-mail address: ronan@unam.mx (L.L. Ronan).
https://doi.org/10.1016/j.tetlet.2019.151414
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: T. D. Héctor Manuel, M. Luis Ángel and L. L. Ronan, Efficient synthesis in water of mixed carbonates of cyanohydrins from aro-
matic aldehydes, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151414

2
T.D. Héctor Manuel et al. / Tetrahedron Letters xxx (xxxx) xxx
Reactions were carried out by the addition of NaCN aqueous solu-
tion (1.2 eq.) to a stirred mixture of the aldehyde (1 eq.), ethyl
chlorocarbonate (1.2 eq.), water and the surfactant at 4 0C.[21] Sev-
eral surfactants, both cationic and anionic (Fig. 1), were tested
under different conditions of temperature and concentration.
Results are summarized in Table 1.
Initially, the reaction was performed without the presence of
any surfactant and cyanocarbonate 3b was obtained in only 23%
yield (Table 1, entry 1). With dodecyltrimethylammonium chloride
(DTMAC) as surfactant, in 10 mol% and 30 min at 4 °C, cyanocar-
bonate 3b was obtained in 99% yield (Table 1, entry 2). Lowering
the concentration of DTMAC to 5 mol% did not affect the yield
(entry 3). However, when the reaction time decreased to 15 min,
the yield dropped to 89% (entry 4). When the substrates were
mixed at room temperature, the reaction temperature immediately
rose to 35 °C, the mixture darkened and 3b was obtained in 57%,
along with large amounts of unreacted aldehyde (Table 1, entry
5). When shifting the surfactant to OLSULP (sodium alpha-olefin-
dodecyltrimethyl sulfonate) under the conditions of entry 3, the
yield slightly decreased to 96% (entry 6), while QUAB18 (octade-
cyltrimethylammonium ethylsulfate) and TBAB (tetrabutylammo-
nium bromide) provided 3b in 92% and 73% yields respectively
(Table 1, entries 7 and 8). From the above data, the reactions con-
ditions of entry 3 (5 mol% DTMAC, 30 min at 4 °C) were selected to
study the scope of the reactions with several aromatic aldehydes.
After the reaction time, the mixture was allowed to reach room
temperature and the resulting emulsion was centrifugated. The
organic layer was separated from water and the product purified
by column chromatography (Silica-Gel, Hexane - EtOAc: 9-1).[22]
The results are summarized in Table 2. It is worth noting that
almost quantitative isolated yields (ꢀ94%) of cyanocarbonates
3a-3n were obtained both from substituted aromatic aldehydes
with electron-donating groups (3b, 3c, 3g, 3h and 3l) and from
electron-withdrawing groups (3d, 3e, 3f, 3i, 3j and 3k) regardless
Table 1
Optimization of the reaction conditions.
Entry
Surfactant
Concentration surfactant (mol%)
Reaction time (min)
Temp. (°C)
Yielda (%)
1
2
3
4
5
6
7
8
30
30
30
15
30
30
30
30
4
4
4
4
23
4
4
23
99
99
89
57
96
92
73
DTMAC
DTMAC
DTMAC
DTMAC
OLSULP
QUATB18
TBAB
10
5
5
5
5
5
5
4
a
Determined by NMR analysis from the crude mixture. Reaction conditions: 4-methylbenzaldehyde (360 mg, 3.0 mmol), ethyl chloroformate (390 mg, 3.6 mmol), and
surfactant in H2O (1 mL) were stirred at 4 °C and NaCN (176 mg, 3.6 mmol) in H2O (1 mL) were added to the reaction mixture.
Fig. 1. Surfactants used in this study.
Please cite this article as: T. D. Héctor Manuel, M. Luis Ángel and L. L. Ronan, Efficient synthesis in water of mixed carbonates of cyanohydrins from aro-
matic aldehydes, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151414

T.D. Héctor Manuel et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
of the substituted position. Similar results were obtained from
thiophene-2-carboxyaldehyde (3m) and furan-2-carboxyaldehyde
(3n). Additionally, no change in the yields and purity of the
cyanohydrins occurred when the reaction was scaled to multi-
grams (30 mmol). To rationalize these data, one may assume that
in the high concentrated ambient of reacting species, when the
addition of the cyanide to the aldehyde takes place, the formed
intermediate A is rapidly captured by ethyl chlorocarbonate, shift-
ing the equilibrium to the right and consequently affording high
yields of the product (Scheme 1). The use of a cationic surfactant
facilitates the introduction of the cyanide anion into the organic
phase.
Cyanocarbonation of aldehydes (isolated yields after column chromatography).
Conclusion
In summary, a facile and efficient preparation of cyanohydrin
ethyl carbonates starting from NaCN, ClCO2Et and a range of elec-
tron-donating and electron-withdrawing substituted aldehydes
has been developed. The use of an ammonium salt as a surfactant
allowed to run the reaction in water. The availability of the sub-
strates, use of aqueous media, mild reaction conditions, short reac-
tion time, operational simplicity and separation procedure,
upscaling ease and quantitative yields make this method a partic-
ularly convenient route for the cyanocarbonation of aldehydes.
Acknowledgments
Financial support from DGAPA-UNAM (PAPIIT Project
IN-207419) is acknowledged. We thank Q. María de la Paz Orta
Pérez for assistance in obtaining elemental analysis. Dr. R. Cerón
Camacho is thanked for helpful discussions.
Appendix A. Supplementary data
aThe aldehyde was dissolved in 3 mL of THF.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151414. These data include
general synthetic procedures, characterization of the compounds,
1H- and 13C NMR spectra.
References
[1] R.J.H. Gregory, Chem. Rev. 99 (1999) 3649–3682.
[2] M. Okimoto, T. Chiba, Synthesis (1996) 1188–1190.
[3] D.H.M. Torres, L.A. Maldonado, L.R. Lagadec, Synth. Commun. 47 (2017) 1250–
1255.
[4] Y.N. Belokon, W. Clegg, R.W. Harrington, E. Ishibashi, H. Nomura, M. North,
Tetrahedon 63 (2007) 9724–9740.
[5] J. Wang, W. Wang, W. Li, X. Hu, K. Shen, Ch. Tan, X. Liu, X. Feng, Chem. Eur. J. 15
(2009) 11642–11659.
[6] N.H. Khan, A. Sadhukhan, N.C. Maity, R.I. Kureshy, H.R. Abdi, S. Sarovanan, H.C.
Bajaj, Tetrahedron 67 (2011) 7073–7080.
[7] N.H. Khan, S. Agrawal, R.I. Kureshy, S.H.R. Abdi, K.J. Prathap, R.V. Jasra, Eur. J.
Org. Chem. 26 (2008) 4511–4515.
[8] S. Aoki, S. Kotani, M. Sugiura, M. Nakajima, Tetrahedron Lett. 51 (2010) 3547–
3549.
[9] A. Baeza, C. Nájera, M.G. Retamosa, J.M. Sansano, Synthesis 37 (2005) 2787–
2797.
[10] K. Iwanami, Y. Hinakubo, T. Oriyama, Tetrahedron Lett. 46 (2005) 5881–5883.
[11] A.T. Au, Synth. Commun. 14 (1984) 743–748.
[12] A. Chanda, V.V. Fokin, Chem. Rev. 109 (2009) 725–748.
[13] B.H. Lipshutz, G.T. Aguinaldo, S. Ghorai, K. Voigtritter, Org. Lett. 10 (2008)
1325–1328.
[14] B.H. Lipshutz, D.W. Chung, B. Rich, Org. Lett. 10 (2008) 3793–3796.
[15] B.H. Lipshutz, A.R. Abela, Org. Lett. 10 (2008) 5329–5332.
[16] D.L. Aubele, Ch.A. Lee, P.E. Floreancig, Org. Lett. 5 (2003) 4521–4523.
[17] K. Nishimoto, S. Kim, Y. Kitano, M. Tada, K. Chiba, Org. Lett. 8 (2006) 5545–
5547.
[18] J.C. Gomes, J. Sirvent, A. Moyano, M.T. Rodrigues Jr., F. Coelho, Org. Lett. 15
(2013) 5838–5841.
[19] K. Manabe, Y. Mori, S. Kobayashi, Tetrahedron 57 (2001) 2537–2544.
[20] K. Kindler, K. Schrader, Arch. Pharm. (Weinheim) 283 (1950) 190–192.
[21] The temperature of the reaction rapidly raises to 20 °C and then lowers to 4 °C.
Otherwise lower yields are obtained.
Scheme 1. Proposed mechanism.
Please cite this article as: T. D. Héctor Manuel, M. Luis Ángel and L. L. Ronan, Efficient synthesis in water of mixed carbonates of cyanohydrins from aro-
matic aldehydes, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151414

4
T.D. Héctor Manuel et al. / Tetrahedron Letters xxx (xxxx) xxx
[22] Typical procedure for cyanocarbonation of 4-methylbenzaldehyde. A solution
of NaCN (176 mg, 3.6 mmol) in H2O (1 mL) was added to a stirred mixture of
DMAC (0.09 mL, 0.15 mmol, 46% wt. aqueous solution), 4-
methylbenzaldehyde (360 mg, 3.0 mmol) and ClCO2Et (390 mg, 3.6 mmol)
in H2O (1 mL) at 4 °C (ice/water bath). The reaction mixture was stirred for 30
(silica-Gel, Hexane-EtOAc: 9-1) to afford 651 mg (2.97 mmol, 99%) of 3b as a
colorless oil. 1H NMR (300.53 MHz, CDCl3), d (ppm): 7.50 (d, J = 8.2, 2H, CHAr),
7.34 (d, J = 8.2 Hz, 2H, CHAr), 6.32 (s, 1H, CH), 4.27 (m, 2H, CH2), 2.4 (s, 3H,
CArCH3), 1.30 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3) d (ppm):
151.3 (CO3), 141.5, 130.4, 129.4, 128.1, 117.9 (CN), 66.7, 65.9, 20.8 (CArCH3),
14.12 (CH3). Anal. Calcd. for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.89; H, 6.02; N 6.56.
minutes and then centrifugated for
1 minute. The organic phase was
separated, and the crude material was purified by column chromatography
Please cite this article as: T. D. Héctor Manuel, M. Luis Ángel and L. L. Ronan, Efficient synthesis in water of mixed carbonates of cyanohydrins from aro-
matic aldehydes, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151414