TBD- or PS-TBD-catalyzed one-pot synthesis of cyanohydrin carbonates and cyanohydrin acetates from carbonyl compounds

Article abstract of DOI:10.3390/molecules21081030

Cyanation reactions of carbonyl compounds with methyl cyanoformate or acetyl cyanide catalyzed by 5 mol % of 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) were examined. Using methyl cyanoformate, the corresponding cyanohydrin carbonates were readily obtained in high yield for aromatic and aliphatic aldehydes and ketones. Similar results were obtained when acetyl cyanide was used as the cyanide source. The polymer-supported catalyst, PS-TBD, also acted as a good catalyst for this reaction. PS-TBD was easily recovered and reused with minimal activity loss.

Full text of DOI:10.3390/molecules21081030

molecules
Article
TBD- or PS-TBD-Catalyzed One-Pot Synthesis of
Cyanohydrin Carbonates and Cyanohydrin Acetates
from Carbonyl Compounds
Satoru Matsukawa *, Junya Kimura and Miki Yoshioka
Department of Science Education, Faculty of Education, Ibaraki University, Ibaraki 310-8512, Japan;
varsil0403@gmail.com (J.K.); 13p1419r@vc.ibaraki.ac.jp (M.Y.)
* Correspondence: satoru.matsukawa.1@vc.ibaraki.ac.jp; Tel.: +81-29-228-8234; Fax: +81-29-228-8329
Academic Editor: Raquel P. Herrera
Received: 30 June 2016; Accepted: 3 August 2016; Published: 10 August 2016
Abstract: Cyanation reactions of carbonyl compounds with methyl cyanoformate or acetyl cyanide
catalyzed by 5 mol % of 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) were examined. Using methyl
cyanoformate, the corresponding cyanohydrin carbonates were readily obtained in high yield for
aromatic and aliphatic aldehydes and ketones. Similar results were obtained when acetyl cyanide was
used as the cyanide source. The polymer-supported catalyst, PS-TBD, also acted as a good catalyst
for this reaction. PS-TBD was easily recovered and reused with minimal activity loss.
Keywords: organocatalyst; basecatalyst; guanidine; cyanation; cyanoester
1. Introduction
The addition of cyanide to carbonyl compounds is among the most fundamental carbon–carbon bond
formation reactions in modern organic chemistry [1–6]. The resultant cyanohydrins are easily converted
into important synthetic intermediates including -hydroxyl-carbonyl compounds and
α
β-amino alcohols.
Multiple cyanation methods have been examined, and trimethylsilyl cyanide has most commonly
been used as the source of the cyanide anion [7,8]. While hundreds of examples have been reported
to this day, the inherent instability of trimethylsilyl cyanohydrins sometimes limits the applications
of this reaction. Therefore, alternative synthetic procedures for the preparation of stable O-protected
cyanohydrins instead of trimethylsilyl cyanohydrin have been developed. Cyanohydrin carbonates
and cyanohydrin acylates are configurationally stable and less prone to hydrolysis than cyanohydrin
trimethylsilyl ethers.
cyanation using cyanoformates and cyanoacylates have recently been developed. Several catalytic
reactions have been recently studied. To date, reactions using tributyltin cyanide [ ], K2CO3 [10],
tertiary amines [11 12], DABCO (1,4-diazabicyclo[2.2.2]octane) [13,14], dimethyl sulfoxide [15],
Therefore, one-pot synthesis of cyanohydrin carbonates and acylated
9
,
TTMPP (tris(2,4,6-trimethoxyphenyl)phsphine) [16], DMAP (N,N-dimethyl-4-aminopyridine) [17],
and N-heterocyclic carbenes [18] as catalysts or activators have been reported. Asymmetric catalytic
reactions have also been reported using cinchona alkaloids [19–25], Y complexes [26–28],
Al complexes [29,30], Ti complexes [31 40], and V complexes [41]. To further extend the scope of
–
this versatile synthetic reaction, we have now examined the use of 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) as a Lewis base catalyst.
It is well-known that TBD is a strong Lewis base owing to its distorted bicyclic
guanidine structure [42,43]
reported using TBD as an organobase catalyst including Henry reactions [44], Wittig and
Horner-Wadsworth-Emmons reactions [45], Michael reactions [46 47], intramolecular aldol
51], aminolysis of esters [52 53], conjugate addition
.
Employing this property, multiple unique reactions have been
,
reactions [48,49], ring-opening polymerization [50
,
,
Molecules 2016, 21, 1030; doi:10.3390/molecules21081030
www.mdpi.com/journal/molecules

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to activated alkenes [54], synthesis of pyrazolines [55], and others [56
,
57]. Although TBD usually
behaves as a base, it also contains an acidic N–H group; therefore, TBD may act as a bifunctional
acid-base catalyst [58 60]. Recently, we have reported the trifluoromethylation of aldehydes [61
and the ring-opening reactions of aziridines [62 63] catalyzed using TBD as an organocatalyst. Here,
–
]
,
we report that TBD acts as an effective organobase catalyst for the cyanation of carbonyl compounds
using methyl cyanoformate or acetyl cyanide as cyanide source.
2. Results and Discussion
Initially, the cyanomethoxycarbonylation reaction of p-anisaldehyde using methyl cyanoformate
was examined in the presence of 5 mol % of TBD in THF at room temperature. The desired product
was obtained in 90% yield after 2 h (Table 1, entry 1). The product was obtained in a lower yield when
DMF (N,N-dimethylformamide), toluene or ClCH2CH2Cl was used as the solvent. An approximately
comparable yield was observed when CH3CN was used (Table 1, entry 2). The yield was decreased
when 1 mol % of TBD was used (Table 1, entry 6). To clarify the scope of this reaction, the cyanation of
several aldehydes was examined in the presence of 5 mol % of TBD. In the case of aromatic aldehydes,
the yield was influenced by the substituents on the aromatic ring. With aromatic aldehydes bearing
an electron-withdrawing group, it was necessary to change the order of reagent addition to obtain
the desired product in good yield. Using other aromatic aldehydes, the products were obtained
in good to high yields. trans-Cinnamaldehyde was subjected to our reaction conditions, and the
1,2-addition product was obtained in 85% yield. Although slightly longer reaction times were required,
aliphatic aldehydes also produced similar high yields.
Table 1.
TBD (1,5,7-triazabicyclo[4,4,0]dec-5-ene) catalyzed cyanation of aldehydes with
methyl cyanoformate.
N
N
N
H
O
TBD
O
O
(5 mol%)
O
OMe
+
NC
OMe
R
H
solvent
rt, time
R
CN
H
1a - j
2a - j
Entry
Aldehyde(1)
CHO
Product
2a
Solvent
Time
Yield (%) a
1
CH3CN
THF
2 h
90
MeO
2
3
2 h
3 h
81
65
60
35
68
ClCH2CH2Cl
DMF
4
3 h
5
6 b
toluene
12 h
12 h
CH3CN
CHO
7
8
2b
2c
CH3CN
12 h
4 h
89
92
CHO
Cl

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Table 1. Cont.
Product Solvent
Entry
Aldehyde(1)
Time
Yield (%) a
CHO
9 c
2d
2e
0.5 h
70
O2N
CHO
10
11
4 h
4 h
96
90
CHO
2f
CHO
12
13
2g
2h
2i
2 h
4 h
4 h
85
75
96
CHO
CHO
14
15
CHO
2j
4 h
4 h
89
88
n-C8H17
CHO
16
2k
O
a
Isolated yield; b 1 mol % of TBD was used; c Aldehyde was added after addition of methyl cyanoformate.
Ketones were also examined using the 10 mol % of TBD (Table 2). In the case of aliphatic
ketones, good results were obtained for both acyclic and cyclic ketones. The reaction proceeded more
smoothly than the reported example [17]. Only 1,2-addition products were observed for unsaturated
ketones. On the other hand, for aromatic ketones, only a small amount of the desired product
was obtained at room temperature even after 24 h. When the reactions were performed at elevated
˝
temperature (50 C), a variety of aromatic ketones were converted to their corresponding cyanohydrin
carbonates in moderate to good yields. In this reaction, novel cyanohydrin carbonates (4c 4g) could
,
be obtained. In addition, 4d and 4e were obtained for the first time as products of this one-pot
method. Unfortunately, in the reaction of 4-methoxyacetophenone, no product was found under
these conditions.
Table 2. TBD catalyzed cyanation of ketones with methyl cyanoformate.
O
TBD
O
O
(10 mol%)
O
OMe
CN
+
NC
OMe
R
R
2
CH CN
1
R
1
3
R
2
rt, time
Product
4a
3a - j
4a - j
Yield (%) a
Entry
Ketone(3)
Time
O
1
4 h
85
90
O
2
4b
1 h

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Table 2. Cont.
Product
Entry
Ketone(3)
Time
Yield (%) a
O
3
4c
4d
4e
4f
1 h
86
O
4
1 h
70
33
31
75
O
5 b
6 b
7 b
24 h
24 h
24 h
O
O
4g
O
8
4h
4i
6 h
55
38
0
Cl
O
9 b
10
24 h
24 h
O2N
MeO
O
4j
a
Isolated yield; b at 50 ˝C.
Acetyl cyanide was also examined in the TBD-catalyzed reaction (Table 3). The acylated
cyanohydrin products were readily obtained in high yields in a similar manner for aromatic aldehydes.
Although the bond between the acetyl and cyanide groups is stronger in acetyl cyanide than in methyl
cyanoformate, the reactivity did not decrease. In the case of 4-nitrobenzaldehyde, the starting material
was rapidly consumed; however, the product yield was not good. In this case, it is likely that attack at
the NO2 group occurred. Longer reaction times were needed in the reaction of aromatic aldehydes
bearing electron-donating groups on the aromatic ring. This trend has been similarly reported in
a recent related report [18]. The aliphatic, heterocyclic, and
give the corresponding products in similarly high yields.
α
,
β-unsaturated aldehydes also reacted to
Furthermore, we applied a polymer-supported TBD, PS-TBD [64
–
67] to this reaction (Table 4).
Polymer-supported catalysts have attracted significant attention in recent decades because of their
inherent advantages in synthetic chemistry, e.g., the simplification of reaction procedures including
the easy recovery of the catalyst using filtration, application to automated systems, and recycling of
the catalyst [68
in the presence of 10 mol % of PS-TBD [63
–
73]. Thus, we examined the cyanomethoxycarbonylation reaction of p-anisaldehydes
74 79]. The reaction proceeded smoothly and the desired
,
–
product was obtained in 95% yield after 3 h at room temperature. A variety of aldehydes reacted
well with methyl cyanoformate to give cyanohydrin carbonates. Aromatic aldehydes with either
electron-donating or electron-withdrawing groups afforded the corresponding products in high yields.

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Aliphatic aldehydes also worked well. In the reaction with aldehyde, the catalytic reactivity of
PS-TBD seems to be slightly lower than TBD. Ketones were also examined; however, the reaction
was very slow. Then, the reaction was performed at elevated temperature. The desired product was
obtained at moderate to yield in 4 h at 50 ˝C. In addition, the recovery and reuse of PS-TBD for the
reaction of p-anisaldehyde with methyl cyanoformate was also examined. After the reaction was
completed, ethyl acetate was added to the reaction mixture and the catalyst was recovered by filtration.
The recovered catalyst was washed, dried and then reused. The catalyst was reused, maintaining its
catalytic activity after three times.
Table 3. TBD catalyzed cyanation of aldehydes with acetyl cyanide.
O
TBD
O
O
(5 mol%)
O
CH
3
+
NC
CH
3
R
H
CH CN
R
CN
3
H
rt, time
1a - l
5a - l
Entry
Aldehyde(1)
Product
Time
Yield (%) a
CHO
1
5a
3 h
6 h
80
CHO
2
3
4
5b
91
94
67
Cl
CHO
CHO
CHO
CHO
5c
24 h
48 h
H3C
5d
MeO
5
6
5e
5f
0.5 h
3 h
40
90
O2N
CHO
7
5g
3 h
90
CHO
8
9
5h
5i
3 h
6 h
6 h
92
70
88
CHO
CHO
10
5j
CHO
11
12
5k
5l
6 h
6 h
85
80
n-C8H17
CHO
O
a
Isolated yield.

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Table 4.
PS (polymer-supported)-TBD catalyzed cyanation of carbonyl compounds with
methyl cyanoformate.
N
N
N
O
PS-TBD
O
O
(10 mol%)
O
OMe
+
NC
OMe
R
1
R
2
CH CN
R
CN
3
H
rt, time
1,3
2, 4
Entry
Carbonyl Compounds
Product
2a
Time
Yield (%) a
CHO
1
2 h
90
MeO
2 b
3 c
4 d
2a
2a
2a
2 h
2 h
2 h
88
92
88
CHO
5
6
2b
2c
12 h
16 h
73
86
CHO
Cl
CHO
7
8
2d
2e
4 h
4 h
94
98
O2N
CHO
CHO
9
2h
2k
2i
4 h
2 h
2 h
90
78
82
CHO
O
10
11
CHO
O
12
4a
24 h
24
13 e
14 e
4a
12 h
24 h
75
70
O
4b
O
15 e
4c
18 h
76
a
Isolated yield; b 2nd run; c 3rd run; d 4th run; e at 50 ˝C.

Molecules 2016, 21, 1030
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A possible mechanism for the TBD-catalyzed cyanation is illustrated in Scheme 1.
`
´
First, the nitrogen atom of TBD activates the cyanoformates or cyanoacylates to form [N C(O)R]CN
intermediate
. Next, the CN´ anion immediately reacts with the carbonyl compounds to give the
alkoxide anion of the cyanohydrin . Finally, the alkoxide anion is carbonylated or acylated to give the
A
B
O-protected cyanohydrin with the regeneration of TBD. In this reaction, acidic N–H group of TBD may
activate the carbonyl group (C).
O
O
O
R
3
R
CN
N
3
R
CN
H
N
N
N
H
N
O
N
O
N
H
N
+
N
H
N
+
N
H
N
+
R
O
R
O
R
R
R
2
1
-
-
O
CN
C
R
CN
A
H
O
B
R
R
2
1
Scheme 1. Proposed mechanism. [N`C(O)R]CN´ intermediate
B and alternative transition state C.
A; alkoxide anion of the cyanohydrin
3. Experimental Section
3.1. General
IR spectra were recorded on a JUSCO FT/IR-430 spectrometer (JASCO Corporation, Tokyo,
1
Japan). H-NMR spectra were determined for solutions in CDCl3 with Me4Si as internal standard
(CDCl3: 7.24 ppm, Me4Si: 0.00 ppm) on a Bruker Avance III instrument (Bruker Corporation, Billerica,
MA, USA). 13C-NMR spectra were determined for solutions in CDCl3 with Me4Si as internal standard
(CDCl3: 77.00 ppm, Me4Si: 0.00 ppm) on a Bruker Avance III instrument (Bruker Corporation).
HRMS data were measured on a JEOL JMS-700 mass spectrometer (JEOL Ltd., Tokyo, Japan).
All reactions were performed under an argon atmosphere using oven-dried glassware.
Flash column chromatography was performed using silica gel Wakogel C-200 (Wako Chemical,
Osaka, Japan). Dehydrate DMF, THF, toluene and CH3CN were purchased from Kanto Kagaku
(Tokyo, Japan) as the “anhydrous” and stored over 4A molecular sieves under Ar. Other commercially
available reagent was used as received without further purification.
3.2. Method
3.2.1. General Procedure for TBD-Catalyzed Cyanation Reactions of Carbonyl Compounds with
Methyl Cyanoformate
TBD was dried in vacuo before use. To a solution of TBD (0.05 mmol) in CH3CN (1 mL) was
added carbonyl compound (1.0 mmol) and methyl cyanoformate (1.25 mmol) at room temperature.
After the reaction was complete (as determined by TLC), the reaction mixture was quenched with
water. The resultant mixture was extracted with EtOAc (3
were washed with water and brine and dried with Na2SO4. After the filtration, the residue was
ˆ
10 mL). The combined organic layers

Molecules 2016, 21, 1030
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concentrated in vacuo. The crude product was purified by column chromatography on silica gel
(EtOAc:hexane = 1:5 Ñ 1:3) to give the corresponding product.
3.2.2. General Procedure for TBD-Catalyzed Cyanation Reactions of Aldehydes with Acetyl Cyanide
TBD was dried in vacuo before use. To a solution of TBD (0.10 mmol) in CH3CN (1 mL) was
added aldehyde (1.0 mmol) and acetyl cyanide (1.5 mmol) at room temperature. After the reaction
was complete (as determined by TLC), the reaction mixture was quenched with water. The resultant
mixture was extracted with EtOAc (3
water and brine and dried with Na2SO4. After the filtration, the residue was concentrated in vacuo.
ˆ
10 mL). The combined organic layers were washed with
The crude product was purified by column chromatography on silica gel (EtOAc:hexane = 1:10
to give the corresponding product.
Ñ
1:5)
3.2.3. General Procedure for PS-TBD Catalyzed Cyanation Reactions of Carbonyl Compounds with
Methyl Cyanoformate
PS-TBD was dried in vacuo before use. To a solution of PS-TBD (0.10 mmol) in CH3CN (1 mL)
was added carbonyl compound (1.0 mmol) and methyl cyanoformate (1.25 mmol) at room temperature.
After the reaction was complete (as determined by TLC), EtOAc (10 mL) was added to the mixture
and PS-TBD was separated by filtration. The filtrate was washed with water and brine and dried with
Na2SO4. After the filtration, the residue was concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (EtOAc:hexane = 1:5
The recovered catalyst is reusable after washing (acetone and water) and drying in vacuo.
Ñ
1:3) to give the corresponding product.
3.3. General Characterization of the Products
Cyano(4-methoxyphenyl)methyl methyl carbonate (2a) [11]: IR (neat): 2245, 1761 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ
3.80 (s, 3H), 3.82, (s, 3H), 6.18 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H);
55.5, 55.7, 66.4, 114.6, 115.9, 123.2, 129.8, 154.1, 161.4. The corresponding
13C-NMR (125 MHz, CDCl3):
δ
spectra are shown in Supplementary Materials.
Cyano(phenyl)methyl methyl carbonate (2b) [11]: IR (neat): 2249, 1760 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
3.77 (s, 3H), 6.18 (s, 1H), 7.35–7.46 (m, 5H); 13C-NMR (125 MHz, CDCl3):
δ 55.9, 66.6, 115.7, 127.9,
129.3, 130.7, 131.1, 154.1.
Cyano(4-chlorophenyl)methyl methyl carbonate (2c) [11]: IR (neat): 2250, 1758 cm´1; 2347, 1762 cm´1
;
1H-NMR (500 MHz, CDCl3):
3.84 (s, 3H), 6.21 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H);
13C-NMR (125 MHz, CDCl3): δ 56.0, 65.8, 115.3, 129.2, 129.3, 129.6, 136.9, 153.9.
δ
Cyano(4-nitrophenyl)methyl methyl carbonate (2d) [16]: IR (neat): 2251, 1760 cm´1; 1H-NMR (500 MHz,
CDCl3):
2.20 (s, 3H), 6.49 (s, 1H), 7.71 (d, J = 8.7 Hz, 2H), 8.30 (d, J = 8.7 Hz, 2H); 13C-NMR (125 MHz,
δ
CDCl3): 20.3, 61.6, 115.1, 124.4, 128.7, 138.1, 149.0, 168.6.
Cyano(naphthalen-1-yl)methyl methyl carbonate (2e) [15]: IR (neat): 2247, 1768 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ
3.77 (s, 3H), 6.18 (s, 1H), 7.51–7.58 (m, 3H), 7.80–7.96 (m, 4H); 13C-NMR (125 MHz, CDCl3):
δ 56.0, 65.3, 115.8, 122.6, 125.0, 126.4, 127.7, 129.1, 129.2, 130.0, 131.8, 133.9, 154.2.
Cyano(naphthalen-2-yl)methyl methyl carbonate (2f) [15]: IR (neat): 2254, 1757 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ
3.85 (s, 3H), 6.42 (s, 1H), 7.51–7.56 (m, 3H), 7.84–7.96 (m, 4H); 13C-NMR (125 MHz, CDCl3):
δ 55.9, 66.8, 115.8, 124.1, 127.1, 127.7, 127.9, 128.1, 128.4, 128.5, 129.5, 132.8, 134.0, 154.2.
Cyano-3-phenylpropen-2-yl methyl carbonate (2g) [15]: IR (neat): 2260, 1759 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ 3.86 (s, 3H), 5.88(dd, J = 1.1, 6.8 Hz, 1H), 6.20(dd, J = 6.8, 15.8 Hz, 1H), 6.98 (d, J = 15.8 Hz,

Molecules 2016, 21, 1030
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1H), 7.33–7.38 (m, 3H), 7.40–7.46 (m, 2H); 13C-NMR (125 MHz, CDCl3):
128.2, 129.5, 134.2, 138.4, 154.0.
δ
55.9, 65.2, 114.9, 117.6, 127.2,
Cyano-3-phenylpropyl methyl carbonate (2h) [15]: IR (neat): 2240, 1760 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
2.22–2.30 (m, 2H), 2.85 (t, J = 7.8 Hz, 2H), 3.86 (s, 3H), 5.13 (t, J = 7.8 Hz, 2H), 7.18–7.21 (m, 3H),
7.29–7.33 (m, 2H); 13C-NMR (125 MHz, CDCl3):
δ
30.4, 33.8, 55.8, 64.0, 116.2, 126.7, 128.2, 128.4, 128.7,
129.0, 138.7, 154.0.
1
Cyano(cyclohexyl)methyl methyl carbonate (2i) [15]: IR (neat): 2247, 1758 cm´1; H-NMR (500 MHz,
CDCl3):
δ 1.06–1.25 (m, 5H), 1.65 (d, J = 12.7 Hz, 1H), 1.89 (m, 6H), 3.79 (s, 3H), 4.98 (d, J = 6.0 Hz,
1H) 3.80 (s, 3H), 6.28 (s, 1H), 6.37 (dd, J = 1.9, 3.4 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1H), 7.45 (m, 1H);
13C-NMR (125 MHz, CDCl3): δ 25.2, 27.7, 27.9, 40.1, 55.7, 69.5, 115.7, 154.3.
Cyano(1-octyl)methyl methyl carbonate (2j) [16]: IR (neat): 2249, 1760 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
0.81 (m, 3H), 1.19–1.21 (m, 12H), 1.87 (dd, J = 6.8, 15.8 Hz, 2H), 3.79 (s, 3H), 5.13 (t, J = 6.8 Hz, 1H);
13C-NMR (125 MHz, CDCl3): δ 14.0, 22.6, 24.4, 28.8, 29.2, 29.5, 31.7, 32.3, 55.7, 64.9, 116.5, 154.3.
1
Cyano(furan-2-yl)methyl methyl carbonate (2k) [11]: IR (neat): 2247, 1768 cm´1; H-NMR (500 MHz,
CDCl3):
δ 3.80 (s, 3H), 6.28 (s, 1H), 6.37 (dd, J = 1.9, 3.4 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1H), 7.45 (m, 1H);
13C-NMR (125 MHz, CDCl3): δ 56.0, 59.3, 111.2, 113.2, 143.5, 145.4, 153.9.
1-Cyano-1-methyl-3-phenylpropyl methyl carbonate (4a) [11]: IR (neat): 2250, 1760 cm´1
;
1H-NMR (500 MHz, CDCl3):
δ 1.82 (s, 3H), 2.17–2.34 (m, 2H), 2.82–2.90 (m, 2H), 3.83 (s, 3H),
7.16–7.24 (m, 3H), 7.26–7.31 (m, 2H); 13C-NMR (125 MHz, CDCl3):
126.5, 128.4, 128.7, 139.7, 153.2.
δ 24.5, 30.2, 41.6, 55.3, 74.0, 118.2,
1-Cyano-1-ethylhexyl methyl carbonate (4b) [16]: IR (neat): 2250, 1759 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
0.85 (t, J = 6.9 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H), 1.24–1.33 (m, 4H), 1.35–1.54 (m, 2H), 1.88–2.10 (m, 4H),
3.78 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 7.9, 13.8, 22.3, 23.2, 29.8, 31.3, 36.0, 55.1, 78.5, 117.8, 153.2.
1-Cyanocyclohexyl methyl carbonate (4c): colorless oil; IR (neat): 2250, 1760 cm´1; 1H-NMR ( 500 MHz,
CDCl3 ) :
3.79 (s, 3H); 13C-NMR (125 MHz, CDCl3):
calcd for C9H14NO3: 184.0973; found: 184.0991 [M + H]+.
δ
1.15–1.35 (m, 1H), 1.53–1.64 (m, 3H), 1.70–1.77 (m, 2H), 1.80–1.85 (m, 2H), 2.26–2.28 (m, 2H),
δ
22.0, 24.3, 35.0, 55.1, 75.0, 118.2, 153.0; HRMS (FAB): m/z:
1
1-cyanocyclohex-2-en-1-yl methyl carbonate (4d) [80]: IR (neat): 2245, 1753 cm´1; H-NMR (500 MHz,
CDCl3 ):
δ 1.68–72 (m, 2H), 1.97–1.99 (m, 2H), 2.40 (t, J = 6.6 Hz, 2H), 3.81 (s, 3H), 5.98 (d, J = 10 Hz,
1H), 6.99 (ddd, J = 7.1, 7.1, 4.1 Hz, 1H); 13C-NMR (125 MHz, CDCl3 ):
δ 20.9, 22.7, 24.3, 51.9, 74.4, 112.5,
116.9, 129.8, 152.9.
1-Cyano-1-methyl-3-phenylprope-2-yl methyl carbonate (4e) [81]: IR (neat): 2250, 1760 cm´1
;
,
1H-NMR (500 MHz, CDCl3) :
δ 1.84 (s, 3H), 3.72 (s, 3H), 6.10 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 16.0 Hz
1H), 7.29–7.30 (m, 3H), 7.43–7.44 (m, 2H); 13C-NMR (125 MHz, CDCl3 ):
117.3, 124.0, 128.8, 130.5, 134.4, 152.9.
δ 14.2, 21.1, 55.4, 60.4, 73.8,
1-Cyano-1-phenylethyl methyl carbonate (4f) [11]: IR (neat) 2250, 1752 cm´1; 1H-NMR (500 MHz, CDCl3):
2.01 (s, 3H), 3.77 (s, 3H), 7.37–7.46 (m, 3H), 7.53–7.55 (m, 2H); 13C-NMR (125 MHz, CDCl3):
29.9,
55.4, 75.7, 117.9, 124.5, 129.1, 129.5, 137.6, 152.9.
δ
δ
1-Cyano-1-phenylpropyl methyl carbonate (4g): pale yellow oil; IR (neat) 2249, 1758 cm´1
1H-NMR (500 MHz, CDCl3):
1.03 (t, J = 7.4 Hz, 3H), 2.05–2.12 (m, 1H), 2.27–2.34 (m, 1H), 3.74 (s, 3H),
;
δ

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7.36–7.42 (m, 5H); 13C-NMR (125 MHz, CDCl3):
δ
8.5, 36.0, 55.4, 65.6, 80.4, 117.0, 124.8, 129.0.
HRMS (FAB): m/z: calcd for C9H14NO3: 220. 0968; found: 220. 0979 [M + H]+.
1-Cyano-1-(4-chlorophenyl)ethyl methyl carbonate (4h) [11]: IR (neat) 2250, 1760 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ
1.99 (s, 3H), 3.76 (s, 3H), 7.38 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H); 13C-NMR (125 MHz,
CDCl3): δ 29.7, 55.5, 66.0, 75.1, 117.5, 126.1, 129.3, 135.6, 136.1, 152.8.
1-Cyano-1-(4-nitrophenyl)ethyl methyl carbonate (4i) [11]: IR (neat) 2251, 1749 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ
2.00 (s, 3H), 3.76 (s, 3H), 7.70 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H); 13C-NMR (125 MHz,
CDCl3): δ 29.7, 55.8, 65.8, 74.8, 117.0, 123.8, 124.4, 125.7, 152.8.
Cyano(phenyl)methyl methyl acetate (5a) [14]: IR (neat) 2250, 1742 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
2.17 (s, 3H), 6.39 (s, 1H), 7.44 (m, 3H), 7.51 (d, J = 11.1 Hz, 2H); 13C-NMR (125 MHz, CDCl3):
δ 20.4,
62.8, 116.1, 127.9, 129.2, 130.4, 131.7, 168.9.
1
Cyano(4-chlorophenyl)methyl methyl acetate (5b) [18]: IR (neat) 2245, 1756 cm´1; H-NMR (500 MHz,
CDCl3):
δ
2.15 (s, 3H), 6.36 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H); 13C-NMR (125 MHz,
CDCl3): δ 20.4, 62.1, 115.7, 129.3, 129.5, 130.2, 136.6, 168.8.
Cyano(4-methylphenyl)methyl methyl acetate (5c) [18]: IR (neat) 2250, 1753 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ 2.13 (s, 3H), 2.37 (s, 3H), 6.35 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H);
13C-NMR (125 MHz, CDCl3): δ 20.5, 21.3, 62.7, 116.2, 127.9, 128.8, 129.9, 140.7, 169.0.
Cyano(4-methoxyphenyl)methyl methyl acetate (5d) [18]: IR (neat) 2249, 1747 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ 2.12 (s, 3H), 3.81 (s, 3H), 6.34 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H);
13C-NMR (125 MHz, CDCl3): δ 20.5, 55.4, 62.6, 114.5, 116.3, 123.8, 129.6, 161.1, 169.0.
1
Cyano(4-nitrophenyl)methyl methyl acetate (5e) [82]: IR (neat): 2251, 1760 cm´1; H-NMR (500 MHz,
CDCl3):
δ
2.20 (s, 3H), 6.49 (s, 1H), 7.71 (d, J = 8.7 Hz, 2H), 8.30 (d, J = 8.7 Hz, 2H); 13C-NMR (125 MHz,
CDCl3): δ 20.3, 61.6, 115.1, 124.4, 128.7, 138.1, 149.0, 168.6.
Cyano(naphthalen-1-yl)methyl methyl acetate (5f) [18]: IR (neat) 2249, 1755 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ 2.17 (s, 3H), 7.02 (s,1H), 7.50 (dd, J = 7.1, 8.1 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.60 (t, J = 6.2 Hz,
1H), 7.71 (d, J = 6.2 Hz, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.94 (d, J = 9.9 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H);
13C-NMR (125 MHz, CDCl3):
133.9, 169.0.
δ 20.4, 61.3 116.1 122.5, 125.0, 126.6, 126.9, 127.6, 129.1, 130.0, 131.5,
Cyano(naphthalen-1-yl)methyl methyl acetate (5g) [82]: IR (neat) 2250, 1753 cm´1; 1H-NMR (500 MHz,
CDCl3):
δ 2.17 (s, 3H), 6.57 (s, 1H), 7.53–7.57 (m, 3H), 7.87 (t, J = 9.3 Hz, 2H), 7.91 (d, J = 8.6Hz, 1H),
8.00 (d, J = 1.3 Hz, 1H); 13C-NMR (125 MHz, CDCl3):
δ
20.6, 63.1, 116.2, 124.3, 127.1, 127.6, 127.1, 127.6,
127.9, 128.1, 128.4, 129.5, 132.9, 133.9, 169.0.
1
Cyano-3-phenylpropen-2-yl methyl acetate (5h) [32]: IR (neat) 2251, 1751 cm´1; H-NMR (500 MHz,
CDCl3):
δ 2.15 (s, 3H), 6.00 (d, J = 6.7 Hz, 1H), 6.18 (dd, J = 6.7, 15.8 Hz, 1H), 6.95 (d, J = 15.8 Hz, 1H),
7.31–7.37 (m, 3H), 7.41 (d, J = 7.9 Hz, 2H); 13C-NMR (125 MHz, CDCl3):
δ 20.3, 61.4, 115.4, 118.2, 127.0,
128.7, 129.3, 134.3, 137.7, 168.8.
Cyano-3-phenylpropeyl methyl acetate (5i) [18]: IR (neat) 2248, 1755 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
2.11 (s, 3H), 2.22 (dd, J = 7.6, 15.0 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 5.25 (t, J = 6.8 Hz, 1H),
7.17 (d, J = 7.2 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 7.2 Hz, 2H); 13C-NMR (125 MHz, CDCl3):
δ 20.3, 30.7, 33.7, 60.5, 116.7, 126.7, 128.3, 128.7, 139.0, 169.1.

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Cyano(cyclohexyl)methyl methyl acetate (5j) [18]: IR (neat) 2248, 1755 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
1.07–1.21 (m, 4H), 1.21–1.30 (m, 2H), 1.66–1.69 (m, 1H), 1.73–1.80 (m, 3H), 1.84–1.92 (m, 1H),
2.13 (s, 3H), 5.15 (d, J = 6.6 Hz, 1H); 13C-NMR (125 MHz, CDCl3):
δ 20.3, 25.3, 25.7, 28.1, 40.0, 65.6,
116.2, 169.2.
Cyano(1-octyl)methyl methyl acetate (5k) [83]: IR (neat) 2218, 1756 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
0.83 (t, J = 7.0 Hz, 3H), 1.15–1.33 (m, 14H), 1.57 (quin, J = 6.8 Hz, 2H), 1.99 (s, 3H), 4.00 (t, J = 6.8 Hz,
2H); 13C-NMR (125 MHz, CDCl3): δ 14.0, 20.9, 22.6, 25.8, 28.5, 29.2, 29.4, 31.8, 64.6, 117.6, 171.1.
Cyano(furan-2-yl)methyl methyl acetate (5l) [82]: IR (neat) 2248, 1753 cm´1; 1H-NMR (500 MHz, CDCl3):
δ
2.14 (s, 3H), 6.42 (dd, J = 1.9, 3.4 Hz, 1H), 6.45 (s, 1H), 6.66 (d, J = 3.4 Hz, 1H), 7.49 (dd, J = 0.8, 1.9 Hz,
1H); 13C-NMR (125 MHz, CDCl3): δ 20.3, 55.7, 111.0, 112.6, 114.1, 144.1, 145.0, 168.7.
4. Conclusions
In conclusion, we have demonstrated the TBD-catalyzed cyanation reaction of carbonyl
compounds using methyl cyanoformate or acetyl cyanide as cyanide sources. A broad range of
aldehydes and ketones reacted to produce O-protected cyanohydrins in the presence of 5–10 mol %
of TBD. Furthermore, a polymer-supported catalyst, PS-TBD, also acted as a good catalyst for this
reaction. PS-TBD was easily recovered and reused with minimal loss of activity. These reactions
provide a simple and convenient method for synthesis of highly functionalized α-hydroxyl-carbonyl
compounds and β-amino alcohols.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
8/1030/s1.
Author Contributions: S.M. conceived the ideas, analyzed the data, and wrote the paper; J.K and M.Y. performed
the experiments and analyzed the data; and all authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2a–2j, 4a–4i, 5a–5l are available from the authors.
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