Cyano-phosphorylation of aldehydes catalyzed by a nucleophilic N-heterocyclic carbene

Article abstract of DOI:10.1248/cpb.54.397

The first method for cyano-phosphorylation of aldehydes with diethyl cyanophosphonate in the presence of N-heterocyclic carbene prepared from 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride and KOt-Bu, as a nucleophilic catalyst, is described.

Full text of DOI:10.1248/cpb.54.397

March 2006
Notes
Chem. Pharm. Bull. 54(3) 397—398 (2006)
397
Cyano-Phosphorylation of Aldehydes Catalyzed by a Nucleophilic
N-Heterocyclic Carbene
Yoshimasa FUKUDA, Yuka MAEDA, Kazuhiro KONDO,* and Toyohiko AOYAMA*
Graduate School of Pharmaceutical Sciences, Nagoya City University; 3–1 Tanabe-dori, Mizuho-ku, Nagoya 467–8603,
Japan. Received October 18, 2005; accepted December 12, 2005; published online December 14, 2005
The first method for cyano-phosphorylation of aldehydes with diethyl cyanophosphonate in the presence of
N-heterocyclic carbene prepared from 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride and KOt-Bu, as a nu-
cleophilic catalyst, is described.
Key words cyano-phosphorylation; N-heterocyclic carbene; imidazolium salt; nucleophilic catalyst
N-Heterocyclic carbenes prepared from imidazolium salts
The cyano-phosphorylation of various aldehydes 3—10
and bases, have been used mainly in transition metal-cat- was performed as shown in Table 1. The aldehydes except
alyzed reactions as ligands.1,2) However, their suitability as for trans-cinnamaldehyde (9) were reacted with N-hetero-
nucleophilic catalysts has been underdeveloped.3—11) We re- cyclic carbene 2 prepared from 5 mol% of the imidazolium
cently reported a catalytic method leading to the synthesis of chloride 1 and 4 mol% of KOt-Bu, and 1.2 mol eq of DEPC
various cyanohydrins using N-heterocyclic carbene 2 pre- in THF, affording the corresponding cyanohydrin-O-phos-
pared from 1,3-bis(2,4,6-trimethylphenyl)imidazolium chlo- phonates in good yields.16) A polar solvent such as DMF was
ride (1) and KOt-Bu as a nucleophilic catalyst in cyanosilyla- also a suitable solvent (entry 5). The use of ketones such as
tion reactions.12) Cyanohydrins and their trimethylsilyl ethers acetophenone and methyl vinyl ketone afforded little or none
are versatile intermediates in organic synthesis,13,14) but the of the desired products.
instability of cyanohydrins and their trimethylsilyl ethers is
sometimes problematic for further transformations. There-
fore, the development of a one-pot cyanation-O-protection
reaction with a stable protecting group is desirable. In 1983,
the above one-pot reaction of carbonyl compounds with di-
ethyl cyanophosphonate (DEPC) in the catalytic amount of
In summary, N-heterocyclic carbene 2 was found to func-
lithium diisopropylamide has been reported by Shioiri et tion as catalyst in cyano-phosphorylation reaction of aldehy-
al.15) Herein, we disclose the first catalytic method leading to des with DEPC. Ongoing efforts are focused on developing
the synthesis of various cyanohydrin-O-phosphonates using an asymmetric version17,18) of this reaction with a chiral N-
N-heterocyclic carbene 2 prepared from 1,3-bis(2,4,6- heterocyclic carbene.
trimethylphenyl)imidazolium chloride (1) and KOt-Bu as a
nucleophilic catalyst in cyano-phosphorylation reactions.
Experimental
IR spectra were measured on a JASCO IR Report-100 diffraction grating
IR spectrophotometer. 1H- (270 MHz) and 13C-NMR (68 MHz) spectra were
measured on a JEOL JNM-EX-270 NMR spectrometer. MS spectra were
Table 1. Cyano-Phosphorylation of Various Aldehydes with 2 as a Cata-
lysta)
measured on a JEOL JMS-SX-102A instrument. Commercially available
aldehydes and reagents were used without any purification. THF was dis-
tilled from Na/benzophenone ketyl under a nitrogen atmosphere. DMF was
distilled from CaH2 under reduced pressure. Silica gel column chromatogra-
phy was performed on Fuji silysia PSQ 60B.
Yield (%) of
Representative Procedure for the Cyano-Phosphorylation Reaction
Entry
Aldehyde
Solvent
cyanohydrin-
To a stirred solution of 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride
(1) (5.1 mg, 15 mmol) in THF (1.0 ml) was added KOt-Bu (1.4 mg, 13 mmol)
at rt and the mixture was stirred for 15 min at the same temperature. After
dissolving the imidazolium chloride 1 completely, the mixture was cooled to
0 °C. Then, benzaldehyde (6) (32.1 mg, 0.302 mmol) and DEPC (59.0 mg,
0.362 mmol) were added to this mixture. The reaction mixture was stirred
for 5 min at the same temperature, then quenched with water and extracted
with EtOAc. The organic extracts were successively washed with water and
brine, dried (Na2SO4) and concentrated. Purification by silica gel chromatog-
raphy (hexane : EtOAcꢀ4 : 1) gave phosphoric acid cyano-phenyl-methyl
ester diethyl ester (76.3 mg, 94%) as a colorless oil. The physical data were
comparable to those reported.19)
The physical data of the known cyanohydrin-O-phosphonates shown
below were comparable to those of the corresponding literature: Phosphoric
acid 1-cyano-3-phenyl-propyl ester diethyl ester.19) Phosphoric acid cyano-
cyclohexyl-methyl ester diethyl ester.20) Phosphoric acid 1-cyano-2,2-di-
methyl-propyl ester diethyl ester.20) Phosphoric acid (4-chlorophenyl)-cyano-
methyl ester diethyl ester.19) Phosphoric acid cyano-(4-methoxyphenyl)-
methyl ester diethyl ester.19) Phosphoric acid 1-cyano-3-phenyl-allyl ester di-
ethyl ester.21) Phosphoric acid 1-cyano-allyl ester diethyl ester.20)
O-phosphonateb)
1
2
THF
THF
91
94
3
4
5
6
7
t-Bu-CHO 5
Ph-CHO 6
THF
THF
DMF
THF
THF
98
94
91
92
90
6
4-Cl-C6H4-CHO 7
4-MeO-C6H4-CHO 8
8c)
9e)
THF
THF
19d)
90
a) All reactions were performed with 5 mol% of 1, 4 mol% of KOt-Bu and
1.2 mol eq of DEPC in the solvent (0.3 M solution of aldehydes). b) Isolated yield.
c) Reaction conditions: rt, 30 min. d) Accompanied by recovery of the starting mate-
rial (30%). e) Reaction conditions: rt, 15 min.
∗ To whom correspondence should be addressed. e-mail: kazuk@phar.nagoya-cu.ac.jp; aoyama@phar.nagoya-cu.ac.jp © 2006 Pharmaceutical Society of Japan

398
Vol. 54, No. 3
3th ed., John Wiley and Sons, Inc., New York, 1999, pp. 348—349.
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