Cyanide ion promoted addition of acyl phosphonates to ethyl cyanoformate: Synthesis of tertiary carbinols via tandem carbon-carbon bond formations

Article abstract of DOI:10.1021/jo0710073

(Chemical Equation Presented) New cyanation/phosphonate-phosphate rearrangement/C-acylation reactions of cyanophosphate anion with cyanoformate esters are described. Phase-transfer cocatalysts facilitate cyanide-catalyzed reactions between acyl phosphonates and cyanoformates to afford protected tertiary carbinol products in good to excellent yields (74-95%). Ethyl cyanoformate is used as a cyanide source and electrophile. The scope of the reaction was investigated by using a number of benzoyl and acyl phosphonates along with ethyl cyanoformate. Representative chemoselective reduction of the product 5a afforded ethyl 3-amino-2-hydroxy-2-phenylpropanoate (13) in good yield.

Full text of DOI:10.1021/jo0710073

Cyanide Ion Promoted Addition of Acyl
Phosphonates to Ethyl Cyanoformate: Synthesis
of Tertiary Carbinols via Tandem
Carbon-Carbon Bond Formations
Ayhan S. Demir,* Barbaros Reis, O¨ mer Reis, Serkan Eymu¨r,
Mehmet Go¨llu¨, Servet Tural, and Gu¨lu¨zar Saglam
Department of Chemistry, Middle East Technical UniVersity,
06531 Ankara, Turkey
FIGURE 1. Synthesis of cyanohydrine with quaternary carbon center.
asdemir@metu.edu.tr
(Figure 1, route A). The source of cyanide, furthermore, deter-
mines the type of protecting group on the hydroxyl functionality,
which is, most of the time, crucial for the sake of subsequent
transformations. Although this approach has been widely investi-
gated,1 other promising methods include a three-component
domino reaction that utilizes a cyanide source,2 carbanion
precursors, and an electrophile (Figure 1, route B). It is in this
way that two sequential C-C bond formations take place via a
cyanide ion promoted carbanion generation from a carbanion
precursor and its subsequent reaction with the electrophilic
carbon center. This sequence of reactions has an obvious
advantage over the traditional approach for the synthesis of
cyanohydrins with quaternary carbon centers.
The viability of an approach based on the use of acyl anions
obviously depends on the availability of these valuable entities.
Acyl anions are available though polarity reversal (umpolung)
of the carbonyl compounds and adds a dimension of flexibility
to a synthetic design.3 Although acyl anion equivalents were
traditionally obtained by functional group manipulation and the
stoichiometric strong base deprotonation of the corresponding
carbonyl compounds, recently impressive progress has been
made in the catalytic methods for the generation of these useful
entities.4 From this end, the nucleophile-promoted Brook
rearrangement of acylsilanes has been introduced as a powerful
and useful way of generating acyl anion equivalents in a variety
of C-C bond-forming reactions.2c-f,5 Recently, Johnson’s group
and then our group introduced acyl phosphonates 1 as acyl anion
precursors based on a nucleophile-promoted phosphonate-
phosphate rearrangement in the regioselective synthesis of cross-
benzoin products 3.6 In this transformation, the addition of
cyanide anion to acyl phosphonates 1 forms the intermediate
alkoxide 2a that rearranges to the critical acyl anion intermediate
ReceiVed May 12, 2007
New cyanation/phosphonate-phosphate rearrangement/C-
acylation reactions of cyanophosphate anion with cyanofor-
mate esters are described. Phase-transfer cocatalysts facilitate
cyanide-catalyzed reactions between acyl phosphonates and
cyanoformates to afford protected tertiary carbinol products
in good to excellent yields (74-95%). Ethyl cyanoformate
is used as a cyanide source and electrophile. The scope of
the reaction was investigated by using a number of benzoyl
and acyl phosphonates along with ethyl cyanoformate.
Representative chemoselective reduction of the product 5a
afforded ethyl 3-amino-2-hydroxy-2-phenylpropanoate (13)
in good yield.
The synthesis of cyanohydrins has gained much attention due
to the importance of cyanohydrins as a synthetic building block
for a variety of pharmaceutically desirable compounds.1 In fact,
these compounds have a dense functionality, the transformations
of which provide easy access to many other valuable functional
groups. Therefore, a plethora of methods has been devised for
the synthesis of these targets in a racemic and an enantioselective
manner. The typical method for their synthesis is the addition
of a cyanide source, in various forms, to the corresponding
carbonyl compounds in a single C-C bond-forming event
(2) (a) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425. (b)
Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70, 256. (c)
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10.1021/jo0710073 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/23/2007
J. Org. Chem. 2007, 72, 7439-7442
7439

TABLE 2. Addition of Acyl Phosphonates 1 to Ethyl Cyanofomate
SCHEME 1
SCHEME 2
TABLE 1. Addition of 1a to Ethyl Cyanoformate in Various
Solvents
entry
solvent
yield (%) (KCN)
yield (%) (KCN-18-crown-6)
1
2
3
4
6
7
Et2O
THF
toluene
DMF
CHCl3
CH3CN
<5
<5
75
91
88
82
68
79
56
<5
2b, which in turn reacts with the electrophile 2f to provide the
product 3 in a similar fashion as the well-known benzoin
reaction. Therefore, the critical acyl anion equivalents are
available from acyl phosphonates 1. Unlike the similar reagent
acylsilanes, acyl phosphonates are readily available on a
multigram scale from acyl chlorides and trialkyl phosphites via
an Arbuzov reaction without needing any special condition or
apparatus. This apparently makes them more advantageous in
terms of practical issues. Furthermore, it is a highly intriguing
question as to whether acyl phosphonates can be utilized in a
sequence of reactions as depicted in Scheme 1 for the generation
of carbanion and their consequent reactions with carbon
electrophiles as a generalized strategy for the synthesis of
quaternary cyanohydrins. Similar work on acylsilanes was
performed by Johnson et al.2d-f,m We report our initial results
herein toward the investigation of this goal by utilizing alkyl
cyanoformates as a cyanide source and electrophile.
(4) (a) Enders, D.; Kalfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743.
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M.; Janzen, E.; Kolter, D.; Feldmann, R.; Dunkelmann, P.; Mu¨ller, M. AdV.
Synth. Catal. 2002, 344, 96. (d) Demir, A. S.; Reis, O. Tetrahedron 2004,
60, 3803. (e) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003,
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M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (i) Read, de Alaniz,
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a The compounds are nearly pure after workup. No further purification
is needed.
For the investigation of the reaction of the ethyl cyanoformate
4 with acyl phosphonates 1, we planned to gain direct and
uncatalyzed access to ethoxycarbonylcyanophosphate 5 by using
ethyl cyanoformate 4 as a cyanide source and an electro-
(6) (a) Demir, A. S.; Reis, O.; Igdir, A. C.; Esiringu, I.; Eymur, S. J.
Org. Chem. 2005, 70, 10584. (b) Demir, A. S.; Reis, O.; Kayalar, M.;
Eymur, S.; Reis, B. Synlett 2006, 3329. (c) Demir, A. S.; Reis, O.; Esiringu,
I.; Reis, B.; Baris, S. Tetrahedron 2007, 63, 160. (d) Bausch, C. C.; Johnson,
J. S. AdV. Synth. Catal. 2005, 347, 1207. (e) Moisture can be the source of
the proton.
7440 J. Org. Chem., Vol. 72, No. 19, 2007

SCHEME 3
SCHEME 4
phile.2 Moreover, we hoped that the 4 could supply a catalytic
amount of cyanide ion by decomposition in order to provide
cyanohydrine, which can subsequently start the reaction. The
formation of cyanohydrine, via phosphonate-phosphate re-
arrangement, and followed by C-acylation should in turn form
tertiary carbinol.
In an initial reaction, which is shown in Scheme 2, ben-
zoylphosphonate 1a was reacted with ethyl cyanoformate 4 at
ambient temperature in ether and monitored by TLC, in which
no product formation was observed. However, in the presence
of catalytic quantities of KCN, benzoylphosphonate 1a reacted
slowly with ethyl cyanoformate in Et2O to afford the desired
acylation product 5a in a very low yield. The reaction was
repeated with various solvents, and as shown in Table 1, only
DMF gave a satisfactory yield. The limited solubility of the
KCN in the medium could have hindered the reactivity.
According to Johnson’s work,2d-f the phase-transfer catalysts
were employed in order to increase the concentration of cyanide
ion in solution. The 18-crown-6 proved to be optimal for
attaining a better solubility of KCN.7
Different solvents are employed for the addition reaction, and
as shown in Table 1, the highest yield is obtained by using THF
(91%). The substrate scope was further investigated in the
context of cyanoformate and phosphonate ester structures. For
this, ethyl phosphonate 6 was used and the product 7 was
obtained in 90% yield. The use of benzyl cyanoformate 8 in
place of ethyl cyanoformate with 1a furnished 9 in comparable
yield (88%).
With the efficient catalyst system 18-crown-6 and KCN in
THF, the reaction scope was studied using a variety of acyl
phosphonates. In general, benzoyl and acyl phosphonates gave
good to excellent yields (74-95%, Table 2). In all cases, the
reaction takes 15-20 min. The change of the color of the
reaction mixture to red is a good indicator for stopping the
reaction as a prolonged reaction time causes the decomposition
of the product. In many cases the crude product is so pure that
further purification is not essential.
As shown in Scheme 2, the reaction of 1a with a catalytic
amount of KCN/18-crown-6 in ether at ambient temperature
was studied. The highest yield (75%) was obtained in a short
reaction period (20 min monitoring of the reaction by TLC).
Under the given conditions, the competing proton abstraction
(7) Evans, D. A.; Truesdale, L. K. Tetrahedron Lett. 1973, 4929.
product,6c the cyanohydrin O-phosphate 2e, was also formed
J. Org. Chem, Vol. 72, No. 19, 2007 7441

(5i, 5j, 5k; 3-4%), which was separable from the desired
product by chromatography.6d
Benzoylphosphonates with the electron-withdrawing and
electron-donating groups attached to the phenyl ring affected
the yield slightly as shown in Table 2.
Representative chemoselective reduction of the product 5a
afforded ethyl 3-amino-2-hydroxy-2-phenylpropanoate (13) in
good yield.
Experimental Section
General Procedure. An oven-dried Schlenk flask with a
magnetic stir bar was charged with 0.5 mmol of acyl phosphonate.
Subsequently, 1 mL of dry THF, 0.6 mmol of ethyl cyanofor-
mate, 0.025 mmol of 18-crown-6, and 2 mg of KCN was added
under argon. The reaction was monitored by TLC (completed within
15-20 min). After the completion of the reaction, the reaction was
extracted with ether, and the organic layer was washed with brine
three times. The organic phases were combined and concentrated
under reduced vacuum. If needed, the crude product was puri-
fied with automatic flash column chromatography using ether-
petroleum ether as eluent.
As shown in Scheme 3, 5a is converted into R-keto ester 10
by using 0.5 N NaOH in THF.8 Interesting conversion of 5a is
carried out to the corresponding amino ester 11 either by using
Pd/C, H2, HCl, then Na2CO3 in good yield,9 or CoCl2, NaBH4
in moderate yield.2d-f
By using ethyl cyanoformates as a cyanide source and
electrophile, a new cyanide ion promoted cyanation/phosphate-
phosphonate rearrangement/C-acylation sequence was developed
that results in the efficient formation of polyfunctionalized
unsymmetrical malonic acid derivatives.
(Ethoxycarbonyl)(cyano)(phenyl)methyl dimethyl phosphate
(5a): yield 142 mg (91%); yellow liquid; IR (neat) ν ) 2963, 1769,
In this transformation, the addition of cyanide anion to acyl
phosphonates 1 forms the intermediate alkoxide 2a, which
rearranges to the carbanion 2b that in turn reacts with the ethyl
cyanoformate 4 in order to provide the product 5. The proposed
catalytic cycle is outlined in Scheme 4.
In conclusion, we developed a convenient, one-pot procedure
for preparing various polyfunctionalized tertiary carbinol with
the concomitant formation of two new carbon-carbon bonds
starting from readily available acyl phosphonates and ethyl
cyanoformate under very mild conditions in good to excellent
yields (74-95%). Phase-transfer cocatalysts and cyanide ions
have been used successfully in the formation of cyanohydrine.
The general applicability of the reaction with a range of acyl
phosphonate and ethyl cyanoformate has been demonstrated.
1
1255, 1042 cm-1; H NMR (CDCl3) δ 1.21 (3H, t, J ) 7.3 Hz),
3.79 (3H, d, J ) 11.5 Hz), 3.88 (3H, d, J ) 11.5 Hz), 4.20-4.30
(2H, m), 7.37-7.41 (3H, m), 7.62-7.64 (2H,m); 13C NMR (CDCl3)
δ 12.6, 54.0 (d, J ) 5.5 Hz), 54.3 (d, J ) 5.5 Hz), 63.3, 76.7 (d,
J ) 6.3 Hz), 115.3, 124.6, 128.0, 129.6, 131.6 (d, J ) 9.6 Hz),
163.3 (d, J ) 2.3 Hz); 31P NMR (CDCl3) δ -1.64. Anal. Calcd
for C13H16NO6P: C, 49.85; H, 5.15; N, 4.47. Found: C, 49.66; H,
5.35; N, 4.78.
Acknowledgment. The financial support from the Scientific
and Technical Research Council of Turkey (TUBITAK), the
Turkish Academy of Sciences (TU¨ BA), the Turkish State
Planning Organization, and the Middle East Technical Univer-
sity is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and characterization data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Kurihara, T.; Santo, K.; Harusava, S.; Yoneda, R. Chem. Pharm.
Bull. 1987, 35, 4777.
(9) (a) Testa, E.; Fontanella, L.; Bovara, M. Liebigs Ann. Chem. 1964,
671, 97. (b) Testa, E.; Fontanella, L.; Cristiani, G. F.; Mariani, L. Liebigs
Ann. Chem. 1961, 639, 166.
JO0710073
7442 J. Org. Chem., Vol. 72, No. 19, 2007