Cyanide-catalyzed additions of acyl phosphonates to aldehydes: A new acyl donor for benzoin-type reactions

Article abstract of DOI:10.1002/adsc.200505097

Acyl phosphonates have been utilized as new acyl donors for cyanide-catalyzed benzoin-type reactions. Cyanation of acyl phosphonates, followed by a [1,2]-phosphoryl migration generates the active acyl anion intermediate. The presumed (cyano)phosphate anion reacts with a variety of aryl aldehydes to yield phosphate ester-protected, unsymmetrical benzoins in good to excellent yields. The unsymmetrical benzoin product can be obtained after deprotection of the phosphate ester with an aqueous amine solution.

Full text of DOI:10.1002/adsc.200505097

COMMUNICATIONS
Cyanide-Catalyzed Additions of Acyl Phosphonates to
Aldehydes: A New Acyl Donor for Benzoin-Type Reactions
Cory C. Bausch, Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, U.S.A.
Fax: (þ1)-919-962-2388, e-mail: jsj@unc.edu
Received: February 23, 2005; Accepted: April 15, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: Acyl phosphonates have been utilized as
new acyl donors for cyanide-catalyzed benzoin-type
reactions. Cyanation of acyl phosphonates, followed
by a [1,2]-phosphoryl migration generates the active
acyl anion intermediate. The presumed (cyano)phos-
phate anion reacts with a variety of aryl aldehydes to
yield phosphate ester-protected, unsymmetrical ben-
zoins in good to excellent yields. The unsymmetrical
benzoin product can be obtained after deprotection
of the phosphate ester with an aqueous amine solu-
tion.
tinuing effort to uncover new strategies for polarity re-
versal catalysis, this communication documents our
progress in the development of acyl phosphonates (1d)
as acyl donors for a new cyanide-catalyzed benzoin-
type reaction with aldehydes [Eq. (1)].
Keywords: benzoin condensation; cyanide catalysis;
ketones; phosphate ester; rearrangement; umpolung
ð1Þ
Our ongoing interest in acyl anion catalysis led us to con-
The cyanide-catalyzed benzoin reaction is an expedi- sider the viability of alternative acyl donors in conjunc-
tious route to a-hydroxy ketones [Eq. (1), R2 ¼H]. tion with nucleophilic catalysts.[5,6] A seminal report by
The reaction proceeds via a catalytically-generated (hy- Schowen demonstrated that benzil [1c, Eq. (1)] could
droxy)nitrile anion that functions as an acyl anion equiv- be utilized as an acyl donor in benzoin-type reactions.[7]
alent.[1] Regioselectivity issues in the catalytic process Later work from Demir and Reis expanded upon that in-
have been addressed through the application of stoi- itial report, showing the application of the reaction to a
chiometrically-generated acyl anion equivalents. Meta- broader range of aromatic diketone and aldehyde reac-
lated dithioacetals,[2] (silyloxy)nitriles[3] and (cyano)- tion partners.[8] Considering the [1,2]-acyl migration im-
phosphates[4] are representative stoichiometrically-gen- plicit in these reactions, we viewed with some interest a
erated acyl anion equivalents employed to synthesize report by Kurihara and co-workers describing cyano-
unsymmetrical benzoin products. While effective, these phosphate anions as effective nucleophilic partners
routes are not without attendant efficiency considera- with aldehyde electrophiles (3-M, Scheme 1).[4] It oc-
tions: added steps in making the starting materials, stoi- curred to us that 3-M could be generated from an acyl
chiometric reagents, and in the case of the dithiane phosphonate (1d) via [1,2]-phosphoryl migration.[9,10]
chemistry, deprotection with Hg(II). As part of a con- Pending carbonyl addition, phosphoryl transfer, and ret-
rocyanation, a complete catalytic cycle could be envi-
sioned.
The projected application was not without practical
merit. Acyl phosphonates are easily synthesized and pu-
rified in one step via the Michaelis–Arbuzov reaction of
acyl chlorides and trialkyl phosphites.[11] The phosphate
ester-protected benzoin products that would result from
a phospha-benzoin reaction also have documented util-
ity as benign instruments of inorganic phosphate photo-
Scheme 1. Access to (cyano)phosphate anions.
release.[12,13]
Adv. Synth. Catal. 2005, 347, 1207–1211
DOI: 10.1002/adsc.200505097
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Cory C. Bausch, Jeffrey S. Johnson
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Preliminary results revealed that cyanide successfully
With the optimum catalytic conditions identified, the
catalyzed acyl phosphonate addition to aldehydes (Ta- scope of the reaction was explored (Table 1). The reac-
ble 1). The conditions for the cross-silyl benzoin and tion works well with benzoyl diethylphosphonate and
the benzil addition were attempted and modified, with a variety of aryl aldehydes (entries 1–5). Reactivity
the [18-crown-6/KCN] complex[14] in diethyl ether pro- was diminished considerably when an electron-poor
viding the optimal catalyst/solvent combination. Reac- acyl phosphonate was employed (entry 6). The catalyst
tion times ranged from 20–60 min at 0–258C. The use loading was increased to 15 mol % at ambient tempera-
of KCN in DMF was successful, but led to concurrent re- ture, but slight regioisomerization occurs before com-
gioisomerization of the unsymmetrical benzoin product. plete consumption of the starting material. (Cyano)-
Reactivity decreased with alternative phase-transfer phosphate 3-H is also observed. Electron-rich acyl phos-
catalysts such as Bu4NBr and Bu4PBr; poorer conver- phonates give good yields with 10 mol % catalyst at am-
sion was also observed in THF and toluene. The condi- bient temperatures. Heteroaromatic aldehydes can be
tions were further simplified with the use of undried, un- utilized, giving moderate yields with 15 mol % catalyst
purified diethyl ether, without the need of an inert at- loading at 08C.
mosphere.
Table 1. Cyanide-catalyzed phospha-benzoin reactions.[a]
Entry
1
R1/R2
Ph/Et
R3
Product
Yield [%][b]
4-ClC6H4
80
2
3
4
Ph/Et
Ph/Et
Ph/Et
4-MeOC6H4
85
88
93
2,3-(MeO)2C6H3
3,5-(MeO)2C6H3
5
6
Ph/Et
Ph
Ph
88
54
4-ClC6H4/Me
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Cyanide-Catalyzed Additions of Acyl Phosphonates to Aldehydes
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Table 1 (cont.)
Entry
R1/R2
R3
Ph
Product
Yield [%][b]
7
4-MeOC6H4/Me
88
8
Ph/Et
2-napthyl
75
56
9Ph/Et
2-thienyl
10
4-MeOC6H4/Me
4-MeC6H4
90
[a]
R1C(O)PO(OR2)2 (1.0 equiv.), R3CHO (1.1 equivs.), KCN/18-crown-6 (0.10–0.15 equivs.) in Et2O at 0 to 238C.
Yield of isolated, analytically pure material.
[b]
The main obstacle encountered with this reaction is thiolate cleanly gives the derived thioether 5 in 84%
the propensity for regioisomerization if the product is yield [Eq. (2)].
left in the presence of KCN long past consumption of
the acyl phosphonate. For most combinations of aryl
acyl phosphonates and aryl aldehdyes, the standard con-
ditions of 10 mol % catalyst at ambient temperature are
sufficient, but in some cases the temperature needs to be
decreased or the catalyst loading increased. The reac-
tion is not tolerant of alkyl acyl phosphonates, as only
undefined decomposition is observed. Aryl acyl phos-
phonates do give desired products with aliphatic alde-
hydes, but only minimal reactivity is achieved, even
ð2Þ
with electron-rich acyl phosphonates. Advantages of us- We evaluated a number of reaction conditions with the
ing acyl phosphonates are the ease of starting material intent of developing an efficient deprotection protocol
synthesis, the ability to use unpurified, undried solvent, to reveal the a-hydroxy ketone products. The (keto)-
and the fact that an inert atmosphere is not required. phosphates were remarkably stable in aqueous acid:
The only by-product is 3-H, which presumably occurs even at elevated temperatures only starting material
from protonation of 3-M; however, it is formed in mini- was recovered. Attempts with simple basic conditions
mal quantities and can be easily separated by flash chro- (e.g., K2CO3/MeOH or NaOH/MeOH) gave the desired
matography. In cases where slight regioisomerization benzoin product, but with competing oxidation to the di-
occurs, the isomers are separable by flash chromatogra- ketone. The same reactions were attempted with de-
phy, which allows for isolation of the desired product.
gassed water under an inert atmosphere; these condi-
Preliminary observations indicate that the phosphate- tions afforded the desired benzoin product and its re-
protected benzoin can directly participate in SN reac- gioisomer in varying amounts. We ultimately found
tions. The reaction of phosphate 4c with lithium ethane- that an aqueous amine solution will cleave the phos-
Adv. Synth. Catal. 2005, 347, 1207–1211
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Cory C. Bausch, Jeffrey S. Johnson
COMMUNICATIONS
Table 2. Deprotection of (keto)phosphates.
A new benzoin-type reaction has been discovered us-
ing acyl phosphonates as the acyl anion precursor. The
reaction gives moderate to excellent yields for aryl-
aryl’ couplings of acyl phosphonates and aldehydes.
These products can be deprotected using an aqueous
amine solution to give the free unsymmetrical benzoins.
Entry
1
Product
Yield [%]
64
Experimental Section
General Procedure for the Preparation of Acyl
Phosphonates
Acyl phosphonates were prepared by the literature method.[11]
A flame-dried, 25-mL round-bottomed flask with a magnetic
stir bar and addition funnel was charged with 51.7 mmol of
acyl chloride under argon. The addition funnel was charged
with 51.7 mmol of trialkyl phosphite which was added drop-
wise at a rate such that the temperature did not exceed 408C.
After 30 min, the product was purified by vacuum distillation.
2
3
56
74
2-Diethylphosphoryloxy-2-(4-methoxyphenyl)-1-
phenylethanone (4b); Representative Procedure for
the Addition of Acyl Phosphonates to Aldehydes
phate ester and reveal the desired a-hydroxy ketone.[15]
Optimal conditions entail the treatment of the phos-
phate with distilled diethylamine in degassed water.
A 25-mL, round-bottomed flask with a magnetic stir bar was
charged with benzoyl diethylphosphonate (0.41 mmol,
1.0 equiv.)
and
4-methoxybenzaldehyde
(0.45 mmol,
The results of the deprotection studies are summarized 1.1 equivs.). Et2O (2 mL) was added to make a 0.2 M solution,
followed by [18-crown-6-KCN] (0.041 mmol).[14] After 30 min
at 238C, Et2O (10 mL) was added and the organic layer was
in Table 2.
As a prerequisite for any future asymmetric variant of
washed twice with H2O (10 mL). The organic extracts were
the title process, it was important to determine whether
dried (MgSO4), filtered, and the solventwas removed with a ro-
the deprotection conditions would compromise the ster-
tary evaporator. The product was purified by flash chromatog-
eochemical integrity of an enantioenriched benzoin
raphy with 40% EtOAc/hexanes to afford the product as a
[Eq. (3)].
cloudy oil; yield: 132.8 mg (85%). Spectral data correspond to
those previously reported.[4] Analytical data for the title com-
pound: 1H NMR (400 MHz, CDCl3): d¼7.91 (d, 2H, J¼
8.0 Hz), 7.49(t, 1H, J¼7.6 Hz), 6.87 (d, 2H, J¼8.8 Hz), 6.63
(d, 1H, J¼8 Hz), 4.24–4.14 (m, 2H), 3.96–3.86 (m, 2H), 3.77
(s, 3H), 1.33 (t, 3H, J¼7.6 Hz), 1.16 (t, 3H, J¼7.2 Hz).
ð3Þ
Acknowledgements
We gratefully acknowledge the National Institutes of Health
To perform the analysis, an enantioenriched benzoin
(National Institute of General Medical Sciences – GM068443)
was synthesized using reported methods,[16] yielding for support of this research. J. S. J. is an Eli Lilly Grantee and
a 3M Nontenured Faculty Awardee.
(S)-6e with an enantiomeric excess of 82%. This hy-
droxy ketone was protected with diethyl chlorophos-
phate and pyridine, furnishing the phosphate-protected
benzoin in 82% ee. Deprotection of the phosphate ester
using a 9:1 diethylamine/water solution at ꢀ108C gives
the free benzoin 6e in 75% yield and 70% ee after 1 h.
We therefore conclude that it is possible to largely retain
the stereochemical integrity of the a-stereocenter under
these conditions. Efforts are ongoing to reduce the ster-
eochemical loss in this reaction to zero.
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