Chemoselective allylic addition of allyltrichlorosilane to α- oxocarboxylic acids: Synthesis of tertiary α-hydroxy carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(00)00692-4

Allyltrichlorosilane can add to α-oxocarboxylic acids in the presence of DMF and HMPA. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reaction. The reaction presumably proceeds in an intramolecular fashion through a 'rigid' bicyclic transition state assembly involving a hypervalent silicate species, which produces the chemoselectivity approaching 100%. (C) 2000 DuPont Pharmaceuticals Company.

Full text of DOI:10.1016/S0040-4039(00)00692-4

Tetrahedron Letters 41 (2000) 4523±4526
Chemoselective allylic addition of allyltrichlorosilane to
a-oxocarboxylic acids: synthesis of tertiary a-hydroxy
carboxylic acids
Zhe Wang,* Guoyou Xu, Dengjin Wang, Michael E. Pierce and Pat N. Confalone
DuPont Pharmaceuticals Company, Research & Development, Chambers Works, Deepwater, NJ 08023, USA
Received 10 April 2000; accepted 27 April 2000
Abstract
Allyltrichlorosilane can add to a-oxocarboxylic acids in the presence of DMF and HMPA. The a-carboxylic
substituent exerts a remarkable neighboring group e€ect on the reaction. The reaction presumably proceeds
in an intramolecular fashion through a `rigid' bicyclic transition state assembly involving a hypervalent
silicate species, which produces the chemoselectivity approaching 100%. # 2000 Dupont Pharmaceuticals
Company. Published by Elsevier Science Ltd. All rights reserved.
Tertiary a-hydroxy carboxylic acids are fairly common structural units in complex natural
products, such as integerrimine,1 monocrotaline2 and methynolide.3 Considerable e€orts in this
area have resulted in several synthetic methods for the synthesis of tertiary a-hydroxy carboxylic
derivatives, for example, dihydroxylation of a,b-unsaturated esters4 and enolate addition to a-keto
esters.5 However, few methodologies have been reported for the direct synthesis of tertiary a-hydroxy
carboxylic acids. Previously, we have described our studies of allylboration of a-oxocarboxylic
acids for the direct construction of tertiary a-hydroxy carboxylic acids.6 The main advantage of
this strategy is the ease of controlling the newly formed carbon±carbon bond through a favorable
bicyclic transition state.
ꢀ1†
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Dupont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00692-4

4524
The addition of various allylmetal reagents to carbonyl compounds is one of the highly favor-
able methods for carbon±carbon bond formation. Among many allylic metallo systems studied
thus far, borane or boronate, silane, stannane and indium have emerged as the most useful
systems.7 Whereas the allylboration of carbonyl compounds proceeds through a favorable chairlike
transition state, the common allylsilation (employing allyltrimethylsilane) of carbonyl compounds
takes place via an acyclic transition state in the presence of stoichiometric amounts of strong
Lewis acids for the activation of the carbonyl partner.7 By increasing the Lewis acidity by replacing
the alkyl substituents on Si by electron-withdrawing groups, for example by ¯uoride or chloride,
one can increase the reactivity of silane reagents, and consequently can increase the stereo- and
regioselectivities of the allylsilation reactions.7 Over the past few years, studies of the allylsilation
of aldehydes using allyltrihalosilanes as reagents have appeared frequently; however, the allylic
addition of allyltrihalosilanes to ketones has been very limited.7 Interestingly, Sakurai reported
that a-hydroxy ketones react with allyltri¯uorosilane in the presence of triethylamine to a€ord
tertiary a-1,2-diols in high diastereoselectivity via a bicyclic transition state.8 Herein, we wish to
report the allylsilation of a-oxocarboxylic acids (1) by commercially available allyltrichlorosilane
(2) to produce tertiary a-hydroxy carboxylic acid (3), as shown in Eq. (1).
Initially, this reaction was conducted utilizing 2 to react with 1 in the presence of triethylamine
in dichloromethane. In contrast to our previous observations6 and to Sakurai's communication,8
this reaction condition a€ords a very low yield of the corresponding adduct and a long period of
reaction time. We then turned our attention to evaluate other Lewis bases to catalyze this reaction.
Recently, Kobayashi9 and Denmark10 revealed that DMF or HMPA coordinates to the silicon
atom of 2 to form a hypervalent silicate, which in turn reacts with aldehydes via a cyclic chairlike
transition state to a€ord the corresponding homoallylic alcohol in a regio- and diastereoselective
manner. Applying HMPA and/or DMF as Lewis bases in our study, we found that either DMF
or HMPA can catalyze the addition reaction. However, the optimized condition involves the use
of a combination of 1.0 equivalent of DMF and HMPA, respectively, to catalyze the addition
reaction of 2 with 1. In our case, it is necessary to have an extra equivalent of Lewis base to
complex with the proton from the carboxylic acid group to drive the reaction to completion.
Under these reaction conditions, the allyltrichlorosilane reagent 2 can easily add to both aliphatic
and aromatic substrates in 3 to 16 h at room temperature in high yield (Table 1). Stoichiometric
studies using benzoylformic acid as substrate revealed that 1.2 equivalents of 2 is sucient
enough to complete the reaction; however, it takes 9 h in propionitrile and 15 h in THF. On the
other hand, when 2.0 equivalents of allyltrichlorosilane are employed, reactions can be completed in
less than 4±5 h in either propionitrile or in THF. The solvent studies revealed that the preference
of the solvent for the addition reaction is in the order of CH3CH2CNˆCH3CN>THFꢁCH2Cl2.
For example, under the standard conditions (1.0 equivalent of HMPA and 1.0 equivalent of
DMF as catalysts, 2.0 equivalents of 2 at room temperature) the allylic addition of benzoylformic
acid takes 3±4 h in CH3CH2CN or in CH3CN, 4±5 h in THF and 10±12 h in CH2Cl2 for the
completion of the reaction.
In contrast to the allylation of a-oxocarboxylic acids (1) by 2, which proceeds rapidly and
smoothly in the presence of HMPA and DMF at room temperature to yield the desired tertiary
a-hydroxy carboxylic acids (3) chemoselectively, the corresponding allylation of a-oxocarboxylic
ester or ketone under the same conditions reacts very slowly. For example, the reaction of 2 with
benzoylformic methyl ester in the presence of DMF/HMPA requires 60 h at room temperature
for complete conversion; and methyl benzylphenone does not react with 2 under the same
conditions. The selectivity and the enhanced reactivity of the a-oxocarboxylic acids suggest that

4525
Table 1
Synthesis of tert-a-hydroxy carboxylic acidsa
the reaction proceeds via a 1,3-bridged cyclohexane-like transition state. Thus, the a-carboxylic
group not only activates the neighboring keto group, but also participates in the allylation
reaction through complexation with the silicon atom, which in turn complexes with the keto
group to form a bicyclic transition state assembly with a hypervalent silicate species as shown in
Eq. (1).
The proposed transition state assembly is consistent with the increased reactivity of the carboxylic
acid compared to the esters as well as the rate enhancement with at least 2 equivalents of DMF
and/or HMPA. Our results are summarized in Table 1. Typically, a-oxocarboxylic acids (1) are
treated with HMPA and DMF (1.0 equivalent, respectively), at room temperature for 2 min,
and then with allyltrichlorosilane (2, 2.0 equivalents) at room temperature for 4±16 h. Upon
completion of the reaction, the reaction mixture is quenched with water. After basic hydrolysis
and acidic workup, the desired a-tertiary hydroxy carboxylic acids 3 are obtained in 54±96%
yield (Table 1).
In summary, we have demonstrated that the a-oxocarboxylic functionality exerts a remarkable
neighboring group e€ect on the allylic addition reaction of allyltrichlorosilane to a-oxocarboxylic
acid to form the corresponding tertiary a-hydroxy carboxylic acid employing DMF and HMPA
as catalysts. The reaction presumably proceeds through a `rigid' bicyclic transition state assembly
involving `hypervalent' silicate species. The asymmetric version of this reaction is currently under
investigation.11

4526
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mmol) and DMF (0.37 g, 5.0 mmol) was added allyltrichlorosilane (1.75 g, 10.0 mmol), dropwise. The reaction
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0ꢂC, and basi®ed to pH >12.0 with aqueous 5.0N NaOH. The mixture was washed with tert-butylmethyl ether.
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1
a pale yellow solid. H NMR (CDCl3), ꢀ: 2.86±2.97 (dd, J=7.0, 18.7 Hz, 2H), 5.17±5.25 (t, J=8.4, 6.1 Hz, 2H),
5.76±5.81 (t, J=8.4, 7.3 Hz, 1H), 6.99 (s, 1H), 7.15 (s, 1H), 7.25 (s, 1H); 13C NMR (CDCl3), ꢀ: 45.27, 77.03,
120.60, 124.71, 125.52, 127.20, 131.05, 144.87, 178.33. HRMS: calcd for C9H9O3S (M^1): 197.0273. Found:
197.0275.