Mild two-step process for the transition-metal-free synthesis of carbon-carbon bonds from allylic alcohols/ethers and grignard reagents

Article abstract of DOI:10.1021/ja100747n

Chemical Equation Represented A mild two-step process for the regioselective, transition-metal-free preparation of carbon-carbon bonds from allylic alcohols/ethers and Grignard reagents is described. This process obviates the need for the harsh deprotecti

Full text of DOI:10.1021/ja100747n

Published on Web 03/08/2010
Mild Two-Step Process for the Transition-Metal-Free Synthesis of
Carbon-Carbon Bonds from Allylic Alcohols/Ethers and Grignard Reagents
Xinping Han, Yanhua Zhang, and Jimmy Wu*
Department of Chemistry, Dartmouth College, HanoVer, New Hampshire 03755
Received January 27, 2010; E-mail: jimmy.wu@dartmouth.edu
Table 1. Scope of the Alcohol and Ether Substitution Reaction
In contrast to the immense amount of effort devoted to develop-
ing transition-metal-mediated allylic substitution reactions with soft
nucleophiles (the Tsuji-Trost reaction),1 far fewer methods exist
for allylic substitution reactions utilizing hard nucleophiles such
as Grignard reagents.2 Substitution reactions with Grignard nu-
cleophiles are predominantly catalyzed by Cu(I) salts,3 although
variants promoted by other transition metals are also known.4
Uncatalyzed reactions with Grignard reagents are rare and suffer
from problems such as poor yields and regioselectivities.5 In recent
years, there has been an intense push toward developing chemistry
that is more environmentally benign. A part of this larger goal is
a reduction in the use of transition metals, which can sometimes
be toxic, expensive, or difficult to properly dispose of in large
quantities. Herein we report a mild two-step procedure for the
regioselectiVe, transition-metal-free allylic substitution reaction
between Grignard reagents and phosphorothioate esters prepared
from the corresponding allylic alcohols and ethers.
Recently, several groups have reported that under certain limited
conditions, allylic alcohols and ethers can be used directly in
substitution reactions with soft nucleophiles.6 While there have been
scattered reports of the direct use of allylic ethers as electrophiles,
many of these examples required stoichiometric additives.7 Grignard
reagents have been used as nucleophiles with substrates containing
heteroatom directing groups.8 Because of their stability toward most
reaction conditions, including those that are not compatible with
typical leaving groups utilized in allylic alkylation reactions, such
as acetates and carbonates, unactivated alkyl ethers could potentially
serve as useful protecting groups for allylic alcohols. However,
protecting-group strategies involving methyl ethers are less fre-
quently seen in synthesis because their high stabilities often require
the use of harsh deprotection methods (e.g., BBr3, TMSI, AlBr3,
etc.) that may not be compatible with other functional groups in
the rest of the molecule.9
a Isolated yield after silica gel chromatography.
expanded to include protecting groups commonly used for alcohols,
such as benzyl, tert-butyldimethylsilyl (TBS), and benzoyl ethers
(eq 2).
While attempting to carry out a photochemical thiol-ene10
reaction between cyclopentenyl methyl ether and diethylphospho-
rothioic acid (λ > 300 nm, CH2Cl2, rt, 2 h), we were surprised that
the expected saturated product was not obtained. Instead, we isolated
4a (73% yield), in which substitution of the methyl ether had
occurred. Furthermore, attempts to promote substitution reactions
between allylic ethers and other sulfur nucleophiles (i.e., thioacetic
acid) with p-TsOH resulted in decomposition. Intrigued by the mild
conditions under which the allylic methyl ether had been removed,
we decided to explore the scope of the substitution reaction.
Attempts to carry out substitution reactions with various second-
ary and tertiary aliphatic and/or benzylic alcohols and ethers resulted
only in the recovery of starting materials (eq 3). When we conducted
a competition experiment between secondary, tertiary, and allylic
alcohols, only the product resulting from substitution of the allylic
alcohol was observed (eq 4). These results suggest that the thiolation
reaction may be specific to allylic leaving groups.
A wide range of substituted acyclic and cyclic alcohols and ethers
are compatible with the reaction (Table 1). Importantly, the use of
trisubstituted alkenes furnished products 4c-h as single regioiso-
mers, while the reactions between 1 and either of the regioisomeric
allylic ethers 5 or 6 furnished the same product 7 in good yields
(eq 1). The scope of the allylic thiolation reaction was then
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10.1021/ja100747n  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Grignard Coupling Reaction with 4a
Conveniently, compound 1 is an odorless oil that can be prepared
in multigram quantities from diethyl phosphite and S8 in one step
with no purification necessary. Furthermore, unlike secondary allylic
phosphate esters, which are highly moisture sensitive,11 phospho-
rothioate esters 4a-k and 7 are robust compounds that can be
chromatographed and stored for extended periods without any
special precautions.
Control experiments indicated that although the use of UV light
had an appreciable accelerative effect on the observed reaction rate,
its presence was not required.12 The reaction between 1 and
2-cyclohexen-1-ol was conducted in the presence and in the absence
of UV light while maintaining the same internal temperature. The
reaction conducted with UV light was appreciably faster than the
corresponding dark reaction.
To determine whether or not the allylic thiolation reaction is
stereospecific, we carried out the substitution reaction on scalemic
allylic ether 3c, which was prepared via Corey-Bakshi-Shibata
reduction of the corresponding ketone followed by methylation.
When 3c was treated with 1 in the presence of UV light or in the
dark, nearly racemic phosphorothioate ester 4c was obtained
(Scheme 1). The observation that racemization and convergence
of regioisomeric allylic ethers to a single product occurs (eq 1)
suggests the formation of prochiral common intermediates. Among
other possibilities, we postulate that these intermediates can be either
allylic carbocations derived from heterolytic ionization of starting
materials/products (path a/b) and/or allylic radicals generated from
homolytic photochemical cleavage13 of the carbon-sulfur bond of
the product (path c). We believe that the minimal amount of residual
enantioenrichment that is observed may arise from the formation
of tight or solvent-separated ion pairs.14
a Isolated yield. b Product coeluted with the protonated Grignard
reagent. Yields were somewhat lower because of physical losses in the
isolation process.
With allylic phosphorothioate esters in hand, we then proceeded
to examine their effectiveness as electrophiles in uncatalyzed C-C
bond-forming reactions with Grignard reagents. From Table 2, it
is apparent that the alkylation reaction with 4a is broadly applicable
to a wide range of nucleophiles. The reaction is tolerant of both
electron-withdrawing (entries 3-6) and donating (entry 7) groups
as well as vinylic substrates (entry 10). Moreover, both primary
and secondary alkyl Grignard reagents also participate in the
substitution reaction (entries 11 and 12). To the best of our
knowledge, the use of allylic phosphorothioate esters in C-C bond-
forming reactions with Grignard reagents or any other nucleophile
has not been previously reported.15
Scheme 1. Proposed Mechanism for Product Racemization
In principle, the reaction of substituted allylic phosphorothioate
esters can proceed by either an SN2- or SN2′-type mechanism, each
of which furnishes a different regioisomeric product. We therefore
surveyed the alkylation reactions between 4c, 4e, and 4h and a
range of nucleophiles (Table 3). The use of aromatic and alkenyl
nucleophiles resulted in SN2-type displacements (entries 1-6).
However, we were pleased that the use of secondary aliphatic
Grignard reagents resulted in a reversal of regioselectivity in which
SN2′-type substitution reactions dominated (entries 7-12). These
are highly sterically congested compounds that possess adjacent
quaternary and tertiary centers. We were also able to demonstrate
that t-BuMgBr is capable of participating in the coupling reaction
in which one of the products possesses adjacent quaternary carbon
centers (entry 12).
While it is possible that reactions via paths a, b, and c may all
occur simultaneously, we conducted crossover experiments sup-
porting the premise that allylic phosphorothioates are potentially
photolabile functional groups (Scheme 1, path b/c). When a 1:1
mixture of 4c and diisopropylphosphorothioic acid 13 was exposed
to UV light (eq 5), we obtained a 2:1 mixture of diethyl and
diisopropyl phosphorothioate esters (4c and 14, respectively). 4c
was recovered nearly quantitatively when the reaction was con-
ducted in the absence of UV light.
The divergent regioselectivities of the products obtained with
aliphatic and aromatic Grignard reagents can be partially rational-
ized by invoking a radical-based mechanism in the former case.
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C O M M U N I C A T I O N S
Table 3. Regioselective Grignard Coupling Reactions
1 and 2), the yields were significantly reduced. The use of aliphatic
Grignard reagents led to virtually unselective reactions (entries 3
and 4). While allylic halides 42 and 43 could be stored for short
periods at room temperature, they were not stable toward silica
gel and had to be used without purification. The disparate
regioselectivities observed in alkylation reactions of 42 and 43 with
aliphatic Grignard reagents and the operational difficulties associated
with handling secondary allylic halides20 in which the alkene is
ꢀ,ꢀ-disubstituted differentiate our methodology from the use of
other types of allylic electrophiles.
In conclusion, we have reported a simple two-step process for
the transition-metal-free synthesis of sterically hindered quaternary
and tertiary C-C bonds starting from a diverse set of allylic alcohols
and ethers. A thorough investigation of the mechanistic and
stereochemical aspects of both reactions is underway.
Acknowledgment. The authors are grateful to Dartmouth
College and the Walter and Constance Burke Foundation for their
generous financial support.
Supporting Information Available: Experimental details and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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