On the nature of the chain-extending species in organolithium initiated stereospecific reagent-controlled homologation reactions using α-chloroalkyl aryl sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2014.08.123

The reaction of an organolithium with an α-chloroalkyl aryl sulfoxide ostensibly generates an α-chloroalkyllithium by sulfoxide-lithium exchange, but the actual identity of the chain-extending species in chlorosulfoxide-based StReCH reactions is not certain. To explore this issue, racemic 2-cyclohexyl (4R^?,5R^?)-4,5-diphenyl-1,3,2-dioxaborolane was homologated by treatment with scalemic (S)-chloromethyl phenyl sulfoxide and n-BuLi (THF, -78 °C). The reaction proceeded without a detectable level of kinetic resolution, a finding consistent with chloromethyllithium being the active chain-extending species rather than a chiral sulfurane intermediate.

Full text of DOI:10.1016/j.tetlet.2014.08.123

Tetrahedron Letters 56 (2015) 2980–2982
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Tetrahedron Letters
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On the nature of the chain-extending species in organolithium
initiated stereospecific reagent-controlled homologation reactions
using
a-chloroalkyl aryl sulfoxides
⇑
Amanda L. Hoyt, Paul R. Blakemore
Department of Chemistry, Oregon State University, Corvallis, OR 97331, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of an organolithium with an a-chloroalkyl aryl sulfoxide ostensibly generates an a-chloro-
Received 12 August 2014
Accepted 28 August 2014
Available online 6 September 2014
alkyllithium by sulfoxide–lithium exchange, but the actual identity of the chain-extending species in
chlorosulfoxide-based StReCH reactions is not certain. To explore this issue, racemic 2-cyclohexyl (4R⁄,
5R⁄)-4,5-diphenyl-1,3,2-dioxaborolane was homologated by treatment with scalemic (S)-chloromethyl
phenyl sulfoxide and n-BuLi (THF, À78 °C). The reaction proceeded without a detectable level of kinetic
resolution, a finding consistent with chloromethyllithium being the active chain-extending species rather
than a chiral sulfurane intermediate.
Dedicated to the memory of Professor Harry
H. Wasserman
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Carbenoid
Kinetic resolution
Pseudorotation
Sulfoxide–metal exchange
Sulfurane
Introduction
The stereospecific reagent-controlled homologation (StReCH) of
boronic esters using stereodefined carbenoids generated by the
addition of organolithium reagents to a-chloroalkylsulfoxides has
been successfully demonstrated for the preparation of a variety
of stereochemically complex molecules.1 Ostensibly, this reaction
proceeds via sulfoxide–lithium exchange from
a-chloroalkyl sulf-
oxides 2 with the resulting -chloroalkyllithium 5 going on to
a
homologate the boronic ester by ate-complex formation followed
by 1,2-metallate rearrangement (6 to 7) (pathway A, Scheme 1).
In reality, however, it is not certain that an
is actually involved in the process since an intermediate sulfurane
3 could equally well be responsible for loading the -chloroalkyl
a-chloroalkyllithium
a
moiety on the boronic ester (pathway B). Accordingly, we sought
to design and execute an experiment capable of distinguishing
between the two possibilities and that might also answer some
questions about the sulfoxide–metal (/ligand) exchange process2
(see Scheme 2).
Scheme 1. Organolithium initiated stereospecific reagent-controlled homologation
(StReCH) of boronic esters using -chloroalkylsulfoxides.
a
The exchange of carbanionic ligands about the tricoordinate
sulfur-atom in sulfoxides has been long known3 but it is a process
that languished in comparative obscurity until quite recently. The
transformation first came to prominence as a means to synthesize
enantioenriched dialkyl sulfoxides,3f but it is typically applied
today as a means to access organometallics.4 The mechanism for
the ligand exchange is not certain; however, it is known that net
stereochemical inversion occurs at sulfur. Consistent with this
finding would be a direct SN2 displacement but more likely are
⇑
Corresponding author. Tel.: +1 541 737 6728; fax: +1 541 737 2062.
E-mail address: paul.blakemore@science.oregonstate.edu (P.R. Blakemore).
http://dx.doi.org/10.1016/j.tetlet.2014.08.123
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. L. Hoyt, P. R. Blakemore / Tetrahedron Letters 56 (2015) 2980–2982
2981
resolution with (S)-14 and RLi (R – Ph) is suggestive, but does not
emphatically prove, that chloromethyllithium (19) is the relevant
active chain-extending species. We now report execution of this
experiment and observation of the last type of result.
Results and discussion
The key carbenoid precursor, chloromethyl phenyl sulfoxide
(14), was prepared in scalemic form by catalytic enantioselective
sulfoxidation of thioanisole (20) using the Bolm–Ellman–Jackson
protocol,7 followed by stereoinvertive chlorination of the product
sulfoxide (22) with N-chlorosuccinimide (NCS) conducted in the
presence of potassium carbonate to minimize racemization.8,1e
The same chlorosulfoxide was prepared in racemic form more
expediently by oxidation of 20 by H2O2–MeOH followed by NCS
mediated chlorination (Scheme 4). The requisite (4R⁄,5R⁄)-4,5-
Scheme 2. Putative pathways for sulfoxide–metal (/ligand) exchange.
pathways involving sulfurane intermediates.5 In this regard, two
routes based on a principle of apical-in/apical-out substitution
are reasonable: (1) an SN2-like trajectory via sulfurane 9 wherein
the incoming carbanion (Rin) adds opposite the outgoing nucleo-
fuge (Rout), and (2) a more complex pathway involving apical addi-
tion of the incoming carbanion to a site opposite the SAO bond to
give a sulfurane intermediate (11) which must experience a pair of
pseudorotations (with Rout the pivot ligand for the first event and
then Rin the pivot ligand for the second pseudorotation)6 to arrive
at another sulfurane (12) that allows ejection of the nucleofuge in a
manner that is the exact reverse of the initial addition step (i.e.,
apical-out, opposite the SAO bond).
diphenyl-1,3,2-dioxaborolanes ( )-13 (R0 = BnCH2, Ph, c-C6H11
)
were typically prepared by esterification of commercial boronic
acids with the diol [( )-23] formed by dihydroxylation of trans-stil-
bene under standard conditions (see Supplementary data for
details).
The basic efficacy of homologation using chlorosulfoxide 14 was
evaluated using racemic material (Table 1). The process was found
to be inefficient but this was not necessarily an issue since the
occurrence of any kinetic resolution would be easy to detect in
the chain extension product at low conversion. Good chemical
behaviour was realized from B-phenethyl boronate 13a which
was successfully homologated by chlorosulfoxide 14 using three
different organolithium initiators (entries 1–3). Unfortunately,
boronate substrate 13a and its homologue 15a were too close in
To glean the nature of the chain-extending species in StReCH, be
it an
a-chloroalkyllithium or one of the sulfurane isomers as
described above (9 or 12), the following experiment using kinetic
resolution as a reporter of chirality of the carbenoid was designed
(Scheme 3). Thus, homologation of a racemic chiral boronic ester
(13) by enantioenriched chloromethyl sulfoxide 14 is conducted
by the addition of some RLi (R – Ph) to the pair of compounds.
The reaction is not run to complete conversion and the homologa-
tion product (15) and unconverted starting material (13) are ana-
lysed for %ee. Realization of kinetic resolution (%ee – 0) would
reveal that the chain-extending agent is a scalemic species and
therefore chloromethyllithium (19), which is achiral, is ruled out.
In this scenario, sulfuranes 17 (of type 9) and 18 (of type 12) and
chloromethyllithiumÁsulfoxide complex 19Á16 remain potential
candidates. To decide between these alternatives, the experiment
is repeated with PhLi as the initiating organolithium. In this case
(R = Ph), only 17 is still a chiral species and the observation of
kinetic resolution (%ee – 0) infers that this intermediate (17) and
not 18 or 19Á16 is the chain-extender. If %ee becomes zero upon
changing from RLi (R – Ph) to PhLi, then the active carbenoid is
sulfurane 18 or organolithium sulfoxide complex 19Á16. To
distinguish between these final two possibilities, the experiment
is repeated with RLi (R – Ph) with wholly racemic substrates
[( )-13 and ( )-14] but in the presence of scalemic 16; if kinetic
resolution occurs under these conditions then 19Á16 and not 18
is the active chain-extending species. Failure to realize any kinetic
Scheme 4. Synthesis of (S)-14 and ( )-14.
Table 1
Evaluation of homologation efficacy using chloromethyl phenyl sulfoxide (14) as
carbenoid precursor under various reaction conditions
Entry
R0
13
RLi
Solvent
Yield 15a (%)
Yield 16 (%)
1b
2b
3b
4c
5c
6c
7c
BnCH2
BnCH2
BnCH2
Ph
Ph
c-C6H11
c-C6H11
13a
13a
13a
13b
13b
13c
13c
n-BuLi
t-BuLi
PhLi
n-BuLi
t-BuLi
n-BuLi
t-BuLi
THF
PhMe
THF
THF
PhMe
THF
13
19
18
0
<3
11
6
7
28
41
13
33
11
16
PhMe
a
The pair of 13 and 15 was isolated as a two component mixture by SiO2 chro-
matography of the reaction residue, the effective yield for 15 is based on mass
determination for this mixture and 1H NMR analysis.
b
Stoichiometry of 13/14/RLi = 2:1:1.
Stoichiometry of 13/14/RLi = 1:1:1.
c
Scheme 3. Experiment to probe the nature of chain-extending species in StReCH.

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A. L. Hoyt, P. R. Blakemore / Tetrahedron Letters 56 (2015) 2980–2982
detectable limit, cannot be wholly discounted. Nonetheless, we
extrapolate the findings herein to tentatively conclude that, in all
likelihood, -chloroalkyllithiums are the species responsible for
the chain extension of boronic esters in organolithium initiated
StReCH reactions using -chloroalkyl sulfoxides. Although the
a
a
direct intervention of sulfurane intermediates was not uncovered
in this Letter, we believe that the kind of experiment described
could prove useful in detecting their action and their character in
other processes involving sulfoxide–metal (/ligand) exchange.
Acknowledgments
Support for this work by the National Science Foundation Grant
CHE-0906409 is gratefully acknowledged. Drs. Selena Milicevic
Sephton and Mark Sephton are thanked for helpful discussion.
Scheme 5. Kinetic resolution not detected during chain extension of boronate ( )-
13c by chlorosulfoxide (S)-14 (73% ee).
polarity to be separated; a necessity for later probing of kinetic res-
olution which was to be conducted via chiral stationary phase
HPLC analysis of the syn-1,2-diphenylethan-1,2-diol obtained by
boronate hydrolysis. No more than a trace of homologue 15b could
be obtained from B-phenyl boronate 13b because an apparent
sensitivity to oxidation precluded its isolation (entries 4 and 5).
B-cyclohexyl boronate 13c was found to possess the desired attri-
butes for the key experiment: it could be successfully chain
extended with 14 and the substrate and its homologue were sepa-
rable by semi-preparative HPLC using an achiral column.
With an optimal boronate substrate and reaction conditions for
chain extension identified, the key experiment was performed
using scalemic chlorosulfoxide (S)-14 (73% ee). An equimolar
mixture of B-cyclohexyl boronate 13c and chlorosulfoxide (S)-14
in THF solvent at À78 °C was treated with a single equivalent of
n-BuLi (Scheme 5). After warming to room temperature and a
work-up, boronates 13c and 15c were separated from other reac-
tion mixture components using SiO2 column chromatography
and then these two non-polar materials were carefully separated
from each other by semi-preparative HPLC on an achiral column.
syn-1,2-Diphenylethan-1,2-diol (23) was liberated from both the
recovered substrate 13c and the chain extended product 15c by
oxidative hydrolysis and each sample was subjected to HPLC anal-
ysis on a chiral stationary phase. Neither sample exhibited a level
of enantiomeric excess above the effective detection limit of the
instrument (%ee 60.7% from duplicated measurements) and the
materials obtained were not differentiable from an authentic sam-
ple of racemic diol [( )-23] when the same analysis method was
applied. The experiment was repeated with essentially identical
results and it was concluded that kinetic resolution of boronate
( )-13c by the carbenoid species generated in situ from chlorosulf-
oxide (S)-14 and n-BuLi does not occur.
Supplementary data
Supplementary data (full experimental procedures, character-
ization data, and 1H and 13C NMR spectra for all compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.08.123.
References and notes
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Conclusion
Failure to detect a significant level of kinetic resolution in the
experiment described above is consistent with the active chain-
extender being chloromethyllithium (19), an intrinsically achiral
species. However, given the nature of the experiment conducted,
the possibility that some chiral carbenoid species is involved, but
that it fails to kinetically resolve the racemic boronate beyond a