Electrochemically driven stereoselective approach tosyn-1,2-diol derivatives from vinylarenes and DMF

Article abstract of DOI:10.1039/d1sc00760b

We have developed an electrochemically driven strategy for the stereoselective synthesis of protectedsyn-1,2-diols from vinylarenes withN,N-dimethylformamide (DMF). The newly developed system obviates the need for transition metal catalysts or external oxidizing agents, thus providing an operationally simple and efficient route to an array of protectedsyn-1,2-diols in a single step. This reaction proceedsviaan electrooxidation of olefin, followed by a nucleophilic attack of DMF. Subsequent oxidation and nucleophilic capture of the generated carbocation with a trifluoroacetate ion is proposed, which gives rise predominantly to asyn-diastereoselectivity upon the second nucleophilic attack of DMF.

Full text of DOI:10.1039/d1sc00760b

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Electrochemically driven stereoselective approach
to syn-1,2-diol derivatives from vinylarenes and
DMF†
Cite this: Chem. Sci., 2021, 12, 5892
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
*
Da Sol Chung,‡ Steve H Park,‡ Sang-gi Lee and Hyunwoo Kim
We have developed an electrochemically driven strategy for the stereoselective synthesis of protected syn-
1,2-diols from vinylarenes with N,N-dimethylformamide (DMF). The newly developed system obviates the
need for transition metal catalysts or external oxidizing agents, thus providing an operationally simple
and efficient route to an array of protected syn-1,2-diols in a single step. This reaction proceeds via an
Received 8th February 2021
Accepted 22nd March 2021
electrooxidation of olefin, followed by
a nucleophilic attack of DMF. Subsequent oxidation and
DOI: 10.1039/d1sc00760b
nucleophilic capture of the generated carbocation with a trifluoroacetate ion is proposed, which gives
rise predominantly to a syn-diastereoselectivity upon the second nucleophilic attack of DMF.
rsc.li/chemical-science
a chemical oxidant system (e.g. hypervalent iodines) oen leads
to limited functional group compatibility. In this regard, we
Introduction
envisioned an electrochemical alkene oxidation as an ideal
approach. Electrocatalytically driven organic synthesis allows to
precisely select the redox potential for use, which circumvents
selectivity and compatibility issue that oen arise from its
The dihydroxylation of alkenes is a fundamental and straight-
forward transformation for the preparation of 1,2-diols, which
is widely used in the preparation of key intermediates in
fragrances, pharmaceuticals and functional materials.1 There
are several classical methods that are capable of achieving this
goal, including the Woodward–Prevost reaction2a–c and the
epoxidation followed by ring-opening,2d in which both reactions
proceed via cyclic intermediates that dene the stereochemistry
of the product (eqn (1) in Scheme 1A). A concerted syn-dihy-
droxylation mediated by OsO4 along with its asymmetric
version, the Sharpless dihydroxylation, has also been recog-
nized as the most widely used synthetic method for 1,2-diols
(eqn (2) in Scheme 1A).3 Despite these landmark achievements,
the replacement of the use of an expensive and highly toxic
osmium catalyst led to the dioxygenation of alkenes employing
other metal-based catalysts which has successfully been devel-
oped in the presence of stoichiometric chemical oxidants such
as PhI(OAc)2 or dioxygen (eqn (3) in Scheme 1A).4 More recently,
transition-metal free approaches such as peroxide5 or radical-
mediated protocols6 have emerged as the alternative synthetic
routes to 1,2-diols, although it is sometimes difficult to predict
stereochemical outcome (eqn (4) in Scheme 1A).
Most of these precedent examples however still rely on the
use of transition metals for the requisite redox process or
otherwise require additional synthetic steps for the preparation
of reaction mediators. In addition, an employment of
Department of Chemistry and Nanoscience, Ewha Womans University, 03760 Seoul,
Korea. E-mail: sanggi@ewha.ac.kr; khw7373@ewha.ac.kr
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc00760b
‡ These authors contributed equally to this work.
Scheme 1 Synthetic approaches to 1,2-diols from alkenes.
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purely chemical counterparts.7 Despite recent efforts in the stoichiometric amount of water is requisite for the reaction
development of electrochemical dialkoxylation,8 it is highly (entry 3). We found that the employment of acids weaker than
desirable to develop
approach for 1,2-diol derivatives using feedstock chemicals.
a
conventional and stereoselective TFA were detrimental to the reaction (entries 4 and 5). On the
other hand, acids stronger than TFA were productive, albeit
Herein, we report an electrochemical syn-diformyloxylation with slightly reduced efficiencies (entries 6 and 7). Switching the
of vinylarenes using DMF as an oxygen source (Scheme 1B). This solvent from DMF into CH3CN signicantly hampered the
newly developed catalyst-free approach provides a straightfor- reactivity, even under high excess amount of DMF (entries 8 and
ward and efficient route to a wide range of protected syn-1,2- 9). We have also found that the reactivity was not signicantly
diols in a single step. Electrochemical oxidation of alkenes to its affected when electrolysis was conducted under a constant
radical cation enabled the direct addition of DMF, in which the current of 2 mA (entry 10). Notably, the reaction under O2
formyloxy group derived from DMF can readily be converted atmosphere was not benecial for the desired transformation,
into hydroxyl group.9 Subsequent oxidation and a facile nucle- showing a signicant drop in reaction efficiency (entry 11).
ophilic capture of the generated carbocation with a tri- Similarly, the reactivity was found to be slightly diminished
uoroacetate ion is proposed to grant high syn- when the reaction was conducted open to air (entry 12).
diastereoselectivity upon second nucleophilic attack of DMF.
To investigate the scope and functional group compatibility
of the current diformyloxylation protocol, an array of terminal
vinylarenes were initially examined (Table 2). Vinylarenes with
different functional groups such as simple alkyls (2–4), acetoxy
(5), ester (6) and halogen (7–9) groups at para-position were well
tolerated. An ortho-substituted vinylarene (10), 2-vinyl-
naphthalene (11) and 1,1-disubstituted olen (12) were also
smoothly participated in the reaction without difficulties.
Importantly, vinyl heterocycles derived from dibenzofuran (13)
and carbazole (14) were also applicable to the current protocol,
while pyridine, quinolone and thiophene derived vinyl hetero-
arenes were reluctant to participate in the reaction mainly due
to the formation of polymeric side products. Interestingly, 1,2-
diacetoxylation (15) product was obtained when N,N-dimethy-
lacetamide (DMA) was employed as a solvent. Moreover, the
reactivity toward biorelevant structures was examined to illus-
trate the installation of protected 1,2-diol group as a late-stage
synthesis, furnishing estrone (16) and tyrosine (17) deriva-
tives. It was also notable to see that a readily oxidizable electron
rich alkene such as phenyl vinyl ether,10 could also be engaged
in this reaction (18).
Results and discussion
We set out to investigate our proposed olen diformyloxylation
by choosing 4-tert-butylstyrene (1) as the model substrate (Table
1). Aer optimization, we observed that the application of
a constant cell voltage of 2.5 V (corresponding to an anodic
potential of 1.3 V vs. SCE) enabled the formation of a formyl
protected diol 2 in 90% yield (entry 1). The optimal conditions
employed triuoroacetic acid (TFA, 5.0 equiv.) and water (3.0
equiv.) as additives, TBABF4 as the electrolyte, carbon felt and
platinum plate as the anode and cathode respectively, in DMF. A
control experiment without applied potential revealed that
electric current is necessary for reactivity (entry 2). The reaction
efficiency was signicantly diminished when the reaction was
conducted in the presence of molecular sieves, suggesting that
Table 1 Reaction parameter optimizationa
To explore the stereoselectivity of the current procedure, we
next set out to examine the scope of various internal alkenes. As
summarized in Table 2, diformyloxylation of a wide range of
internal alkenes granted access to products bearing vicinal
stereogenic centers with good diastereocontrol. Dioxygenation
of acyclic 1,2-disubstituted alkenes provided formyl-protected
syn-diol products in good to excellent diastereomeric ratios
(19–24, >7 : 1). Notably, substrates having labile groups on
allylic positions underwent desired transformations without
dissociation of the leaving groups (21–23). The cyclic alkenes
such as dibenzosuberone and indene were viable substrates as
well, albeit in somewhat diminished diastereoselectivity (25–26,
>4 : 1, diastereomeric ratios). Interestingly, the reaction was
found to be highly chemoselective towards a more readily
oxidizable, electronically rich alkene when a substrate bearing
multiple alkenes was tested. For example, cinnamyl cinnamate
gave a mono-dioxygenated product 27 with high chemo- and
diasteroselectivity. Trisubstituted alkenes were also reacted
efficiently to afford the corresponding products in good dia-
steroselectivity (28–29). However, tetrasubstituted or unac-
tivated alkenes derived from simple hydrocarbons were found
to be recalcitrant to the current dioxygenation method (see
Entry
Variation from “standard conditions”
Yield of 2 (%)
1
2
3
4
5
6
7
8
None
95 (90)
<5
33
<5
31
60
50
25
15
No applied voltage
˚
With 4 A molecular sieves
CH3COOH instead of TFA
HCOOH instead of TFA
HOTf instead of TFA
HNTf2 instead of TFA
DMF (20 equiv.) in CH3CN (0.05 M)
DMF (10 equiv.) in CH3CN (0.05 M)
Under constant current (Icell ¼ 2.0 mA)
Under O2 atmosphere (balloon, 1 atm)
Under air atmosphere
9
10
11
12
75
45
70
a
1 (0.2 mmol, 1.0 equiv.), CF3COOH (1.0 mmol, 5.0 equiv.), H2O
(0.6 mmol, 3.0 equiv.), TBABF4 (0.1 M), DMF (3 mL); cell voltage (Ucell
¼ 2.5 V); yields determined by 1H NMR (isolated yields in parenthesis).
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Table 2 Substrate scope of electrochemically driven olefin dioxygenationa
a
Isolated yields are reported. Optimal conditions from Table 1 used. Diastereoselectivity was determined by 1H NMR spectra of crude reaction
mixture. Yield determined by 1H NMR using 1,2-dimethoxyethane as an internal standard. N,N-Dimethylacetamide (DMA) was used as
b
c
a solvent. d 10 equiv. of TFA was used. e 5% of 33 was also obtained along with 32.
Scheme S1 in ESI† for unsuccessful substrates). The electro- intermediacy of our reaction. As hypothesized, we were able to
chemical diformyloxylation tested positive in the radical clock observe the formation of desired diformyloxylation product 34
experiment with cycloproyl-substituted alkene 30, implying the upon treatment of 33 with DMF in the presence of water.
intermediacy of a benzylic radical during the reaction.
The uncommon diastereoselectivity trend observed in this
We have also found that the reaction took place selectively at catalyst-free approach piqued our interest in elucidating its
the terminal position when 1,3-diene was employed as mechanism. The reaction under deuterated DMF-d7 solvent
a
substrate (32). Different from conventional vinylarene revealed that the formyl groups in the product originate from
substrates, however, the dioxygenation product 33 possessing DMF, as we envisioned at the outset (Fig. 1A). In contrast, we
a triuoroacetoxy group at 3-position was obtained as the major found that the reaction with deuterated formic acid did not
product (45%) along with 5% of the desired product (34). This result in incorporation of deuterium on both formyl groups
observation led us to further investigate the possible (Fig. 1B). These ndings suggested that the engagement of
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diastereoselectivity upon choice of the stereoisomeric starting
materials is unusual compared to previous examples that
employ different alkene oxidation strategies.12
To elucidate the origin of the oxygen atoms, we performed an
isotopic labeling study with indene (36) as a substrate, using
97% O18 enriched water as an additive (Fig. 1D). The relative
amounts of doubly-labeled diformyloxylation products (>69.3%)
with singly-labeled (<26.9%) and unlabeled (<4%) products
were determined for both diastereomers (syn- and anti-26),
using high-resolution mass spectroscopy (HRMS). On the other
hand, hydrolysis of the formyloxy groups resulted in signicant
removal of the oxygen 18-label, leading to the formation of
unlabeled diol as the major product for both diastereomers
(syn- and anti-37). These results suggest that both oxygens for
the hydroxyl group originate from DMF during the reaction, not
from water.
Cyclic voltammetry (CV) data showed that the oxidation of
alkene 1 to the corresponding alkene radical cation results in
a feature at around Ep/2 ¼ 1.7 V (vs. SCE; Fig. 1E, black line). The
addition of TFA, DMF, or both did not cause signicant anodic
peak shi of this redox event in thermodynamically more
feasible way, implying that the alkene substrate is directly
oxidized on the carbon anode during the reaction. We also
recognized the possibility of an oxidation of DMF prior to the
alkene. However, such mechanism is proved to be difficult
because of high oxidation potential of DMF (Ep/2 ¼ 2.1 V,
dashed black lines), even in the presence of TFA (dashed blue
lines).
On the basis of these experimental results and precedent
literature,13 a mechanistic rationale is shown in Fig. 2. First,
electrochemical oxidation of the alkene substrate A generates
the alkene radical cation B (the oxidation potentials Eox for the
Fig. 1 Mechanistic investigations. (A) Deuterium labeling experiment
with DMF-d7. (B) Deuterium labeling experiment with formic acid-d2.
(C) Diastereoselectivity test with isomeric vinylarene substrates. (D)
O18-labeling experiments. (E) Cyclic voltammetric experiments.
formic acid with the olen radical cation is less conceivable, in
which the formic acid is initially generated by hydrolysis of DMF
in the presence of strong acid.9a,11 Notably, the stereo-outcome
of this reaction was dependent on the alkenylic geometry of
the starting materials, with the major isomers irrespectively
arising from syn-diformyloxylation. For example, trans- and cis-
b-methylstyrene (trans- and cis-35) both gave corresponding syn-
diformyloxylation products with 10 : 1 and 3 : 1 of diastereo-
meric ratios respectively (Fig. 1C). We note that this retention of
Fig. 2 Mechanistic rationale.
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different vinylarenes tested range from 1.15 V to 1.75 V vs. data and performed the calculations. The manuscript was
SCE).14 The low potential threshold for such electron transfer is written by H. K. and S.-g. L. and S. H. P. contributed to the
reported to be 0.5 V lower than the thermodynamic potential of editing.
the substrate,15 which supports that our measured initial anodic
potential (Ea,i ¼ 1.3 V vs. SCE) is above the onset potential of
Conflicts of interest
alkene oxidation. As an additional note, the anodic potential
was maintained throughout the reaction, showing 1.22 V of the There are no conicts to declare.
nal anodic potential (Ea,f). This result suggests that the desired
reactivity can be achieved at the low potential threshold of the
alkene oxidation. The nucleophilic trapping of B with DMF
Acknowledgements
produces the carbon-centered radical C, which is concurrently This work was supported the National Research Foundation of
oxidized into the dication D on a carbon anode. Indeed, the Korea (NRF) grant funded by the Korea government (MSIT)
second anodic oxidation is calculated to be thermodynamically [NRF-2021R1C1C1004605 (H. Kim)]. D. S. Chung acknowledges
more feasible than the rst oxidation (Eox ¼ 0.69 V vs. SCE, the
National
Research
Foundation
(NRF-
when Ar ¼ Ph and R ¼ Me).16 A facile nucleophilic capture of 2019R1A6A3A13096586). This study made use of the NMR
sterically biased dication D by triuroacetate ion would result in facility supported by Korea Basic Science Institute (National
the predominant formation of an anti-dioxygenated interme- Research Facilities and Equipment Center) grant funded by the
diate F, upon hydrolysis of iminium intermediate E. A nucleo- Ministry of Education (NRF-2020R1A6C101B194).
philic displacement of triuoroacetate group17 from an isolable
intermediate F by DMF eventually furnishes a syn-diformylox-
ylation product H followed by the second hydrolysis. It should
Notes and references
be noted that the high diastereoselectivity observed in linear
alkene substrates suggests that the formation of E occurs prior
to the erosion of diastereocontrol caused by C–C bond rotation.
The reactivity trend upon the choice of acid observed in Table 1
is likely related to the nal nucleophilic displacement step.
Moreover, the role of TFA in affecting diastereoselectivity was
also veried by a series of control experiments with internal
alkene substrate, where TFA is replaced by other acids.18 We
also recognized the possibility of a nucleophilic attack of D
directly from DMF to give anti-diformyloxylation product (H0).
However, this pathway is considered to be less likely because
triuoroacetate is presumably a better nucleophile than DMF to
capture dicationic intermediate D mainly due to its anionic
character. This is also consistent to the predominant syn-dia-
stereoselectivity of the current diformyloxylation protocol.
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In conclusion, we devised an electrooxidative strategy that grants
access to formyl-protected syn-1,2-diols from vinylarenes and
DMF. This reaction is initiated by the electrochemical oxidation of
the alkene substrates followed by the nucleophile attack of DMF.
Mechanistic studies imply that triuoroacetate ion is presumably
engaged in the nucleophilic capture of the carbocation interme-
diate, which gives rise to high syn-diastereoselectivity. A simple
deprotection of formyl protecting groups from the dioxygenated
product was also presented, highlighting synthetic utility of this
electrochemical method toward a variety of 1,2-diols. We antici-
pate this electrochemical synthetic approach promoted by tri-
uoroacetic acid will be broadly applicable in further
development of nucleophilic olen functionalization reactions.
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© 2021 The Author(s). Published by the Royal Society of Chemistry
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