Electrochemically driven desaturation of carbonyl compounds

Article abstract of DOI:10.1038/s41557-021-00640-2

Electrochemical techniques have long been heralded for their innate sustainability as efficient methods to achieve redox reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent reactivity through the formal removal of two hydrogen atoms. To date, the most reliable methods to achieve this seemingly trivial reaction rely on transition metals (Pd or Cu) or stoichiometric reagents based on I, Br, Se or S. Here we report an operationally simple pathway to access such structures from enol silanes and phosphates using electrons as the primary reagent. This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable (1–100 g) and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR shifts. Systematic comparisons to state-of-the-art techniques reveal that this method can uniquely desaturate a wide array of carbonyl groups. Mechanistic interrogation suggests a radical-based reaction pathway. [Figure not available: see fulltext.]

Full text of DOI:10.1038/s41557-021-00640-2

Articles
https://doi.org/10.1038/s41557-021-00640-2
Electrochemically driven desaturation of
carbonyl compounds
1
1
1
2
2
3
Samer Gnaim , Yusuke Takahiraꢀ ꢀ , Henrik R. Wilke , Zhen Yao , Jinjun Li , Dominique Delbrayelle ,
3
1
1
ꢀ✉
Pierre-Georges Echeverria , Julien C. Vantourout and Phil S. Baranꢀ ꢀ
Electrochemical techniques have long been heralded for their innate sustainability as efficient methods to achieve redox
reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent
reactivity through the formal removal of two hydrogen atoms. To date, the most reliable methods to achieve this seemingly
trivial reaction rely on transition metals (Pd or Cu) or stoichiometric reagents based on I, Br, Se or S. Here we report an opera-
tionally simple pathway to access such structures from enol silanes and phosphates using electrons as the primary reagent.
This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable
(
1–100ꢀg) and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR
shifts. Systematic comparisons to state-of-the-art techniques reveal that this method can uniquely desaturate a wide array of
carbonyl groups. Mechanistic interrogation suggests a radical-based reaction pathway.
he removal of one molecule of hydrogen adjacent to a car- popular and recently disclosed methods, and a simple method for
bonyl compound is one of the simplest organic oxidation predicting reactivity is also described.
T
reactions known and is a widely employed tactic in synthe-
1
–3
sis . Classic methods to accomplish this transformation involve Results and discussion
indirect α-functionalization approaches that traverse through The tetramethylsilyl (TMS) enol ether of cyclododecanone 1 was
4
–8
halide, sulfur and selenium derivatives . Chemoselective meth- chosen for the initial optimization of the electrochemically driven
ods that directly afford enones from ketones are, indeed, more desaturation (EDD); an abbreviated summary is depicted in Table 1
desirable and have been extensively explored (Fig. 1). Among (and see Supplementary Tables 1–5). Trial runs using the litera-
them, the Saegusa–Ito reaction, discovered in 1978, remains the ture conditions noted above provided only trace quantities of the
9
most oft-applied method for such applications . In its canonical product. Our prior experiences of electrochemical reaction devel-
26–33
implementation, the formation of a silyl enol ether, followed by opment served as a template for this study . A myriad of elec-
exposure to stoichiometric quantities (from 0.5 to 1.0 equiv.) of trolytes, electrodes and solvents were evaluated. First, an electrolyte
9
palladium delivers the desired α,β-desaturated product . Variants screen revealed that inorganic non-nucleophilic salts proved opti-
–
1
that employ a co-oxidant (for example, O , quinone or [Cu]) to mal (Table 1, entries 4–7) with NaSbF (US$0.56g ) as they deliv-
2
6
1
0,11
lower the Pd levels are also reported . Another popular approach ered the highest conversion. The use of a graphite anode was found
involves the use of stoichiometric o-iodoxybenzoic acid (IBX) to be essential, whereas several materials were suitable for the cath-
1
2,13
–2
through a process based on single electron transfer . Recently, ode (Table 1, entries 8–11). Ultimately, the low cost (~US$0.1cm )
two new methods have also appeared from the Newhouse and and efficiency of graphite motivated its selection for both electrode
Dong groups that allow the use of catalytic amounts of palladium materials. Of all the solvents screened, MeCN, acetone, dimeth-
1
4–20
and copper, respectively . These methods expand the scope of ylacetamide (DMA) and dimethylformamide (DMF) could be
available desaturation methods to nitriles, esters, lactones and employed, but MeCN gave the highest yield across a broad range
lactams and do not require the preparation of enol ethers. As the of substrates. A variety of bases were also tested, and heteroaro-
essence of this reaction involves a formal two-electron oxidation, matic amines proved most promising (Table 1, entries 15 and 16).
it reasonable that even simpler redox approaches might be devel- 2,4,6-collidine (30%v/v, entry 18) emerged as the optimum as it
oped. Indeed, in 1973, the Shono group demonstrated that enol provided the desired product 2 in a 62% isolated yield. The final
acetates can undergo anodic oxidation in AcOH as the solvent to set of EDD conditions tolerated exogenous air and moisture, led to
afford the corresponding enone. To deliver synthetically useful completion in 90minutes or less and can be set up in minutes using
yields of product, α-substitution was required with simple cyclo- a simple undivided cell and a commercial potentiostat.
2
1,22
hexanone substrates to provide <10% enone . Similar reactivity
EDD could be applied to a diverse set of carbonyl derivatives,
was also observed by Moeller and co-workers in their studies of as illustrated in Table 2. As numerous desaturation methods are
silyl enol ether alkylation where trace amounts of enone were iso- available to the practitioner, all of the results are placed in con-
lated as a by-product (<5% yield) . Building on these encourag- text by direct comparison to the powerful Pd, Cu and hypervalent
ing studies, we report herein an electrochemically driven approach iodine-based systems. With regards to ketone substrates, both cyclic
to elicit desaturation that requires no metals or chemical oxidants (from 5- to 15-membered rings) and acyclic derivatives could be
and features a broad substrate scope with inherent scalability. employed (2–17). This stands in contrast to recently developed cat-
The utility of this method is placed in the context of the most alytic methods that operate smoothly on cyclic systems but fail on
2
3–25
1
2
3
Department of Chemistry, Scripps Research, La Jolla, CA, USA. Asymchem Life Science (Tianjin) Co., Ltd, Tianjin, P.R. China. Minakem Recherche,
✉
Beuvry-la-Forêt, France. e-mail: pbaran@scripps.edu
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a
Table 1 | Optimization of the EDD reaction
O
OTMS
O
Oxidant or metal
or
X
X
X
OTMS
O
2,6-lutidine (3.5% v/v),
LiClO4 (0.15 M)
b
Shono
Moeller
MeCN (0.1 M), 1.5 h, C+/C–,
undivided cell, 10 mA, under Ar
OR1
O
O
1
2
R2
R
R1 = Ac
R2
1
Yield (%)a
R
R
= SiR3
= alkyl
Entry
Deviation from above
None
<
10%
R2 = H or alkyl
2
<5%
1
2
3
4
5
6
7
8
9
22 (17)
n.d.
8
n.d.
12
14
30
b
TEAOTs, AcOK in acetic acid
c
H
i
c
LiClO4, 3.5% lutidine in MeCN/ PrOH (1:1)
TBABF4 instead of LiClO4
LiBF4 instead of LiClO4
OR
EDD
H
O
OR
O
NaOTs instead of LiClO4
X
X
or
or
NaSbF6 instead of LiClO4
RVC anode, NaSbF6 instead of LiClO4
Platinium anode, NaSbF instead of LiClO
4
< 5%
n.d.
19
n
n
n
n
6
1
1
1
0
1
2
Nickel foam anode, NaSbF6 instead of LiClO4
RVC cathode, NaSbF6 instead of LiClO4
12
Fig. 1 | α,β-desaturation of carbonyl and enol compounds, state-of-the-art
and design of this work. a, Chemical approaches: the most used chemical
approaches for the desaturation of carbonyl and enol ether compounds.
Acetone instead of MeCN, NaSbF6 instead of LiClO4
DMF instead of MeCN, NaSbF6 instead of LiClO4
DMA instead of MeCN, NaSbF6 instead of LiClO4
TEA instead of lutidine, NaSbF6 instead of LiClO4
Collidine instead of lutidine, NaSbF6 instead of LiClO4
20% collidine, NaSbF6 instead of LiClO4
14
13
11
1
1
1
1
4
5
6
7
18
n.d.
45 (39)
55
ꢀ
to et al. reported a method using stoichiometric palladium, which is
limited to ketones and aldehydes . Newhouse also reported studies
9
using palladium, which also require expensive Zn(TMP) (bis(2,2,6,
18
19
30% collidine, NaSbF instead of LiClO
70 (62)
68
65
64
n.d.
n.d.
n.d.
2
6
4
50% collidine, NaSbF instead of LiClO
6
4
6
-tetramethylpiperidinyl)zinc), and an elevated temperature14–16. Studies
2
2
2
0
1
2
Under air
reported by Chen and Dong require copper, peroxide, and elevated
Non-anhydrous MeCN
No 2,4,6-collidine
No NaSbF
18
temperature and have limited scope . Previous studies from the Nicolaou
lab use stoichiometric ꢀBX, a strong oxidant and are limited to ketones and
aldehydes . b, Electrochemical precedents: the Shono group demonstrated
that enol acetates can undergo anodic oxidation to afford the
23
24
6
1
2
No electrolysis
corresponding enone2 . Moeller and co-workers observed that silyl enol
ether can similarly undergo direct anodic oxidation to form trace amounts
of enone under the described conditions2 . ꢀn both cases, the methods
are limited to ketones, have shown limited functional-group tolerance and
low yields were obtained with non-substituted ketones. c, EDD: the metal,
chemical oxidant free and scalable electrochemical desaturation method
is described. EDD is applicable with various types of carbonyls—ketones,
esters, lactams and aldehydes.
1,22
aꢀsolated yield. bEnol acetate, Shono et al.21. cMoeller and co-workers23,25. TEAOTs,
tetraethylammonium tosylate; TBABF , tetrabutylammonium tetrafluoroborate; n.d., not detected.
4
3,24
methods, the set of conditions reported by the Newhouse group was
found to provide the desaturated α-aryl lactones in moderate yields.
Next, the particularly difficult class of aldehydes were investigated
(32–34), with silyl enol ethers employed). Owing to the instabil-
ity of such desaturated products, the yields observed were mod-
erate (and accompanied by 5–11% of recovered parent aldehyde).
acyclic ones (14 and 15)1 . As the EDD of ketones is reliant on the Other direct catalytic methods for this dehydrogenation are not
formation of a silyl enol ether, regioselective desaturation is possible applicable, with the Saegusa protocol being the only other option.
simply by tuning the conditions (that is, 7 versus 8). Substituents Lactams, a similarly challenging class of carbonyls, were surveyed as
at the α-, β- and γ-positions are all tolerated, as well as Lewis-basic diphenylphosphate-ketenimine acetals, and in select cases (35–37)
heteroatoms (16), alkynes (10), proximal cyclopropanes (15), were viable.
5,18
esters (16 and 17), tert-butyl(dimethyl)silyl (TBS)-protected alco-
The scalability of the method was evaluated using
hols (11) and acid-labile ketals (6). A two-step in situ EDD pro- cyclopentadecanone-derived silyl enol ether 38 on a 4g scale
tocol was also developed to afford enones 6, 12 and 17 in decent (Fig. 2a) to afford enone 12, a key intermediate in the synthesis of
3
6
yields directly from the respective ketone starting material. Esters (R)-muscone 39, a valuable ingredient in the fragrance industry . A
and lactones, substrate classes that have only recently succumbed simple increase of current (from 10 to 300mA) and the use of alter-
1
4,17,18
to direct dehydrogenation
, can also be subjected to EDD using nating polarity (to avoid any accumulation of material at the anode)
the corresponding diphenylphosphate ester derivatives (18–31). enabled the standard EDD reaction to smoothly deliver compound
Such enol derivatives are easily prepared and hydrolytically stable, 12 in a 66% yield. To increase the scale further, the design and
unlike the corresponding silyl ketene acetals. Simple lactones and assembly of a flow apparatus that contained six reaction cells was
benzolactones, which are outside the substrate scope of the IBX undertaken (Fig. 2a). After optimization, 100g of 38 were success-
and Saegusa methodologies, can be smoothly dehydrogenated. As fully converted into compound 12 by increasing the current value to
with the EDD of ketones, the functional-group tolerance here is 3.6A (compared to 300mA in batch) to obtain a 61% isolated yield
also broad and includes aryl halides (22 and 24), CF (30), oxidiz- and 27% recovered starting material 38.
3
able anisoles (23), tosyl-protected amines (29) and alkenes (32).
From a mechanistic standpoint, the EDD reaction accomplishes
In addition, α-aryl lactones also afforded the desired products in the formal removal of two electrons and one proton from the corre-
satisfactory yields (21–23 and 25). The difficulty of desaturating sponding silyl enol ether. The electrochemical oxidation of silyl enol
18
23,24
such substrates has been documented by Dong . They are often ethers was previously disclosed by Moeller and studied mechanis-
25
alternatively accessed through cross-coupling on the correspond- tically by Wright and co-workers . These studies demonstrated that
ing vinyl halide derivatives or through α-bromination/elimination the initial anodic oxidation leads to the formation of an enol ether
sequences3 . Note that in comparing EDD with other precedented radical cation intermediate by using a cyclopropyl ring-opening
4,35
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Articles
Table 2 | Scope of the EDD reaction
NaSbF6 (0.15 M),
H
OR
H
O
OR
O
MeCN/2,4,6-collidine (7:3)
1
0 mA, r.t., 1.5 to 4.0 h
X
X
or
or
EDD
R = TMS, P(O)(OPh)2; X = CH2, O, N
n
n
n
n
Ketones (via TMS-enol ethers)
O
O
O
O
O
O
O
O
O
O
O
Me
Me
Ph
Ph
O
O
Ph
OTBS
2
3
4
5
6
7
8
9
10
11
a
b
a
EDD: 62%
Pd1: 52%
Pd2: 6%
Cu: n.d.
EDD: 62%
Pd1: 85%
Pd2: 71%
Cu: n.a.
EDD: 81%
EDD: 67%
Pd1: 87%
Pd2: 63%
Cu: 7%
EDD: 64%, 35%
Pd1: 92%
Pd2: 68%
Cu: n.d.
EDD: 78%
Pd1: n.d.
Pd2: n.a.
Cu: n.a.
IBX: 9%
EDD: 72%
Pd1: 45%
Pd2: 71%
Cu: 52%
EDD: 33%
EDD: 50%
Pd1: n.d.
Pd2: 19%
Cu: 39%
IBX: 30%
EDD: 67%
Pd1: 72%
Pd2: 75%
Cu: 46%
IBX: 31%
Pd1: 46%
Pd2: 75%
Cu: traces
IBX: n.d.
Pd1: 88%
Pd2: 74%
Cu: 13%
IBX: 85%
IBX: 51%
IBX: 70%
IBX: 60%
IBX: 53%
IBX: 19%
O
Me
Me
O
O
O
O
Me
Me
COOMe
O
Me
N
Me
Me
COOMe
1
2
13
14
15
16
17
b
c
b
EDD: 44%, 54%
Pd1: 65%
Pd2: traces
Cu: n.d.
IBX: 83%
EDD: 88%
Pd1: 81%
Pd2: 31%
Cu: n.a.
EDD: 46%
Pd1: 56%
Pd2: n.a.
Cu: n.d.
EDD: 38%
Pd1: 56%
Pd2: n.a.
Cu: n.a.
EDD: 50%
Pd1: 55%
Pd2: 67%
Cu: n.d.
EDD: 27, 24%
Pd1: 51%
Pd2: 94%
Cu: 45%
IBX: 58%
IBX: 34%
IBX: 31%
IBX: 38%
IBX: n.d.
Esters (via diphenylphosphate-ketene acetals)
NC
F
MeO
Br
O
O
O
O
O
O
O
O
O
O
O
O
O
O
18
19
20
21
22
23
24
EDD: 41%
Pd1: n.a.
Pd2: n.a.
Cu: 73%
IBX: n.a.
EDD: 55%
Pd1: n.a.
Pd2: n.a.
Cu: n.a.
EDD: 53%
Pd1: n.a.
Pd2: 47%
Cu: n.a.
EDD: 54%
Pd1: n.a.
Pd2: 31%
Cu: n.a.
EDD: 36%
Pd1: n.a.
Pd2: 39%
Cu: n.a.
EDD: 41%
Pd1: n.a.
Pd2: 13%
Cu: n.a.
EDD: 58%
Pd1: n.a.
Pd2: 15%
Cu: traces
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
O
O
O
O
O
O
O
O
O
Me
O
OBn
O
OMe
OMe
OEt
TsN
C4H9
H
F3C
O
25
26
27
28
29
30
31
EDD: 64%
Pd1: n.a.
Pd2: 44%
Cu: n.a.
EDD: 54%
Pd1: n.a.
Pd2: 81%
Cu: n.d.
EDD: 71%
Pd1: n.a.
Pd2: 72%
Cu: n.d.
EDD: 81%
Pd1: n.a.
Pd2: 44%
Cu: n.d.
EDD: 54%
Pd1: n.a.
Pd2: 62%
Cu: n.d.
EDD: 52%
Pd1: n.a.
Pd2: n.a.
Cu: n.a.
EDD: 34%
Pd1: n.a.
Pd2: n.a.
Cu: 41%
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
IBX: n.a.
Lactams (via diphenylphosphate-keteniminyl acetals) and aldehydes (via TMS-enol ethers)
O
Me
N
O
O
O
O
CHO
CHO
CHO
Ph
O
t
PivO
H
N
Ph
N
O Bu
O
BocN
H
H
3
2
33
34
35
36
37
b
c
d
EDD: 38%
Pd1: 74%
Pd2: n.a.
Cu: n.a.
EDD: 37%
Pd1: 61%
Pd2: n.a.
Cu: n.a.
EDD: 50%
Pd1: 55%
Pd2: n.a.
Cu: n.a.
EDD: 58%
Pd1: n.a.
Pd2: n.a.
Cu: 48%
IBX: n.a.
EDD: 69%
Pd1: n.a.
Pd2: n.a.
Cu: 32%
IBX: n.a.
EDD: 24%
Pd1: n.a.
Pd2: n.a.
Cu: 30%
IBX: n.a.
IBX: 11%
IBX: 7%
IBX: n.d.
aYield based on GCMS. bUsing an in situ protocol. Yield based on NMR conversion. Prepared from phenyl acetate-keteniminyl acetals. Pd1, Saegusa–ꢀto ([Pd] catalyst with oxidant) . Pd2, Newhouse ([Pd]
c
d
9
1
4–16
t
18
12
catalyst with Zn(TMP)
2
or LiTMP) . Cu, Dong ([Cu] catalyst with (O Bu)
2
)
. ꢀBX, Nicolaou (stoichiometric ꢀBX in DMSO) . n.a., not applicable. n.d., not detected.
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EDD
a
NaSbF6 (0.15 M),
OTMS
MeCN/2,4,6-collidine (7:3)
O
Me
O
1
0 mA, rt
Conjugate addition
4
g scale batch, 66%
1
00 g scale flow, 61%
3
8 from
12
Cyclopentadecenone
39
cyclopentadecanone
US$5 g , TCI
(R)-muscone
–
1
+
+
b
e
OTMS
OTMS
OTMS
H
Anode
NaSbF6 (0.15 M),
MeCN/2,4,6-collidine (7:3)
Step 1
OTMS
Step 3
+
OTMS
OTMS
+
OTMS
OTMS
1
0 mA, r.t., 1.5 h
4
5
46
or
47, 49%
OP(O)OEt2
Me
+
+
H
OP(O)OEt2
H
4
2
Me
OP(O)OEt2
Me
40
41
NaSbF6 (0.15 M),
Workup
MeCN/2,4,6-collidine (7:3)
Step 2
1
0 mA, r.t., 1.5 h
O
48
49
0, 5%a
5
+
5.1 ppm
4.6 ppm
Desired product formation Dimer by-product formation
Collidine
[Collidine–H]
f
Low conversion
OP(O)OPh2
Me
1/2 H2
OTMS
OTMS
OTMS
Me
5
Ph
H
H
ca tCh oa dt he ode
Ketones
H
H
c
NaSbF6 (0.15 M),
MeCN/2,4,6-collidine (7:3)
Radical
cation
trap by O2
51 5.4 ppm
52 5.0 ppm 53 4.8 ppm
54 4.5 ppm
OTMS
OTMS
OTMS
+
O
O
1
0 mA, r.t., 1.5 h,
under air
O
5.6
Esters
OP(O)OPh2
H
4.1
4.1
H
H
O
O
7
7
7
7
1
43
2, 65%
44, 9%
5
5
4.7 ppm
56 4.1 ppm
d
Base (x equiv.),
5.6
Base (equiv.)
Yield of 2
OP(O)OPh2
5.0
BocN
OTMS
OTMS
O
OP(O)OPh2
H
NaSbF6 (0.15 M), MeCN
C+/C–, 10mA, r.t., 1.5 h
0
4
n.a.
H
BocN
Ph(O)CN
45%
57%
70%
Lactams
GCMS yields
2
3
2
3
3
7
7
3
1
2
57 5.5 ppm
58 5.1 ppm
59 4.4 ppm
5
.6
5.0
4.1
1
H NMR
(
ppm)
36
Fig. 2 | Scale-up and mechanistic study of EDD reaction. a, Batch (4ꢁg) and flow (100ꢁg) scale-up of a key intermediate in the synthesis of (R)-muscone .
TCꢀ, Tokyo Chemical ꢀndustry. b, Proposed mechanism of the EDD reaction based on observations. ꢀt is postulated that EDD proceeds through three
elementary steps: step 1, formation of the radical cation intermediate through direct anodic oxidation; step 2, deprotonation of the radical cation
intermediate to afford the allylic radical and step 3, a second oxidation to form an oxonium intermediate. c, Experimental evidence for step 1. d, Experimental
1
a
evidence for step 2. e, Experimental evidence for step 3. f, Prediction of reactivity based on H NMR chemical shift. Yield based on liquid chromatography
mass spectrometry (LCMS) conversion. r.t., room temperature. GCMS, gas chromatography mass spectrometry conversion.
clock. A similar conclusion was made by Moeller and co-workers EDD reaction conditions were applied to compound 1 with vari-
37
when they oxidized various alkyl-enol ethers and thio-enol ethers . ous amounts of 2,4,6-collidine (Fig. 2d). No desired product was
It is therefore postulated that EDD proceeds through three elemen- obtained when the base was excluded, which reinforces the impor-
tary steps: (1) the formation of the radical cation intermediate 40, tance of the base for the EDD reaction and its implication in the
(
2) deprotonation to afford 41 and (3) a second oxidation to form deprotonation step 2 (Fig. 2b). Furthermore, a noticeable improve-
oxonium 42, which affords the desired enone product 5 (Fig. 2b). ment was observed between the reaction efficiency and base con-
To provide empirical support for the proposed mechanism, three centration. Finally, a third experiment was conducted to explore the
control experiments were designed and tested (Fig. 2c–e). First, the formation of an oxonium intermediate (Fig. 2e). Compound 45 was
standard reaction conditions under air revealed the formation of subjected to the reaction conditions and afforded naphthalene 47
the 1,2-diketone side product 44 in 9% yield. The amount of this in a 49% yield. The formation of this product is in accordance with
by-product decreased to 4% when the reaction was performed the formation of intermediate 46, which, after elimination, would
under an inert atmosphere. In addition, the parent ketone was deliver 47. Similarly, when the diethylphosphate 48 derived from
the only product observed when water was added to the reaction. dehydroepiandrosterone was subjected to EDD, diene 50 was also
These results suggest that the formation of compound 44 derived observed as a side-product.
from molecular oxygen via a radical-type mechanism. Next, to
support the crucial role of the base in the deprotonation event, the lactam and lactone substrates with vinylic proton shifts that
During these studies it was empirically noted that the ketone,
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Step 1
Step 2
Step 3
Step 4
5.1 ppm
4.6 ppm
OTMS
7
6
5
4
3
2
1
0
Linear fit (0.991x + 0.036)
O
R
2
= 0.990
TMSO
TMSO
Ph
O
r.m.s.e. = 0.117
O
Ph
O
3
from 60,
19 from 61,
outcome: bad (n/a)
6
0
61
outcome: good (62%)
Example of a docked structure
Calculated
Me
Me
Me
Me
Me
Compound
1
Me
H NMR shift
0
1
2
3
4
5
6
7
Me
Me
O
Me
Me
Experimental chemical shift [ppm]
6
0
4.99 ppm
4.02 ppm
4.50 ppm
Me
COOMe
Me
61
62
Corrected 1H NMR shift (ppm)
COOMe
Me
Me
62
6
0, 4.91
61, 4.12
62, 4.63
17 from 62, outcome: moderate (27% )
Fig. 3 | Gaussian computational experiment to assess the feasibility of the EDD reaction; case study of TꢃS- enolates. A simple four-step protocol
using GAUSSꢀAN16 is described to predict the efficiency of the EDD reaction. Step 1, prepare a list of TMS enol ether substrates of interest. Step 2, use
1
the Gaussian software GꢀAO/WP04/aug-cc-pVDZ//B3LYP/6-31ꢁ+ꢁG(d,p) functional to calculate the H NMR chemical shift of the desired enol ether.
1
Step 3, use the experimentally generated linear regression to correct the calculated H NMR shift of the enol ether. Step 4, predict the outcome of the EDD
reaction. r.m.s.e., root mean square error.
registered between 4.6 and 5.1 ppm showed a good conversion to downstream transformations. Studies in this area continue to the
the desaturated product. However, compounds with NMR shifts present day; the contribution reported here affords a potentially
lower than 4.6 ppm led to the formation of the dimer, hydroly- simple solution to this problem. Drawing from early studies in
sis and other by-products. Compounds with NMR shifts higher electrosynthesis and more recent mechanistic studies of anodic
than 5.1 ppm showed a low reactivity toward oxidation. Based on enol-oxidation, a useful protocol for EDD was uncovered. This
3
7
these findings and Moeller’s reports , it is possible to identify a oxidation protocol can be performed in an undivided cell, on
trend between the oxidation potential of the enol ether (to form multiple scales, without the strict removal of air or water and in
a radical cation intermediate similar to 40) and the electron den- the absence of expensive metals, ligands or stoichiometric organic
sity of the π-system (Fig. 2f and see Supplementary Fig. 10 for oxidants. As with the oxidation of alcohols, for which numerous
details). Compounds such as dehydroepiandrosterone-phosphate methods are available, here this desaturation study is placed into
5
1 and the eight-membered lactam 57 cannot be oxidized context with the most powerful methods currently available to aid
1
under the EDD reaction conditions due to the deshielded the practitioner. Finally, a simple H NMR-based rubric was cre-
vinylic proton, which correlates to a higher oxidation poten- ated to allow users to experimentally or computationally predict
tial (cyclic voltammetry (CV) =2.06–2.47 V). When the vinylic which substrates are suitable for EDD, which should facilitate its
proton was shielded, the oxidation potential became lower rapid adoption.
and reactivity towards EDD was observed (CV =1.54–1.72 V).
However, compounds such as dehydroepiandrosterone-TMS Online content
5
4, lactone-TMS 56 and lactam-TMS 59, whose vinylic pro- Any additional references, Nature Research reporting summaries,
tons are also shielded, afforded low amounts of the desaturated source data, extended data, supplementary information, acknowl-
product (CV =1.32–1.4 V). In this case, the enol derivatives edgements, peer review information; details of author contributions
reacted as nucleophilic radicals rather than as electrophilic radical and competing interests; and statements of data and code availabil-
cations due to the greater cationic stabilization, which renders the ity are available at https://doi.org/10.1038/s41557-021-00640-2.
3
8,39
EDD pathway less favourable . Accordingly, this explains why
electron-withdrawing enol-phosphates are required for esters and Received: 15 June 2020; Accepted: 15 January 2021;
lactams in EDD rather than the corresponding silyl enol ethers.
Based on these observations, one can imagine predicting the
outcome of the EDD reaction by calculating the NMR shift of
the TMS enol ethers of interest (Fig. 3, step 1). With this idea in
mind, a simple protocol using GAUSSIAN16, a quantum chemi-
cal calculation software, was developed. This protocol gave access
to a calculated NMR shift based on the shielding constants using
the gauge-including atomic orbital method in the WP04 data-
base (functional) with an aug-cc-pVDZ basis set using tetra-
Published online: 23 March 2021
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Z.Y. and J.L. designed the flow apparatus and ran the reaction on a 100g scale in flow.
P.-G.E. and D.D. aided in the substrate preparation, control studies and mechanistic
analysis. P.S.B., J.C.V. and S.G. prepared the manuscript.
Data availability
The data supporting the findings of this study are available within the article and its
Supplementary Information.
Competing interests
ꢁ
cknowledgements
The authors declare no competing interests.
Financial support for this work was provided by the NIH (Grant GM-118176), the NSF
no. 1740656) and AGC Inc. (to Y.T.). S.G. thanks the Council for Higher Education,
(
Fulbright Israel and Yad Hanadiv for the generous fellowships. Authors are grateful
to D.-H. Huang and L. Pasternack (Scripps Research) for assistance with the NMR
spectroscopy, to J. Chen, B. Sanchez and E. Sturgell (Scripps Automated Synthesis
Facility) for assistance with HPLC, high-resolution mass spectroscopy and LCMS.
ꢁ
dditional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41557-021-00640-2.
Correspondence and requests for materials should be addressed to P.S.B.
Peer review information Nature Chemistry thanks the anonymous reviewers for their
ꢁ
uthor contributions
contribution to the peer review of this work.
S.G., Y.T. and H.R.W. performed and analysed the experiments. P.S.B., S.G. Y.T. and
J.C.V. designed the experiments. S.G. and H.R.W. performed the computational analysis.
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