Light-Driven Intermolecular Charge Transfer Induced Reactivity of Ethynylbenziodoxol(on)e and Phenols

Article abstract of DOI:10.1021/jacs.8b05870

Ethynylbenziodoxol(on)es (EBXs) have been widely used in organic synthesis as electrophilic alkyne-transfer reagents involving carbon- and heteroatom-based nucleophiles. However, potential reactions of EBXs with phenols remain uninvestigated. Here, we present the formation of (Z)-2-iodovinyl phenyl ethers with excellent regio- and stereoselectivity through the reactivity between EBXs and phenols driven by visible light. We propose that this light-activated transformation proceeds through electron donor-acceptor complexes to enable new reactivity beyond existing mechanisms for alkynylation of carbon- and heteroatom-based nucleophiles. This operationally robust process was employed for the synthesis of diverse (Z)-2-iodovinyl phenyl ethers through irradiating a solution containing a phenyl-EBX, a phenol, and the base Cs₂CO₃ with a commercially available blue LED at room temperature. The (Z)-2-iodovinyl phenyl ether products can be further stereospecifically functionalized to form trisubstituted alkenes, demonstrating the potential of these products en route to chemical complexity.

Full text of DOI:10.1021/jacs.8b05870

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Article
Light driven intermolecular charge transfer induced
reactivity of ethynylbenziodoxol(on)e (EBX) and phenols
Bin Liu, Chern-Hooi Lim, and Garret M. Miyake
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2018
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Light-Driven Intermolecular Charge Transfer Induced Reactivity of
Ethynylbenziodoxol(on)e (EBX) and Phenols
Bin Liu,† Chern-Hooi Lim† & Garret M. Miyake*,†
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Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
ABSTRACT: Ethynylbenziodoxol(on)es (EBXs) have been widely used in organic synthesis as electrophilic alkyne-transfer reagents
involving carbon- and heteroatom-based nucleophiles. However, potential reactions of EBXs with phenols remain uninvestigated.
Here, we present the formation of (Z)-2-iodovinyl phenyl ethers with excellent regio- and stereoselectivity through the reactivity
between EBXs and phenols driven by visible light. We propose that this light-activated transformation proceeds through electron
donor-acceptor complexes to enable new reactivity beyond existing mechanisms for alkynylation of carbon- and heteroatom-based
nucleophiles. This operationally robust process was employed for the synthesis of diverse (Z)-2-iodovinyl phenyl ethers through
irradiating a solution containing a phenyl-EBX, a phenol, and the base Cs2CO3 with a commercially available blue LED at room
temperature. The (Z)-2-iodovinyl phenyl ether products can be further stereospecifically functionalized to form tri-substituted alkenes,
demonstrating the potential of these products en route to chemical complexity.
INTRODUCTION
Ethynylbenziodoxol(on)es (EBXs)1-6 are electrophilic rea-
gents which can be used for the alkynylation of carbon- and het-
eroatom-based nucleophiles.7-19 Specifically, alkynylation of
carbon,7-11,14-17 sulfur,12,13 nitrogen18 and phosphorus19 nucleo-
philes has been successfully developed (Figure 1a). In the pro-
cess, an alkynyl group is transferred to the nucleophile and 2-
iodobenzoic acid is commonly obtained as a stoichiometric by-
product. Other reactions involving EBX reagents such as cop-
per-catalyzed oxyalkynylation of diazo compounds20,21 (Figure
1d) and Pd(II)-catalyzed transformation of alkynylbenziodox-
oles with N‑aryl imines and carboxylic acids have also been re-
ported (Figure 1b-c).22-24 Although reactions of carbon- and het-
eroatom-based nucleophiles with EBX electrophiles have been
extensively investigated, there remains unexplored chemistry
using phenols as nucleophiles. From a synthetic standpoint, the
development of strategies using EBXs and phenols is highly de-
sirable.
Phenol-containing compounds are frequently found in plant
secondary metabolites. Notable examples include vanillin, thy-
mol and eugenol, which have been traditionally utilized as im-
portant food additives for color, flavor, and astringency.25,26 Ad-
ditionally, they are prevalent in a wide range of bioactive natu-
ral products such as, steroid hormones, thyroid hormones and
monoamine neurotransmitters, such as estrone, estradiol, es-
triol,27 triiodothyronine28 and serotonin.29 Phenol motifs are also
important in medicines. Isoproterenol is used for the treatment
of heart block and levalbuterol is used for the treatment of
Figure 1. Development of reactions using ethynylbenzio-
doxol(on)e (EBX) reagents. a) Alkynylation of carbon- and het-
eroatom-based nucleophiles with EBX reagents. b) Palladium-cat-
alyzed reaction of N‑aryl Imines and EBX reagents to make multi-
substituted furans. c) upper: Palladium-catalyzed reaction of EBX
reagents and carboxylic acids; lower: Palladium-catalyzed three-
component reaction of EBX reagents, carboxylic acids, and imines.
d) Copper-catalyzed oxyalkynylation of diazo compounds using
EBX reagents. e) This work: reactions of EBX reagents and phe-
nols under visible light irradiation. Nu: nucleophile.
asthma.30 Industrially, phenol containing compounds are also
one of the most versatile and important organic commodity
chemicals.25 Therefore, direct transformation involving conver-
sion of phenols into a variety of products with a wide range of
properties are highly desirable.
Recently, we reported a visible light promoted C-S cross-cou-
pling reaction of thiophenols and aryl halides in the presence of
a mild base, Cs2CO3.31 The observed reactivity was enabled
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through visible light-induced electron transfer within the elec-
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as halogens (3e-l, 3w, 3x), aldehyde (3q), ester (3r, 3v) and tri-
fluoromethyl (3s) groups. A phenol bearing a boronic acid pi-
nacol ester group also afforded the corresponding 2-iodovinyl
phenyl ether derivative 3a, albeit in modest yield (45%). When
an allylic-containing substrate was employed, TBD was ob-
served to be the best base for this transformation and provided
the corresponding 2-iodovinyl phenyl ether derivative 3ag (SI,
page S8) in 52% yield. Notably, a protected amino acid could
also be transformed to the desired product 3ah (SI, page S8)in
40% yield using TBD as a base, demonstrating the high func-
tional group tolerance of the transformation. Additionally, hy-
droxyl-heteroaryls, ubiquitous among biologically active mole-
cules and pharmaceutical products, similarly reacted to provide
the desired products 3ab, 3ad, 3ae and 3af in 61, 70, 52 and
40% yields, respectively. The 2-iodovinyl phenyl ether prod-
ucts obtained were assigned as (Z)-isomer, as supported from
X-ray diffraction analysis of 3aa (Scheme 1). Density func-
tional theory (DFT) calculations corroborated that the (Z)-iso-
mer of 3b is 3.4 kcal/mol more stable than the corresponding
(E)-isomer. Different alcohols were also explored. With
CF3CH2OH, we were able to obtain the desired product at 31%
yield, albeit with a mixture of Z and E isomers, while no desired
products were isolated with other alcohols, such as 1,1,1,3,3,3-
Hexafluoro-2-propanol, benzyl alcohol and ethanol (Table S3).
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tron donor-acceptor (EDA) complex; e.g. an electron is trans-
ferred from the thiophenoxide (donor) to the aryl halide (accep-
tor). Inspired by this work, we hypothesized that in the presence
of a suitable acceptor, phenol could also be employed as an
electron donor in light-driven transformations utilizing EDA
complexes.32
Herein, we report the formation of EDA complexes33-35 be-
tween nucleophilic phenols and electrophilic EBX reagents.
UtilizingCs2CO3 as a base and under blue LED irradiation, phe-
nols and EBX reagents react to form (Z)-2-iodovinyl phenyl
ethers with excellent regio- and stereoselectivity (Figure 1e). To
the best of our knowledge, this represents the first example of
reactivity between EBX reagents and phenols that exploits vis-
ible light irradiation at room temperature. Notably, in forming
the (Z)-2-iodovinyl phenyl ether products, we discovered an un-
precedented cleavage of the phenyl-I bond of EBX reagents to
yield vinyl halide products. Vinyl halides are important inter-
mediates in organic synthesis and we demonstrate these (Z)-2-
iodovinyl phenyl ethers as versatile synthetic precursors to un-
dergo a range of transition metal-catalyzed cross-coupling reac-
tions, such as Buchwald–Hartwig,36 Ullmann37 and Suzuki38 re-
actions, to generate functionally diverse tri-substituted alkenes.
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RESULTS AND DISCUSSION
Table 1. Initial investigation of the synthesis of (Z)-2-iodo-
vinyl phenyl ether.
We commenced our studies by evaluating 4-methoxyphenol
1b and phenyl-EBX 2a in similar reaction conditions to those
developed for our C-S cross-coupling reaction (Table 1).31 Grat-
ifyingly, reactivity between 1b and 2a was observed after 14 h
of blue LED irradiation at room temperature (Table 1, entry 1)
and the (Z)-2-iodovinyl phenyl ether product 3b was isolated in
46% yield. Compared to the typical alkynylation products and
2-iodobenzoic acid byproduct (Figure 1a) obtained in previous
EBX reactions,7-19 we observed a unique phenyl-I bond cleav-
age to synthesize 3b with benzoic acid or 14 as byproducts; this
new reactivity is attributed to the photoinduced electron transfer
in the EDA complex. Subsequent optimization experiments led
to selection of acetonitrile as the solvent (Table 1, entry 1-4), a
loading of 1b is 1.5 equiv (entry 4-7), and a duration of 14 h
irradiation to achieve good yield (entry 4, 8-9). Among multiple
bases investigated (entry 4, 11-14), the use of 1,5,7-triazabicy-
clo[4.4.0]dec-5-ene (TBD) resulted in the highest yield (78%)
while only trace product was detected in the absence of base
(Table S2). Interestingly, 3b was also formed in the absence of
light when the strong organic base TBD was used, albeit at
lower yield (58%, Table S2). Cs2CO3, which is less expensive
than TBD, is also an excellent base for this transformation
(74%, Table 1, entry 4) and was therefore used throughout the
remainder of this study. Using the inorganic Cs2CO3 base, light
irradiation is mandatory for reactivity (Table S2) while the pres-
ence of oxygen significantly reduces product formation (Table
1, entry 10).
Entry
1
t (h)
14
14
14
14
14
14
14
2
Eq (1b)
1.5
1.5
1.5
1.5
1.0
2.0
3.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Solvent
DMSO
DMAc
DMF
Base
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
Yield (%)
47 (46†)
44
2
3
47
4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
THF
75 (74a)
5
46
6
61
7
51
8
35
9
4
48
10
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12
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14
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14
14
14
14
14
14
14
14
24b
20
MTBD
TBD
40
79 (78a)
Trace
53
TMG
TBD
TBD
37
THF
TMG
20
Reaction conditions: 1b (0.30 mmol), 2a (0.20 mmol), base (0.30
Using the optimized reaction conditions, a variety of phenols
were transformed into the corresponding 2-iodovinyl phenyl
ethers in moderate to good yields with high regio- and stereose-
lectivities (Scheme 1). Overall, no significant electronic effects
of the phenol on the reaction was observed. Explicitly, the re-
action tolerated both electron-donating and electron-withdraw-
ing substituents on the phenol, including amine (3o, 3p, 3v,),
methoxy (3b, 3c, 3x, 3y) and trimethylsilyl (3d) groups as well
mmol), solvent (1.5 ml), room temperature, N2. Yields are deter-
1
mined by H NMR using 1,3,5-trimethoxybenzene as an internal
a
b
standard. Isolated yield. Reaction carried out under air. t: time;
Eq: equivalent; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;
MTBD: 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; TBD:
1,5,7-triazabicyclo[4.4.0]dec-5-ene; TMG: 1,1,3,3-tetramethyl-
guanidine; DMAc: N,N’-dimethylacetamide; DMF: N,N’-dime-
thylformamide; DMSO: dimethyl sulfoxide; THF: tetrahydrofuran.
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Scheme 1. Scope of phenols.
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Reaction conditions: 1 (0.30 mmol), 2 (0.20 mmol), base (0.30 mmol), solvent (1.5 ml), room temperature, N2. Isolated yield reported. TBD:
a
b
1,5,7-triazabicyclo[4.4.0]dec-5-ene; BPin: 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane. TBD used as a base. performed in the dark and ob-
tained as 1H NMR yield. cVCH3CN:VBenzene = 1:1, see Table S1.
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Scheme 2. Scope of ethynylbenziodoxol(on)es.
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Reaction conditions: 1 (0.30 mmol), 2 (0.20 mmol), base (0.30 mmol), solvent (1.5 ml), room temperature, N2. Isolated yield reported.
aVCH3CN:VBenzene = 1:1, see Table S1.
The substrate scope of EBXs was also explored (Scheme 2).
A broad range of functional groups on EBXs, including nitro
(4a), ester (4b), cyano (4c), trifluoromethyl (4d, 4h, 4k), methyl
(4e, 4i, 4n), halogens (4f, 4g, 4j, 4o-q) and methoxy (4r-t)
groups, was well tolerated in this process, affording the corre-
sponding (Z)-2-iodovinyl phenyl ether products in moderate to
good yields. EBX reagents bearing an alkyl group could also be
implemented (4u). No desired product, however, could be ob-
tained with triisopropylsilyl-EBXs (see Supplementary Infor-
mation (SI, page S7)). Markedly, phenyl-EBXs derived from
other substituted 2-iodobenzoic acids (e.g. 2-Fluoro-6-iodo and
2-iodo-5-nitrobenzoic acid, see SI) similarly reacted with 1b to
produce the same product 3b in 87% and 42% yields, respec-
tively. This protocol was also applicable to bistrifluoromethyl-
substituted benziodoxole (see SI, page S7), which reacted with
1b to provide 3b in 52% yield. We note that the use of mixed
solvent (VCH3CN:VBenzene = 1:1) in a number of cases has im-
proved the product yield (see Scheme 1 and 2).
To demonstrate potential synthetic value of the (Z)-2-iodovi-
nyl phenyl ether products, we investigated their chemistry for
subsequent transformations (Figure 2). The vinyl ether 3r effi-
ciently engaged in a series of stereospecific palladium-cata-
lyzed cross-coupling reactions, including Suzuki couplings (5,
7), a Sonogashira reaction (6), an Ullmann reaction (8), and a
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Figure 2. Transition metal-catalyzed transformations of (Z)-2-iodovinyl phenyl ethers. a) Suzuki coupling; b) Sogonashira coupling; c)
Suzuki coupling; d) Ullmann coupling; e) Carbonylation; f) C-H activation; g) Buchwald-Hartwig coupling. PPh3: Triphenylphosphine;
TMHD: 2,2,6,6-Tetramethyl-3,5-heptanedione; dppf: 1,1′-Ferrocenediyl-bis(diphenylphosphine); Xantphos: 4,5-Bis(diphenylphosphino)-
9,9-dimethylxanthene
Buchwald−Hartwig amidation (11). Furthermore, Pd-catalyzed
methoxycarbonylation of 3r generated 9 in 92% yield. Notably,
Pd-catalyzed intramolecular C-H activation furnished
benzo[b]furan 10 in 83% yield. Using nuclear Overhauser ef-
fect spectroscopy (NOESY), we found that compounds 3r, 5, 6,
8, and 9 are (Z)-isomers and that 5, 6, 8, and 9 retained their (Z)-
conformations after metal-catalyzed transformations. On the
contrary, the amidation product of 11 was determined to be an
(E)-isomer (see SI, page S163). Overall, these results demon-
strate the potential of this reaction to provide a unified approach
for the preparation of tri-substituted alkenes from readily avail-
able phenols and EBX reagents.
To further investigate the EDA complex, we analyzed a Job
plot to characterize the complexion between 12b and sodium
phenoxide (Figures S8 and S9). Sodium phenoxide was used as
the donor instead of (phenol + Cs2CO3) because the phenol is
not completely deprotonated by Cs2CO3 and thus the concentra-
tion of the donor is unknown. Using UV-vis spectroscopy, we
monitored the absorbance values at 400 nm (corresponding to
the λmax of the absorption of the EDA complex) and plotted
them as a function of molar fraction of sodium phenoxide. We
obtained a parabolic curve with a maximum absorbance value
at 50% mole fraction of sodium phenoxide, indicating a 1:1
EDA complex between 12b and sodium phenoxide. Further-
more, setting [12b] at a constant value of 0.005M, we measured
the absorbance values at 400 nm as we varied [sodium phenox-
ide] from 0.005 to 0.045M. Using the Benesi–Hildebrand
method,39-40 we plotted 1/absorbance versus 1/[sodium phenox-
ide] and obtained a liner relationship (Figures S10 and S11).
Through linear regression, the y-intercept and slope values al-
lowed for estimation of the association constant of the EDA
complex (KEDA) as 38.9 in DMSO.
A series of experiments and computations were performed to
gain insight into this reactivity between EBXs and phenols (Fig-
ure 3). In the absence of light, we observed that phenol nucleo-
philically adds across the triple bond of EBX 2a to form a vi-
nylbenziodoxolone intermediate (12), which is isolatable (Fig-
ure 3a). This nucleophilic addition step was computed to be ex-
ergonic by 28.3 kcal/mol. We then subjected 12 to our standard
reaction condition. Upon combining vinylbenziodoxolone (12),
1b and Cs2CO3 in MeCN, the solution gradually turned yellow,
distinctly different from the colorless parent compounds (Fig-
ure S7). In accord to the C-S coupling we examined previ-
ously,31 this significant red-shift in the UV-vis absorption sug-
gests the formation of an EDA charge transfer complex. TD-
DFT calculations are consistent with the EDA hypothesis as the
lowest excitation of the vinylbenziodoxolone 12-phenoxide
complex has extensive charge transfer character (Figure 3a, in-
set). Specifically, 75% and 14% of the lowest energy excitation
is composed of πHOMO-πLUMO and πHOMO- πLUMO+1 transitions, re-
spectively, where the πHOMO stems from phenoxide (donor)
while the πLUMO and πLUMO+1 are derived from vinylbenziodox-
olone 12 (acceptor).
Upon blue LED irradiation of the yellow solution (containing
vinylbenziodoxolone (12), phenol 1b and Cs2CO3), we obtained
the desired product 3b, whereas only trace amount of product
was obtained in the absence of light (Scheme S3). Thus, this
observation supports the role of light in phenyl-I bond cleavage
to yield product 3b. We suggest that in the EDA complex, pho-
toinduced electron transfer occurs from the phenoxide (donor)
to the vinylbenziodoxolone 12 (acceptor). DFT calculations
support that the 1 electron reduction of vinylbenziodoxolone 12
leads to spontaneous phenyl-I bond cleavage to generate 3b and
radical intermediates 13 (Figure 3a); in support of the formation
of 13a, a small amount of benzoic acid could be isolated (see
SI). The radical intermediate 13 can then quench to form a C-C
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Figure 3. Mechanistic studies. a) Proposed mechanism for the reactivity between EBXs and phenols under the influence of visible light.
Thermochemistry evaluation was conducted at the M06/Lanl2dz level of theory with CPCM-described solvation in acetonitrile; CPCM:
conductor-like polarizable continuum model. Time-dependent density functional theory (TD-DFT) calculations to model the lowest excited
states of the EDA complex were conducted at the CAM-B3LYP/Lanl2dz/CPCM-MeCN level of theory. HOMO: highest occupied molecular
orbital; LUMO: lowest unoccupied molecular orbital; f: predicted oscillator strength. λcalc: predicted maximum wavelength of absorption of
the lowest excited state. b) 13C-labelling experiment. c) Experiment involving deuterated phenol. d) Experiment involving vinylbenziodox-
oione and sodium phenoxide. e) Light-driven reaction between EBX 2a, diboronate ester and pyridine to yield (iodoethynyl)benzene.
bond, which upon rearrangement and elimination of water, fi-
nally yields the 6H-benzo[c]chromen-6-one byproduct 14. The
free energy change for this step was computed to be -79.7
kcal/mol and the byproduct 14 was successfully isolated (20%
yield, see SI). To further investigate the observed phenyl-I bond
cleavage, we utilized an organic phenoxazine-based photoredox
catalyst,41-44 developed by our group as a strong excited state
reductant, to directly reduce vinylbenziodoxolone 12 under blue
LED irradiation. Consistent with our proposed mechanism, 3b
was isolated in 47% yield (Scheme S3), which supports our
proposition that the phenyl-I bond can be reductively cleaved.
(Scheme 1 and 2). Thus, we hypothesize that the formation of
byproduct 14 only contributes in part to 3b’s formation, as evi-
dent from isolation of 14 in 20% yield. It is also interesting to
note that when TBD was added to a solution containing vi-
nylbenziodoxolone and phenol 1b, a more intense yellow solu-
tion was observed (as compared to the addition of Cs2CO3).
However, in this instance, no light was needed to promote the
formation of 3b (Scheme S3) in good yield. Thus, with TBD,
we propose that thermally activated electron transfer results in
the phenyl-I bond cleavage.45
In addition, we examined reactions using 13C-labeled EBX 2a*
The formation of byproduct 14 may suggest that at least 2.0
equiv of 1b are needed for reaction completion; however, we
empirically determined that 1.5 equiv loading of 1b was opti-
mum, as higher or lower loadings led to decreased yields (Table
1, entries 5, 6 and 7). Also, at 1.5 equiv. loading, in many cases
we obtained yield greater than the theoretical limit of 75%
and phenol-OD. As shown in Figure 3b, the reaction of phenol
1b and 13C-labeled EBX 2a* afforded 3b-13C, where 1H and 13
C
NMR spectrums confirmed the bonding of the phenoxy group
to the 13C atom and showed a vinylic hydrogen signal with a
JC−H coupling constant of 10 Hz (see SI). Furthermore, the re-
action of deuterated phenol(-OD) with EBX 2a afforded 3aj
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(Figure 3c) where the vinylic hydrogen contains about 62%
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ASSOCIATED CONTENT
Supporting Information. General Information; Reaction Devel-
opment and Optimization; X-ray crystallographic coordinates for
structures of 3ab; UV-Visible Spectroscopy; Computational De-
tails; Characterizations; NMR Spectrums.
The Supporting Information is available free of charge on the ACS
Publications website.
AUTHOR INFORMATION
Corresponding Author
Garret M. Miyake
*garret.miyake@colostate.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by Colorado State University and the Ad-
vanced Research Projects Agency-Energy (DE-AR0000683). Re-
search reported in this publication was supported by the National
Institute of General Medical Sciences of the National Institutes of
Health under Award Number R35GM119702. The content is solely
the responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health. C.-H.L is
grateful for an NIH F32 Postdoctoral Fellowship (F32GM122392).
We thank Brian Newell for acquiring and solving the crystallo-
graphic structure of compound 3ab. We acknowledge the use of
computational resources provided by the XSEDE - Comet super-
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