Visible-Light-Promoted Vinylation of Tetrahydrofuran with Alkynes through Direct C-H Bond Functionalization

Article abstract of DOI:10.1021/acs.orglett.5b01053

(Chemical Equation Presented) Mild and direct C-H bond functionalizations and vinylations of tetrahydrofuran with alkynes have been accomplished through visible light photocatalysis, yielding a range of vinyl tetrahydrofurans under the synergistic actions of organic dye-type photocatalyst eosin Y, tert-butyl hydroperoxide (t-BuOOH), and a 45 W household lightbulb. A significant kinetic isotope effect (KIE) was recorded, which helps shed light on the mechanistic course.

Full text of DOI:10.1021/acs.orglett.5b01053

Letter
pubs.acs.org/OrgLett
Visible-Light-Promoted Vinylation of Tetrahydrofuran with Alkynes
through Direct C−H Bond Functionalization
Jing Li, Jing Zhang, Haibo Tan, and David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: Mild and direct C−H bond functionalizations and vinylations of tetrahydrofuran with alkynes have been
accomplished through visible light photocatalysis, yielding a range of vinyl tetrahydrofurans under the synergistic actions of
organic dye-type photocatalyst eosin Y, tert-butyl hydroperoxide (t-BuOOH), and a 45 W household lightbulb. A significant
kinetic isotope effect (KIE) was recorded, which helps shed light on the mechanistic course.
irect functionalization of the inert sp3 C−H bond has
Dbecome an increasingly significant subject in modern
synthetic organic chemistry.1 Progress in this field, when coupled
with reaction economics, operational simplicity, and environ-
mental friendliness, demands further achievements in uncover-
ing new protocols that can function under truly mild conditions.
In recent years, the practices in visible light photocatalysis2 have
actively responded to this critical challenge due to abundant solar
energy, convenient reaction devices, and novel mechanistic
paradigms.3 Not surprisingly, as most organic compounds
cannot directly absorb visible light, the design and implementa-
tion of such processes must therefore require the participation of
an appropriate photocatalyst. Within this context, organic dye-
type photocatalysts, for example, commercially readily available
eosin Y, seem to represent likely superior alternatives to their
transition-metal-derived counterparts, such as ruthenium− and
iridium−pyridyl complexes, in terms of the criteria mentioned
above. These dye photosensitizers therefore attracted our
particular attention.4
In this paper, we report the preparation of a range of vinyl
tetrahydrofurans that serve as recurring structural motifs found in
various biological, pharmaceutical, and natural products.5
Although these structures have been accessed with known
literature disclosures, notably UV light6−11 or metal-medi-
ated12−16 unifications of alkenes or alkynes with tetrahydrofuran
under medium-to-high reaction temperatures or microwave
stimulations, a merge of radical chemistry with organic dye
substance sensitized visible light photocatalysis as uncovered
herein clearly emerged as the arguably simplest alternative.
Our design concept, as shown in Scheme 1, envisioned that a
hydrogen abstraction event might be initiated on tetrahydrofuran
via synergistic interactions of visible light stimulation, organic
dye sensitization, and external oxidation, thereby yielding a
relatively long-lived α-oxy radical species.17 Subsequent radical
addition to an alkyne partner would accomplish formal C−H to
Scheme 1. Visible-Light-Promoted C−H Functionalization
Strategy to Vinyl Tetrahydrofurans
C−C bond conversion and furnish vinyl-functionalized tetrahy-
drofurans. Within this design scenario the choice of an external
oxidant is pivotal since it ideally could function not only as a
hydrogen acceptor but also as a radical precursor. Alkyl
hydroperoxide substances seem to be viable candidates fitting
with this purpose, a representative structure being t-BuOOH.
The challenge in experimental realization of this proposal clearly
lies in identifying reaction conditions that are conducive for
simultaneously supporting operations of all of the above-
mentioned events.
With 1-chloro-4-ethynylbenzene (1) as the model substrate
and a 45 W household bulb as the visible light source, we initially
discovered that the desired vinyl tetrahydrofuran 2 was produced
in 36% yield with an E/Z ratio of 1:1 (entry 1, Table 1) in a mixed
solvent of MeCN and tetrahydrofuran (1:1 volume ratio with
concentration c = 0.05 M) at room temperature with organic dye
eosin Y (0.05 equiv) and t-BuOOH (4.00 equiv, 5.5 M in decane)
under an argon balloon atmosphere for 36 h. When a basic
Cs2CO3 (entry 2), Lewis acidic Mg(ClO4)2 (entry 3), or a
relatively neutral salt HCOONH4 (entry 4) was employed as the
additive, the reaction was found to be completely inhibited. The
yield of 2 was improved to 52% when the protic acid HCOOH
was added into the reaction (entry 5). As a comparison,
CH3COOH was shown to be much less effective (24% yield,
Received: April 12, 2015
© XXXX American Chemical Society
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Table 1. Identification of the Optimal Reaction Conditions
c
d
e
entry
catalyst (0.05 equiv)
additives (2.00 equiv)
solvents (v/v = 1:1)
oxidant (4.00 equiv)
yield (%)
1
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
Ru(bpy)3Cl2
Ir(ppy)3
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
DMF/THF
NMP/THF
toluene/THF
CH2Cl2/THF
Et2O/THF
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
(t-BuO)2
H2O2
36
trace
11
trace
52
24
45
86
7
2
Cs2CO3
3
MgClO4
4
NH4COOH
5
HCOOH
6
CH3COOH
7
4 Å MS
8
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
4 Å MS + HCOOH
9
10
11
12
13
14
15
16
17
18
19
10
32
43
46
49
73
9
DCE/THF
MeOH/THF
THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
34
12
trace
trace
0
Bz2O2
a
20
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
21
22
23
21
0
b
24
eosin Y
0
25
eosin Y
0
a
b
c
d
e
t-BuOOH 70% in water. No light. 4 Å MS loading is 2 wt %. t-BuOOH 5.5 M in decane. 1H NMR yield of E/Z isomers.
entry 6). Interestingly, the addition of 4 Å molecular sieves was
found to be advantageous to the reaction (45% yield, entry 7).
When a combination of HCOOH and 4 Å molecular sieves was
employed, a respectable 86% yield of 2 was recorded (entry 8).
Furthermore, the solvent effect was shown to be fairly significant
during this transformation. When dimethylformamide (DMF),
N-methylpyrrolidone (NMP), toluene, CH2Cl2, Et2O, or 1,2-
dichloroethane (DCE) was used in place of MeCN in the mixed
solvent under otherwise comparable conditions, the product was
furnished in lower yields under otherwise identical reaction
conditions (7−49% in entries 9−14). The yield of 2 was 73%
when MeOH was mixed with THF as the solvent (entry 15) and
was merely 9% when THF was used alone (entry 16). The choice
of an oxidant was also confirmed to be critical, as the use of (t-
BuO)2, H2O2, Bz2O2, or even aqueous t-BuOOH (in 70% water)
led to significant reductions or complete inhibitions in
reactivities (entries 17−20). Furthermore, attempts using
Ru(bpy)3Cl2 or Ir(ppy)3 as an alternative photocatalyst were
again found to be detrimental, leading to either no product or
merely 21% yield, respectively (entries 21 and 22). Finally,
control experiments conducted under the absence of either a
photocatalyst, visible light, or oxidant (entries 23−25)
unambiguously pointed to complete inhibition of the reactivity.
Collectively, these screening results established the optimal
reaction conditions to be the following: 0.05 equiv of eosin Y, 2
wt % of activated powdered 4 Å molecular sieves, 4.00 equiv of t-
BuOOH, and 2.00 equiv of HCOOH in a 1:1 mixed solvent of
MeCN and THF under a balloon-argon atmosphere at room
temperature. Although we began the explorations with a
somewhat defined mechanistic plan, it should be acknowledged
herein that it was only through extensive synergies between
conceptual design and experimental serendipity that we
eventually arrived at the identified protocol.
A series of structurally variable aromatic terminal alkynes 4
were next subjected to the above-defined optimal reaction
conditions, and the results are compiled in Scheme 2. The
reactivity appears to be quite general, yielding smoothly in each
case the corresponding vinyl tetrahydrofuran product 5 in
moderate to good isolated yields (63−86%) and with E/Z
isomeric ratios ranging from 0.3 to 2.0. Neither electron-
withdrawing or -donating properties nor the substitution
patterns (ortho, meta, para) on the aryl rings (i.e., 5a−p) seemed
to have posed a significant influence on the reaction efficiency
and E/Z ratios. An aryl ring with more conjugation (5v) or a
heteroatom (5w) is a comparably competent substrate. This
visible light photocatalytic C−H functionalization method
clearly tolerates a broad spectrum of alkyne partners.
The protocol was further extended to propiolate-type internal
alkynes structured as 6. The results are summarized in Scheme 3.
Again a range of substrates were readily implementable, and the
observed reactivities are virtually irrespective of aryl ring
substitutions, as their corresponding products 7 were all
consistently furnished in 61−86% isolated yields and 0.5−1.3
double-bond E/Z selectivities.
The synthetic application of this new visible light-enabled
photocatalytic C−H functionalization technology was further
manifested through staightforward structural editings on some
pharmaceutically meaningful substances. For example, diosge-
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helps demonstrate the methodology’s value in providing rapid
access into a focused library of a range of structural analogs
bearing newly installed functional groups.
Scheme 2. Reactivity Screenings on Terminal Alkynes
Mechnistic experiments were next conducted to shed light on
the potential reaction pathways. As summarized in Scheme 5,
Scheme 5. Experimental Probes on Reaction Mechanism
again using vinylation of tetrahydrofuran with alkyne 1 as the
model reaction, the addition of a widely known radical scavenger
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) led to complete
inhibition of the intended reactivity, implying strongly
involvement of radical intermediates. Structures 10 and 11,
both readily conceivable from a shared α-oxy radical on THF,
were in fact both detected by high-resolution mass spectrum
(HRMS) analysis of the reactio mixture. Furthermore, addition
of either 2 equiv of deuterated formic acid (DCOOD) or a 1:1
mixtrue of DCOOD and HCOOH to the reaction did not lead to
any deuterium-containing products, thus practically ruling out
the possibility that formic acid might act as the hydrogen source.
Finally, a significant kinetic isotope effect (KH/KD = 4.1) was
recorded in the process, providing direct evidence that C−H
bond cleavage event might have constituted a rate-determining
step.
Scheme 3. Reactivity Screenings on Propiolate Derivates
The observed reactivities coupled with the above inves-
tigations collectively point to a plausible mechanistic network
shown in Scheme 6. The sequence would be initiated through
Scheme 6. Proposed Mechanistic Network
nin, a steroid sapogenin that is often employed in the
preparations of pregnenolone, cortisone, progesterone, and
other related steroid products, serves as an illustrative system.18
As shown in Scheme 4, under the standard conditions, diosgenin
derivate 8 was smoothly converted to 9 in 53% isolated yield and
0.8 E/Z isomeric ratio. This representative structral elaboration
Scheme 4. Synthetic Elaboration on a Diosgenin Derivative
catalytic visible light sensitization of eosin Y which, upon
returning to its ground state, transfers energy to t-BuOOH and in
turn induces scission of its weak O−O bond to give rise to
simultaneously two radical species: hydroxyl radical HO• and
tert-butoxy radical t-BuO•. Abstraction of hydrogen from
tetrahydrofuran would thus generate the key α-oxy radical,
C
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AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
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Figadere, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell, E.; Cortes, D.
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