Visible Light-Induced α-C(sp3)-H Acetalization of Saturated Heterocycles Catalyzed by a Dimeric Gold Complex

Article abstract of DOI:10.1021/acs.orglett.0c01924

Saturated heterocyclic acetals are useful fragments in organic synthesis and other fields. Herein, C(sp3)-H dehydrogenative cross-couplings of ethers, tetrahydrothiophenes, and pyrrolidines were achieved under visible light irradiation by using iodobenzene and an in situ-formed gold complex. The broad functional group compatibility and substrate scope indicate that our strategy is a promising way to synthesize acetal analogues. The method was successfully applied in late-stage modifications of bioactive molecules. Gram scale syntheses and mechanistic studies are also presented.

Full text of DOI:10.1021/acs.orglett.0c01924

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Letter
Visible Light-Induced α‑C(sp3)−H Acetalization of Saturated
Heterocycles Catalyzed by a Dimeric Gold Complex
Xiaojia Si, Lumin Zhang, Zuozuo Wu, Matthias Rudolph, Abdullah M. Asiri, and A. Stephen K. Hashmi*
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ABSTRACT: Saturated heterocyclic acetals are useful fragments
in organic synthesis and other fields. Herein, C(sp3)−H
dehydrogenative cross-couplings of ethers, tetrahydrothiophenes,
and pyrrolidines were achieved under visible light irradiation by
using iodobenzene and an in situ-formed gold complex. The broad
functional group compatibility and substrate scope indicate that
our strategy is a promising way to synthesize acetal analogues. The
method was successfully applied in late-stage modifications of
bioactive molecules. Gram scale syntheses and mechanistic studies
are also presented.
and a base to in situ form a new gold catalyst for new
transformations.
nspired by the demand for mild, straightforward, and
Ienvironmentally friendly chemistry, synthetic chemists have
devoted a great deal of effort to develop new ways to
synthesize valuable products. Selective C−H bond functional-
ization has been recognized as a powerful and straightforward
method.1 Traditional ways are based on a preactivation of
substrates, the requirement of specific and complex ligands,
and the introduction of directing groups for the modulation of
reactivity. All of this represents an obstacle for application.
Because of the high reactivity of open-shell radicals,2 radical-
mediated C(sp3)−H activation merged with hydrogen atom
transfer (HAT) processes3 have been developed as a promising
solution for this problem.
Due to the mild and adjustable reaction conditions,
photochemistry offers a new opportunity for radical chem-
istry.4 In the past several years, our group has contributed to
the development of light-driven organic synthetic method-
ologies.5 The binuclear bis(diphosphine) complex [Au2(μ-
dppm)2]Cl2 [dppm = bis(diphenylphosphino)methane] has
proven to be very useful in photocatalysis.6 In most cases, UVA
light was necessary to excite the gold complexes, which can be
a drawback due to the fact that many functional groups also
show absorption at this short wavelength, which can make
applications more difficult and reduce the functional group
compatibility. Recently, our group found two different
strategies,5e,g which enabled a red shift and the excitation of
gold complexes under blue light-emitting diode (LED)
irradiation. One of the pathways took advantage of the
coordination of a ligand (Ph3P or mercaptan) to the [Au2(μ-
dppm)2]Cl2 complex, and another pathway was based on the
use of a base (Na2CO3) as an additive. Herein, we continue to
apply this new strategy by combining a dinuclear gold catalyst
Acetals derived from cyclic ethers are useful fragments for
organic synthesis and other applications. Several drugs that
contain this motif are applied to treat diseases (Figure 1).
There are also other applications based on structures
containing this motif, such as liquid crystal display devices7
and DNA sequencing.8 In addition, hydroxyl groups can be
protected as tetrahydrofuranyl ethers in multistep organic
syntheses as well as in peptide, nucleotide, carbohydrate,
terpenoid, and steroid chemistry.9 There are different strategies
for the preparation of cyclic ether acetals;10 the most direct
way uses THF in the presence of single-electron oxidants via
radical pathways. Most of the protocols use CCl4 or similar
perhalomethanes10a−c to promote the reaction, but these kinds
of reagents were almost completely banned from use, even in
research, because of toxicity and safety concerns. Hypervalent
iodine compounds can also serve as the oxidant for this
transformation, but high temperatures or microwave con-
ditions are needed.10d,g In 2018, Toste and co-workers
presented a new route11 by using diaryliodonium chlorides
as the HAT reagent in combination with CFL as the light
source; however, the methodology was restricted to cyclic
ether substrates, and no other heterocycles were reported. In
addition, an excess of 2.5 equiv of diaryliodonium chloride was
needed. On the basis of our previous report,5g iodobenzene
Received: June 8, 2020
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© XXXX American Chemical Society
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Scheme 1. Select Optimization Results and Control
a
Studies
Figure 1. Selection of acetal-containing drugs.
can be excited to form an aryl radical and an iodine radical by
an energy transfer (EnT) process with a newly formed gold
complex. On the basis of this principle, we assumed that THF
acetals might be accessible by the reaction of simple
iodobenzene with THF. The formed aryl radical should
quickly be trapped by THF to form an α-heteroatom-stabilized
alkyl radical. The latter could then recombine with the iodine
radical to form 2-iodotetrahydrofuran. A nucleophilic attack
then might give rise to the desired products, a strategy different
from that in Toste’s report.
a
Yield determined by 1H NMR analysis using 1,2,4,5-tetramethyl-
b
c
benzene as the internal standard. n.d. = not detected. Isolated yield.
3e, and 3g) gave moderate yields. No racemization was
observed for substrates with chiral centers (3c and 3h).
Differently substituted phenylethanol derivatives bearing
halogens at different positions (3i and 3j) and a
trifluoromethyl (3l) group were all tolerated. A wide variety
of benzylic alcohols (3m−3s) reacted well, showing no large
difference in yield. The less nucleophilic phenol also reacted
with THF to the desired product in 35% isolated yield, but this
compound decomposed after storage at 4 °C for 2 days. Even
medically relevant heteroaromatic alcohols, which are notori-
ously problematic in many photoredox protocols, performed
well under our reaction conditions, including thiophene, furan,
and pyridine (3u−3w, respectively; 45−65% yields).
We next evaluated other commonly used cyclic ethers
instead of THF for this acetalization. Tetrahydropyran also
reacted adjacent to the oxygen atom in 48% yield (3x). The
diminished reactivity compared to THF might result from
stereoelectronic factors. On the other hand, we found different
aryl iodides influence the yield, maybe because of polarity
match. On the basis of condition optimization, 2-chloroiodo-
benzene was better than others. In the case of 1,4-dioxane
(3y), despite a comparable steric demand, the second oxygen
atom was not functionalized. For 2-methyltetrahydrofuran,
only the less hindered position reacted to give 3z.
In our initial experiments, we found 4-iodoanisole to be a
suitable precursor for this transformation in the presence of the
gold catalyst, but the yield was only 38% (Scheme 1, entries 1,
2, and 5) after irradiation for 24 h. A catalyst screening using
different counteranions (entries 3−4) enabled an increase in
the yield to 60%, with OTf− being the best choice. A slight
increase in the amount of 4-iodoanisole (entries 6−8) and an
extended irradiation time (entry 12) further improved the
reaction. Attempts to lower the catalyst load failed (entries 10
and 11). We found the condition shown in entry 12 to be the
optimum conditions {1.0 equiv of NaHCO3, 1.5 equiv of 4-
iodoanisole, and 1.0 mol % [Au2(μ-dppm)2](OTf)2 irradiated
by blue LED lights for 36 h}. On the basis of entries 7 and 9,
we found reducing the amount of THF does not influence the
yield, but using less ether could reduce cost and is beneficial
for large scale reactions. We used 0.2 mL of THF for further
experiments. The use of simple PPh3AuCl or other widely
applied photocatalysts, like [Ir(ppy)2(dtbbpy)]PF6, [Ru-
(bpy)3](PF6)2, Eosin Y, or Mes-Acr-Me+BF4 , instead of the
−
[Au2(μ-dppm)2]Cl2 complex, resulted in none of the desired
product (entries 13−17, respectively). Decreased yields were
obtained upon irradiation with CFL or UVA light (entries 20
and 21). The control experiments shown in entries 1, 5, 18,
and 19 prove that all of the parameters are significant for a
successful transformation.
With the optimal conditions in hand, we then explored the
scope of this reaction. Different kinds of primary and
secondary alcohols underwent the desired C(sp3)−H acetal-
ization (Scheme 2). Both linear and cyclic allylic alcohols (3d,
Next we expanded the application of this C−H functional-
ization strategy toward the synthesis of thioacetals and α-
alkoxypyrrolidines (Scheme 3). Like the sulfur analogues of
acetals, thioacetals have potential applications in pharmaceut-
ical development and alcohol protection.12 A variety of
alcohols, including simple alkyl alcohol (4a), cinnamyl alcohol
(4b), benzyl alcohols (4d and 4e), and heterocyclic benzyl
alcohol (4f), all directly reacted with thiophene in our new
photoredox C−H activation (functionalization) route in
moderate yields (33−62%). The oxidation of pyrrolidine to
B
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a
Scheme 2. Scope of sp3 C−H Acetalization of Ethers
Scheme 3. Scope of sp3 C−H Acetalization of Thioethers
a
and Amides
a
Reactions were performed on a 0.2 mmol scale by following the
general procedure. Yields are isolated yields.
special liquid electrolyte systems are needed. Various α-
alkoxypyrrolidines were achieved by our strategy. Halogen
(4h), trifluoromethyl (4k), and heterocycles (4l) were
compatible, and the yields were >90%.
Furthermore, we could demonstrate that this methodology
can be applied for late-stage modifications of some bioactive
molecules (Figure 2). Carbohydrates and nucleosides are
common substances in living organisms, and site-selective
modifications of those compounds offer exciting possibilities
for both organic synthesis and pharmaceutical development.
Compounds 5−7 further demonstrate the broad applicability
of our strategy. Ezetimibe is a medication used to treat high
blood cholesterol levels and certain other lipid abnormalities.
The compound includes two hydroxyl groups, but the aliphatic
alcohol was selectively converted while the phenolic hydroxyl
remained under our reaction conditions (8). Another
medicinal compound, podophyllotoxin (9), and the natural
products 5α-cholestan-3β-ol (10), (−)-menthol (11), and
(−)-borneol (12) also underwent this α-C(sp3)−H acetaliza-
tion reaction. In addition, the late-stage modification of
(−)-ambroxide by using acetone as solvent was also successful
and the desired product was obtained in 62% yield (13).
Although 5.0 equiv of ether was necessary, >3.0 equiv could be
recovered during the purification. These applications clearly
suggest that our strategy is a promising synthetic method and a
late-stage modification tool for natural products and drug
molecules.
a
Reactions were performed on a 0.2 mmol scale by following general
b
procedure A. Yields are isolated yields. Reactions were performed on
a 2.0 mmol scale, and the irradiation time was 60 h. Reactions were
performed on a 0.2 mmol scale, using 2-chloroiodobenzene instead of
4-iodoanisole, using 0.2 mL of acetone as solvent, and 5 eq of ethers
was added. Reactions were performed on a 0.2 mmol scale, using 2-
chloroiodobenzene instead of 4-iodoanisole, using 0.2 mL of 1,4-
dioxane as solvent.
c
d
α-alkoxypyrrolidines has been utilized as a starting step for the
synthesis of cyclic lactams, alkaloids, and even the antimalarial
agent isofebrifugine.13 For this kind of transformation,
researchers usually use prefunctionalization.14 Only a few
publications15 have reported the direct modification of
pyrrolidines through electrochemical pathways; however,
After the successful construction of acetals and related
analogues through the dehydrogenation cross-coupling be-
tween saturated heterocyclic rings and alcohols, other control
experiments were conducted to gain deeper insight into the
C
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deuterated compound 12 was detected, which verifies that a
hydrogen atom transfer (HAT) had occurred after the
generation of the phenyl radical. In addition, a significant
kinetic isotope effect (KIE = 3.6) was recorded, providing
evidence that the C−H bond cleavage event might constitute
the rate-determining step. Finally, the reaction was conducted
under UVA in the absence of a gold catalyst. As demonstrated
in Scheme 4 (eq 5), 3q was obtained in only 12% yield
compared to 79% yield under our standard condition. It is
well-known that aryl iodobenzene would split into two free
radicals under UVA irradiation.16 Having in mind our previous
research,5g we rationalized that iodobenzene homolysis was
also a possible route for this transformation, but unlike for the
reported energy transfer process, direct UVA irradiation was
inefficient for this transformation. The quantum yield [Φ =
13.5% (see the Supporting Information)] indicates that a
radical chain mechanism is not involved in the transformation.
On the basis of previous studies5g and our experiments, this
transformation should follow an energy transfer process. The
possible mechanism is shown in Figure 3. A new gold complex
Figure 2. Selective late-stage modification of bioactive molecules.
Reactions were performed on a 0.2 mmol scale (see the Supporting
Information for detailed procedures). Yields are isolated yields.
mechanistic pathway. The transformation was completely
inhibited when 1.0 equiv of the radical scavenger TEMPO
was added. For the reaction system shown in Scheme 4 (eq 2),
Scheme 4. Mechanistic Experiments
Figure 3. Proposed mechanism.
13, formed in situ by the combination of [Au2(μ-dppm)2]-
(OTf)2 and NaHCO3, can be photoexcited to 14 under blue
LED irradiation. Then, the iodobenzene converts to its
photoexcited triplet state through an energy transfer process
(EnT), followed by a homolytic cleavage generating an aryl
radical and an iodine radical. In the THF solvent cage, the aryl
radical is then quickly trapped by THF via a HAT process.
Subsequently, the produced THF radical undergoes radical−
radical recombination with the iodine radical, leading to 2-
iodotetrahydrofuran 15 as the reactive intermediate. As an
alternative, it might also be oxidized to an oxocarbenium ion
16. As reported previously,10 such α-halogenated ethers can
easily be attacked by alcohols to deliver the corresponding
acetals.
In summary, C(sp3)−H dehydrogenative cross-couplings on
ethers, tetrahydrothiophene, and pyrrolidines were successfully
performed with a dimeric gold catalyst, iodobenzene, and blue
LEDs. The wide functional group compatibility and a broad
substrate scopes make our strategy appealing as a synthetic
method with respect to acetals, thioacetals, and α-alkoxypyrro-
lidines. The applications and gram scale experiments also
demonstrate a potential use of the strategy for late-stage
modifications and the construction of other complex
if a gold catalyst and a base were present, the aryl radical
derived from the aryl iodide by blue LED irradiation would be
captured by HAT from 9,10-dihydroanthracene (DHA) to
generate chlorobenzene. These two inhibition experiments
suggest that a radical process is involved and that alcohols are
not participating in the radical-forming process. The yield
dropped to 29% when THF-d8 was used as solvent, and
D
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01924.
Experimental procedures and compound characteriza-
tion (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
A. Stephen K. Hashmi − Organisch-Chemisches Institut,
Heidelberg University, 69120 Heidelberg, Germany; Chemistry
Department, Faculty of Science, King Abdulaziz University
(KAU), Jeddah 21589, Saudi Arabia; orcid.org/0000-
0002-6720-8602; Email: hashmi@hashmi.de
Authors
Xiaojia Si − Organisch-Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
Lumin Zhang − Organisch-Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
Zuozuo Wu − Organisch-Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
Matthias Rudolph − Organisch-Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
(4) (a) Romero, N. A.; Nicewicz, D. A. Organic photoredox
catalysis. Chem. Rev. 2016, 116, 10075. (b) Skubi, K. L.; Blum, T. R.;
Yoon, T. P. Dual catalysis strategies in photochemical synthesis.
Chem. Rev. 2016, 116, 10035. (c) Twilton, J.; Le, C. C.; Zhang, P.;
Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. The merger of
transition metal and photocatalysis. Nat. Rev. Chem. 2017, 1, 52.
(d) Xie, J.; Jin, H. M.; Hashmi, A. S. K. The recent achievements of
redox-neutral radical C-C cross-coupling enabled by visible-light.
Chem. Soc. Rev. 2017, 46, 5193.
Abdullah M. Asiri − Chemistry Department, Faculty of Science,
King Abdulaziz University (KAU), Jeddah 21589, Saudi
Arabia; orcid.org/0000-0001-7905-3209
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01924
Notes
The authors declare no competing financial interest.
(5) (a) Xie, J.; Shi, S.; Zhang, T.; Mehrkens, N.; Rudolph, M.;
Hashmi, A. S. K. A highly efficient gold-catalyzed photoredox α-
C(sp3)-H alkynylation of tertiary aliphatic amines with sunlight.
Angew. Chem., Int. Ed. 2015, 54, 6046. (b) Xie, J.; Zhang, T.; Chen, F.;
Mehrkens, N.; Rominger, F.; Rudolph, M.; Hashmi, A. S. K. Gold-
catalyzed highly selective photoredox C(sp2)-H difluoroalkylation and
perfluoroalkylation of hydrazones. Angew. Chem., Int. Ed. 2016, 55,
2934. (c) Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K.
Monofluoroalkenylation of dimethylamino compounds through
radical-radical cross-coupling. Angew. Chem., Int. Ed. 2016, 55, 9416.
(d) Zhang, L.; Si, X.; Yang, Y.; Zimmer, M.; Witzel, S.; Sekine, K.;
Rudolph, M.; Hashmi, A. S. K. The combination of benzaldehyde and
nickel-catalyzed photoredox C(sp3)-H alkylation/arylation. Angew.
Chem., Int. Ed. 2019, 58, 1823. (e) Zhang, L.; Si, X.; Yang, Y.; Witzel,
S.; Sekine, K.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Reductive
C-C coupling by desulfurizing gold-catalyzed photoreactions. ACS
Catal. 2019, 9, 6118. (f) Si, X.; Zhang, L.; Hashmi, A. S. K.
Benzaldehyde- and nickel-catalyzed photoredox C(sp3)-H alkylation/
arylation with amides and thioethers. Org. Lett. 2019, 21, 6329.
(g) Zhang, L.; Si, X.; Rominger, F.; Hashmi, A. S. K. Visible-light-
induced radical carbo-cyclization/gem-diborylation through triplet
energy transfer between a gold catalyst and aryl iodides. J. Am. Chem.
Soc. 2020, 142, 10485.
ACKNOWLEDGMENTS
X.S., L.Z., and Z.W. are grateful for Ph.D. fellowships from the
China Scholarship Council (CSC).
■
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