Chemodivergent Photocatalytic Synthesis of Dihydrofurans and β,γ-Unsaturated Ketones

Article abstract of DOI:10.1002/adsc.202100260

A synthetic procedure, catalysed by Ir(ppy)₃ under visible-light irradiation, for the chemodivergent synthesis of 2,3-dihydrofurans (3) or β,γ-unsaturated ketones (7) starting from α-halo ketones (1) and alkenes (2) has been developed. The mild reaction conditions and the redox-neutral nature of the process make it particularly sustainable avoiding the use of both sacrificial reactants and stoichiometric strong oxidants. Careful experimental investigations, supported by DFT calculations, allowed to disclose in details a possible mechanistic pathway and to direct the synthesis chemodivergently either toward 3 or 7, depending not only on the nature of the substrates, but also on the choice of the experimental conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202100260

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DOI: 10.1002/adsc.202100260
Chemodivergent Photocatalytic Synthesis of Dihydrofurans and
β,γ-Unsaturated Ketones
Arianna Quintavalla,a,* Ruben Veronesi,a Davide Carboni,a Ada Martinelli,a
Nelsi Zaccheroni,a Liviana Mummolo,a and Marco Lombardoa,*
a
Alma Mater Studiorum – University of Bologna, Department of Chemistry “G. Ciamician”, Via Selmi 2, 40126 Bologna, Italy
E-mail: arianna.quintavalla@unibo.it; marco.lombardo@unibo.it
Manuscript received: February 27, 2021; Revised manuscript received: April 9, 2021;
Version of record online: May 4, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100260
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Abstract: A synthetic procedure, catalysed by Ir(ppy)3 under visible-light irradiation, for the chemodivergent
synthesis of 2,3-dihydrofurans (3) or β,γ-unsaturated ketones (7) starting from α-halo ketones (1) and alkenes
(2) has been developed. The mild reaction conditions and the redox-neutral nature of the process make it
particularly sustainable avoiding the use of both sacrificial reactants and stoichiometric strong oxidants.
Careful experimental investigations, supported by DFT calculations, allowed to disclose in details a possible
mechanistic pathway and to direct the synthesis chemodivergently either toward 3 or 7, depending not only on
the nature of the substrates, but also on the choice of the experimental conditions.
Keywords: photocatalysis; dihydrofurans; β,γ-unsaturated ketones; chemodivergent; DFT; iridium; heterocycles
Introduction
Dihydrofurans are important five-membered heterocy-
clic scaffolds which widely appear in natural
products,[1]
drugs
and
medicinally
relevant
compounds,[2] materials and dyes[3] (Figure 1). In
addition, they are usefully exploited as synthetic
intermediates[4] or reactants for the preparation of
materials.[5] For these reasons, the synthesis of both
2,3- and 2,5-dihydrofurans has attracted much interest
in the past decades and still today, as demonstrated by
the high number of protocols proposed in the last two
years. Several different synthetic strategies have been
developed.[4a,6] In particular, the most employed ap-
proach to the construction of substituted 2,3-dihydro-
furans is the [3+2] annulation, accomplished through
many different protocols. Among the traditional
methods we can mention the “interrupted” Feist-
Bénary reaction,[7] the oxidative coupling reaction
between 1,3-dicarbonyl compounds and olefins medi-
ated by stoichiometric manganese(III),[8] cerium
(IV),[8d,9a–b] or copper(II),[9c] the 1,3-dipolar reaction
involving diazocarbonyl compounds and alkenes cata-
Figure 1. Notable 2,3- and 2,5-dihydrofurans.
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lyzed by rhodium(II),[10] ruthenium(II),[11] or copper radical synthetic approach to substituted 2,3-dihydro-
(II).[12] More recently, some innovative examples of [3 furans (Scheme 1c), occurring under mild reaction
+2] annulations have been proposed: i) the reaction conditions with low photocatalyst loading, starting
between ketones and alkenes mediated by copper,[13] from olefins and α-haloketones as easily accessible and
palladium,[14] or potassium persulfate,[15] by cooperative stable substrates, avoiding large excesses of reagents
systems indium(III)/silver(I)[16] or I2/oxidant,[17] or and, most important, in the absence of additives or
electrochemically promoted;[18] ii) several base-pro- additional strong oxidants (redox-neutral conditions).
moted additions to functionalized olefins,[19] alkynyl Scheffer proposed in 2005 the photorearrangement of
systems,[20] or carbonyls;[21] iii) Morita–Baylis–Hill- syn-7-benzoylnorbornene derivatives leading to cis-
man-type annulations;[22] iv) some copper-catalyzed fused 2,3-dihydrofurans.[32] However, this photochem-
formal cycloadditions involving active methylene ical transformation was intramolecular and promoted
compounds and unusual acceptors;[23] v) gold(I)-cata- by high-energy UV-irradiation, showing a limited
lyzed syntheses of silyl-2,3-dihydrofurans.[24]
substrate scope. Afterwards, some photocatalyzed
Some approaches different from [3+2] annulation intermolecular reactions between olefins and α-halo (or
have also been described for 2,3-dihydrofurans con- α-acetoxy) carbonyls were proposed to synthesize
struction, as for example the cyclization of olefinic lactones,[33] γ-hydroxyketones[34] or furans[35] (Sche-
dicarbonyl
compounds,[25]
catalytic
[4+1] me 1a). In particular, Wu[35b] and Zhu[35c] failed to avoid
cycloadditions,[26] the ring opening of cyclopropanes[27] aromatization to furans and, therefore, they were
or cyclopropenes,[28] the arylation of 2,5- unable to provide 2,3-dihydrofurans. The aromatization
dihydrofurans.[29] Although remarkable results have leading to furans is a major drawback of many
been obtained, each of the reported protocols has its synthetic approaches to dihydrofurans.[13a,36] Only
own merits and demerits. In particular, almost all the Greaney et al. proposed a photoredox catalytic reaction
published methods require stoichiometric amounts of between bromoesters or bromonitriles and styrenes
transition metals or high catalyst loadings (with related obtaining the corresponding γ-hydroxy derivatives.[37]
cost and toxicity concerns), a large excess of a Among the tested substrates, a single α-bromo-β-
substrate, suitable substituted reagents, harsh reaction ketoester was employed providing some 2,3-dihydro-
conditions (high temperature and/or strongly acidic furans (Scheme 1b). However, these products were
solvent), and, in many cases, stoichiometric or excess sometimes accompanied by a comparable amount of
of an additional strong oxidant. These disadvantages the corresponding lactones. In addition, to reach
result in a poor functional group compatibility, which acceptable yields the protocol required the use of a
hinders a wide application of these protocols. There-
fore, there is still a need for sustainable and flexible
transformations that exceed these limitations.
As part of our ten years research interests in the
synthesis of bioactive heterocyclic molecules,[30] we
envisioned that a redox-neutral photocatalytic approach
could be usefully applied to the synthesis of substituted
2,3-dihydrofurans. The photochemistry applied to
organic synthesis has undergone a big boost over the
past 10 years.[31] The use of visible light as green
energy source, through an energetically controlled
irradiation, has enabled mild and selective activation of
photocatalysts or substrate-catalyst complexes. Indeed,
compared to ultraviolet irradiation, the transparent
properties of most organic substrates for visible light
minimize the side reactions. It has resulted in the
development of several photocatalyzed economical and
environmentally benign transformations occurring
under mild conditions, without the need of a special
instrument or apparatus, and with great tolerance of
functional groups. Moreover, visible light photochem-
istry has demonstrated to give access to peculiar
reactivities and, in particular, to environmentally
friendly free radical reactions, avoiding the tradition-
ally employed toxic and hazardous initiators or
reagents. We decided to exploit the advantages of
visible light photocatalysis to develop an efficient
Scheme 1. Photoredox catalytic reactions between olefins and
α-halo or α-acetoxy carbonyls.
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large excess of olefin (5 equivalents) and of Zn(OAc)2
as additive in 20 mol% amount.
According to published literature, we supposed that
the formation of lactone 5aa and hemiketal 6aa was
due to the presence of water.[33,38] Therefore, to
minimize their formation, we tried the reaction in pure
organic solvents (entries 2–3) but the transformation
Results and Discussion
Protocol optimization. Our preliminary investigations did not proceed. Assuming that water could confine
focused on the reaction between methyl 2-bromo-3- the generated hydrobromic acid,[39] we repeated the
oxobutanoate 1a and 1,1-diphenylethylene 2a pro- reactions in organic solvents in the presence of 2,6-
moted by Ru(bpy)3Cl2 as photocatalyst (Table 1, lutidine as base (entries 4–5), however the conversion
entries 1–6). We were delighted by the formation of remained very low. We concluded that Ru(bpy)3Cl2
the desired 2,3-dihydrofuran 3aa in good yield (54%) required water to efficiently act as photocatalyst in this
employing only a slight excess of 1 (1.2 equivalents) process, maybe not only to increase its solubility, but
and MeCN/H2O (1/4) as the reaction medium (entry 1). also due to a proton-coupled electron transfer (PCET)
However, although 3aa was the major product, three in which water acts as hydrogen bond donor.[34,40] Still,
other species were detected: the brominated hemiketal under these conditions the formation of side-products
4aa, the lactone 5aa and the hemiketal 6aa.
5aa and 6aa was unavoidable.
Table 1. Reaction conditions optimization study.
Entry 1 (X)
Photocatalyst
Solvent
Conversion (%)[a] Yield (%)[b]
3aa 4aa 5aa 6aa 7aa
1
2
3
4
5
6
7
8
1a (Br)
Ru(bpy)3Cl2 6H2O
Ru(bpy)3Cl2 6H2O
Ru(bpy)3Cl2 6H2O
Ru(bpy)3Cl2 6H2O
Ru(bpy)3Cl2 6H2O
1a’ (Cl) Ru(bpy)3Cl2 6H2O
fac-Ir(ppy)3
MeCN/H2O (1/4) 90
54
nd
nd
nd
nd
nd
22
9
59
44
61
53
nd
nd
nd
–
8
18
nd
nd
nd
nd
nd
18
–
–
–
–
–
10
nd
nd
nd
nd
nd
44
–
–
–
–
–
–
MeCN
<10
nd
nd
nd
nd
nd
–
–
–
–
–
nd
nd
nd
nd
nd
–
–
13
6
14
18
nd
nd
nd
–
DMF
<5
<5
<5
<5
MeCN
DMF[c]
MeCN/H2O (1/4)
MeCN/H2O (1/4) 100
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
MeCN
23
9
MeCN[c]
MeCN[c,d]
MeCN[c,e]
MeCN[c,f]
100
100
100
90
10
11
12
13
14
15
16
fac-Ir(ppy)3
–
Ir[dF(CF3)ppy]2(dtbbpy)PF6 MeCN[c]
<5
<5
<5
20
nd
nd
nd
–
nd
nd
nd
–
nd
nd
nd
–
Eosin Y
MeCN[c,g]
MeCN[c]
MeCN[c]
3DPA2FBN[h]
Coumarin[h,i]
Reaction conditions: 1 (1.2 eq.), 2a (0.1 mmol), photocatalyst (1 mol%), solvent (1 mL), blue LED (465 nm), freeze pump thaw (1
cycle), rt, 24 h.
1
[a] Determined by H NMR spectroscopic analysis of the crude mixture using triphenylmethane as internal standard and integrating
the signals of remaining reagent 2a.
1
[b] Determined by H NMR spectroscopic analysis of the crude mixture using triphenylmethane as internal standard and integrating
the signals of the products.
[c] 2,6-Lutidine (1 eq.) was added.
[d] 2 mL of solvent.
[e] 2 eq. of 1a’.
[f] 2 eq. of 2a.
[g] Green LED (520 nm).
[h] 3 mol%.
[i] For the structure of employed coumarin see ref. [45]. rt=room temperature, bpy=2,2’-bipyridine, ppy=2-phenylpyridinato,
dtbbpy= 4,4’-di-tert-butyl-2,2’-dipyridyl, DPA=diphenylamine, 2FBN =3,5-difluoro benzonitrile, DMF= N,N-dimeth-
ylformamide, nd=not determined.
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The brominated hemiketal 4aa derived from methyl conversions but many by-products. The optimal result
2,2-dibromo-3-oxobutanoate always present in a cer- was obtained with the inorganic base Na2HPO4, that
tain percentage in substrate 1a. Indeed, methyl 2- promoted a very clean reaction furnishing the dihy-
bromo-3-oxobutanoate 1a (like many other bromoace- drofuran 3aa in 84% yield.
toacetates) is not commercially available and its syn-
Reaction scope and chemodivergence. With the
thesis provides a mixture of mono- and di-bromo optimized conditions in our hands, we turned our
derivatives, which are extremely difficult to be attention to the reaction scope and different olefins 2
separated.[41] Moreover, 1a proved to be not fully were employed (Scheme 2).
stable over time.[41] For all these reasons, we decided
Several substituted 1,1-diarylethylenes 2b–f were
to move on to chlorinated analogues, many of which tested. When only one aromatic ring was substituted,
are stable and commercially available or easily both electron-donating (3ab and 3ac) and electron-
synthesized. The relatively low oxidation potential of withdrawing (3ad) groups were well tolerated, in ortho
III/II*
the excited photocatalyst Ru(bpy)3Cl2 (E1/2
=
e para positions. When the two aromatic rings were
À 0.81 V vs SCE)[42] required the use of bromoacetoa- both substituted, electron-withdrawing groups (EWGs)
cetates, as the reaction did not take place with methyl were tolerated but the process slowed down (3ae).[46]
2-chloro-3-oxobutanoate 1a’ (entry 6). Therefore, we Differently, two electron-donating groups (EDGs)
turned our attention to the more reducing photocatalyst (3af) influenced the reactivity to the point of triggering
fac-Ir(ppy)3 (E1/2IV/III* =À 1.73 V vs SCE),[42] which the formation of a remarkable amount (37%) of β,γ-
used under the conditions optimized for Ru(bpy)3Cl2 unsaturated β-ketoester 7af. As observed also by other
provided a mixture of three products (entry 7), where authors,[16,35c] very electron-rich aromatic rings favor
hemiketal 6aa was the major one (44%). Aiming to the formation of the conjugated double bond. It is
increase the dihydrofuran 3aa yield by reducing both noteworthy that aryl chlorides remained untouched
lactone 5aa and hemiketal 6aa, we carried out the
reaction in pure MeCN with and without base (entry 9
and 8, respectively). The disappearance of both the
side-products confirmed that their formation was
favored by water. High conversion and good yield
(59%) of 3aa were obtained only in the presence of a
base (entry 9), although accompanied by a certain
amount (13%) of β,γ-unsaturated β-ketoester 7aa. To
optimize the conditions we diluted the reaction mixture
(entry 10) or increased the reactants quantity (1a’:
entry 11, 2a: entry 12, respectively), but significant
improvements were not observed. The solvents screen-
ing (see Supporting Information) confirmed pure
MeCN as the best reaction medium. Lastly, we carried
out a brief photocatalysts screening. As expected,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (E1/2IV/III* =À 0.89 V vs
SCE)[42] was unable to promote the reaction (entry 13).
Some organic photocatalysts were also tested. Eosin Y
*
+
[E*ox (cat /cat*)=À 1.15 V vs SCE][43] (entry 14),
*
+
3DPA2FBN [E*ox (cat /cat*)=À 1.60 V vs SCE][44]
(entry 15), and a highly reducing coumarin recently
*
+
proposed by Cozzi et al. [E*ox (cat /cat*)=À 1.89 V
vs SCE][45] (entry 16) were not able to promote the
dihydrofuran formation. Our optimization study con-
tinued by investigating the reaction time (see Support-
Scheme 2. Alkenes 2 scope. Optimized reaction conditions: 1a’
ing Information) and 24 hours was identified as the
(1.2 eq.), 2 (0.1 mmol), Ir(ppy)3 (1 mol%), Na2HPO4 (1 eq.),
best one. Since we observed a significant role of the
base in this process (Table 1, entries 8–9), we inves-
MeCN (1 mL), blue LED (465 nm), freeze pump thaw (1
cycle), rt, 24 h. All the products were obtained as racemates.
1
tigated the effect of base equivalents on 3aa formation
(see Supporting Information). The best performance
with the model substrates was achieved with stoichio-
metric base, whereas an excess did not improve the
reaction outcome. At last, the nature of the base was
studied (see Supporting Information). Some organic
bases showed low conversions, others provided high
NMR yields determined by H NMR spectroscopic analysis of
the crude mixture using triphenylmethane as internal standard
and integrating the signals of the products. Yields after flash
[a]
chromatography reported in brackets.
Reaction time: 72 h.
[b]37% (NMR yield) of product 7af was also detected. The two
products were inseparable. [c]46% (NMR yield) of lactone 5ah
was also detected. [d] 2.5 eq. of alkene.
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(3ad, 3ae and 3al), demonstrating the orthogonality
between these photoredox conditions and the classic
transition metal-based protocols. The presence of aryl
chlorides allows later stage functionalizations. We
proceeded with the evaluation of 1-alkyl-1-arylethy-
lenes 2g–i, which successfully provided the corre-
sponding dihydrofurans 3ag–3ah and the structurally
ambitious spiro compound 3ai. However, we observed
that the steric hindrance present on the olefin signifi-
cantly affects the reaction outcome,[46] as demonstrated
by 1-isopropyl-1-phenylethylene 2h, which reacted
slowly and also generated the corresponding lactone
5ah (46%) (see Supporting Information for our
hypothesis on 5ah formation). Particularly worth-
mentioning were the results obtained with the vari-
ously substituted styrenes 2j–l, which furnished the
corresponding dihydrofurans 3aj–3al in good yields
without significant formation of the corresponding
furans, thanks to the mild and redox-neutral reaction
conditions. 4-Nitro styrene was also tested but no
reaction took place, probably because this alkene is too
electron-poor. The developed method was successfully
applied to 1,2-disubstituted olefin 2m providing the
corresponding dihydrofuran 3am preferentially as
trans-isomer.[16,37,47] Lastly, we tested the trisubstituted
alkene 2n and, although the reaction took longer, the
crowded dihydrofuran 3an was obtained in good yield
(75%). At this point we turned our attention to 1,1-
dialkylethylenes, which are unable to provide stabi-
lized benzylic radical and/or cationic intermediates.
Dibutylethylene 2o furnished dihydrofuran 3ao in
acceptable yield (43%), however the results obtained
from dialkyl olefins (2o–q) were generally worse. This
behavior was confirmed by the comparison between
products 3ai and 3aq: in both cases we observed the
formation of the spiro compound, but the yield doubled
in the presence of an aromatic substituent on the olefin
(3ai). Also using 1,1-dialkylethylenes, the increase of
steric hindrance reduced the reaction efficiency (3ao
vs 3ap). Moreover, we subjected 1-decene to our
reaction conditions, as an example of monosubstituted
aliphatic alkene. However, a complex mixture of
different products was obtained. We concluded the
olefins investigation employing 1-vinyl-2-pyrrolidi-
none 2r as heteroatom-substituted alkene, which
provided the desired dihydrofuran 3ar in good yield
(70%). There is only one previous synthesis of
Scheme 3. α-Haloketones 1 scope. For optimized reaction
conditions see Scheme 2. NMR yields determined by H NMR
1
spectroscopic analysis of the crude mixture using triphenyl-
methane as internal standard and integrating the signals of the
products. Yields after flash chromatography reported in brack-
ets. [a] Reaction time: 48 h. [b] Reaction time: 72 h. [c] 19%
(NMR yield) of product 7ga was also detected. Yield after flash
chromatography of 3ga was not given due to its conversion to
7ga on silica gel. [d] 2.5 eq. of 1. [e]2.5 eq. of 2. [f] ir=isomeric
ratio; the major isomer 7gg is characterized by the trisubstituted
double bond.
dihydrofurans with an analogous substitution pattern, good results obtained with methyl 2-chloro-3-oxobuta-
based on the use of α-diazoesters with rhodium(II)- noate 1a’ (product 3aa, Scheme 3 – Chart A), we
catalysis.[48] Moreover, it is interesting to underline that tested some differently substituted chlorinated β-
Zhang and Yu applied an iridium-based photocatalytic ketoesters (1b–c). Dihydrofuran 3ba was isolated in
protocol to 1-vinyl-2-pyrrolidinone 2r in the presence excellent yield (86%) starting from substrate 1b
of α-bromo β-ketoesters and they obtained exclusively characterized by an aromatic ketone. This result is
the corresponding β,γ- (or α,β-) unsaturated remarkable because many authors reported that under
derivatives.[49]
similar conditions aromatic ketones preferentially
Afterwards, we turned our attention to the reactivity generate α-tetralones or 1-naphthols, resulting from the
of various α-haloketones 1 (Scheme 3). Based on the addition of an intermediate (cationic or radical) to the
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phenyl ring.[35a,50] As demonstrated by the good yields obtained under the same reaction conditions and with
of products 3aa and 3ba, methyl and ethyl esters were the same olefin by varying only the halogen present in
both well tolerated. However, the increase of steric the ketone (Cl in 1g’ vs Br in 1g, respectively) is
hindrance on the ester portion reduced the reactivity,[51] difficult to be rationalized and, in the vast majority of
as the isopropyl derivative 1c reacted more slowly, cases, the halogen role is not explored in depth when
furnishing the dihydrofuran 3ca in acceptable but new photoredox processes are proposed. Nevertheless,
lower yield (55%). We proceeded replacing the ester Yoon has recently demonstrated that the counterion
group with other functional groups, such as ketone can exert a remarkable impact on the observed rate of
(1d) or nitrile (1e). The 1,3-diketone 1d worked fairly radical reactions promoted by photoredox catalysts.[55]
under our reaction conditions (product 3da, Scheme 3 Usually, the chemoselectivity between dihydrofuran
– Chart A). Conversely, 2-chloro-3-oxo-3-phenylpro- and β,γ-unsaturated ketone formation was described as
panenitrile 1e provided the corresponding dihydrofur- dependent on the solvent,[9a,50b,56] the metal oxidant[57]
an 3ea with lower conversion and yield.[16] We also or on the additive.[58] However, Lei observed that
tested the reactivity of dimethyl 1-chloro-2-oxopropyl- different halides have distinct effects on the copper-
phosphonate (1f), bearing a less conventional EWG at mediated
redox
processes
leading
to
α-position. It proved to be not very reactive, however dihydrofurans.[13c,59] In our photocatalytic transforma-
it cleanly generated dihydrofuran 3fa in acceptable tion, the employed halide might affect several reaction
yield (46%).[52] 4-Phosphonyl-2,3-dihydrofurans can be steps, starting from the reduction of the α-haloketone
exploited as synthetic precursors of antiviral operated by the excited fac-Ir(ppy)3 and the oxidation
compounds.[53] Lastly, we applied our protocol to 2- of the radical intermediate to carbocation operated by
chloro-2-nitro-1-phenylethan-1-one characterized by a the [Ir(IV)]X species. Different kinetics of these steps,
nitro substituent as EWG at α-position. However, we due to the halogen variation, could favor different
observed a low olefin conversion and the formation of reaction pathways. Furthermore, the oxidation of the
different unidentified products.
radical intermediate by the [Ir(IV)]X species provides
Afterwards, we turned our attention to α-haloke- a carbocation pre-associated with the halide,[60] with
tones lacking EWGs at α-position. 2-Chloro-1-phenyl- the nucleophilicity parameters suggesting a favored
1-propanone 1g’ provided dihydrofuran 3ga in good trapping for bromide with respect to chloride (13.8 for
yield (62%, Scheme 3 – Chart A), but a considerable bromide, 12.0 for chloride).[61] Moreover, in the case of
amount (19%) of β,γ-unsaturated product 7ga was also α-bromo-ketones and -ketoesters, we cannot com-
detected. Conversely, starting from cyclic ketone 2- pletely exclude a contribute due to the abstraction of a
chlorotetralone 1h we isolated the corresponding α- bromo-radical from the reagent by the generated
alkenylation derivative 7ha as the only reaction radical intermediate.[54a,62] Lastly, the halide (especially
product (Scheme 3 – Chart B). Further similar in the case of bromide) might not to be fully innocent
unexpected results were provided by 2-chloroacetophe- in the reaction mixture due to its redox properties.[33]
none 1i’ and 2-chloro-4-fluoro acetophenone 1j,
In order to obtain β,γ-alkenyl ketones 7 in good to
which, unlike the propyl analogue 1g’, furnished the excellent yields, we decided to exploit our photo-
corresponding β,γ-alkenyl ketones 7ia and 7ja as the catalytic protocol as new strategy for the α-alkenyla-
only reaction products, even if in moderate yields tion of carbonyl substrates. In particular, a process able
(32% and 51% respectively; Scheme 3 – Chart B). In to provide β,γ-alkenyl ketones avoiding the intrinsic
these latter cases, the low process efficiency was limitation of their rearrangement into the α,β-
probably due to the formation of a relatively unstable unsaturated[49] is highly desirable. The β,γ-alkenyl
primary alkyl radical intermediate, as observed also by ketone motif is present in several natural bioactive
other authors.[54]
compounds (Figure 2)[63] and the further manipulations
At this point, we were curious about the behavior possible on these scaffolds make them very attractive
of bromoketones under our optimized conditions. as synthetic intermediates.[64]
From methyl 2-bromo-3-oxobutanoate 1a we obtained
For these reasons the synthesis of β,γ-alkenyl
the expected dihydrofuran 3aa with a much lower ketones has aroused great interest in the last decades.
yield (31%) than the corresponding chlorinated β- The α-alkenylation of carbonyl substrates is the most
ketoester 1a’ (84%), being present in the crude employed and synthetically useful approach to achieve
mixture the β,γ-alkenyl derivative 7aa (18%) and other these products and two are the main strategies: a) the
unidentified species. However, the most intriguing addition of enolates to terminal alkynes[64g,65] or
result was recorded with 2-bromo-1-phenyl-1-propa- halogenated olefins;[66] b) the coupling between α-
none 1g generating the β,γ-unsaturated product 7ga haloketones and terminal alkynes.[50c,67] The vast
with quantitative yield (96%, Scheme 3 – Chart B), majority of the published procedures using unfunction-
whereas its chlorinated analogue 1g’ preferentially alized olefins works on α-halo-esters, -amides or
provided dihydrofuran 3ga (62%, Scheme 3 – Chart -active methylene compounds.[49,54a,68] Very few exam-
A). The different products distribution (3 vs 7) ples describe the direct α-alkenylation of α-haloketones
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already observed (Scheme 2) peculiar behavior of 1,1-
di-p-methoxyphenylethylene 2f, which allowed us to
quantitatively obtain the α-alkenylation product 7bf
starting from chloro β-ketoester 1b (Scheme 3 – Chart
B).
By analyzing in details our products library
(Schemes 2 and 3), it was clear that several character-
istics of the starting materials affected the efficiency
and, more importantly, the products distribution of our
photocatalytic radical process (Scheme 4). We ob-
served that the electronic properties of the ketone α-
Figure 2. A selection of bioactive compounds containing the substituent (R5) played a crucial role. EWGs as ester
β,γ-alkenyl ketone moiety.
(1a–c), ketone (1d), nitrile (1e), and phosphonate (1f)
preferentially led to dihydrofurans 3. Conversely,
unsubstituted (1i–l) or alkyl-substituted (1g–h, 1m–n)
by reaction with unactivated olefins[69] and all these α-haloketones preferentially provided the correspond-
protocols were developed for different substrates, ing β,γ-alkenyl derivatives 7. As previously mentioned,
being the ketone mentioned as single example. More- the employed halogen (X) seemed to have a slight
over, only fully α-substituted carbonyls were used to influence on the reaction outcome, with bromine
avoid the product rearrangement to α,β-unsaturated favoring the α-alkenylation product compared to
derivative. On this basis, we developed the first chlorine (1g vs 1g’, products 7ga vs 3ga, respec-
photoredox catalytic coupling between α-haloketones tively).
and unfunctionalized olefins providing variably sub-
Concerning the group directly linked to the
stituted β,γ-alkenyl ketones in good yields. Different α- carbonyl (R4), alkyl- and aryl-substituents were both
haloketones (1g–n) were tested with 1,1-diphenyl- well tolerated in the synthesis of both dihydrofurans 3
ethylene 2a and all the substrates selectively furnished and β,γ-alkenyl ketones 7. However, in the case of
the corresponding β,γ-alkenyl ketones 7 as the only cyclic α-chloro ketones, we obtained a good reactivity
reaction product (Scheme 3 – Chart B). Starting from with α-chloro tetralone 1h (63% yield of 7ha;
the aceto-derivatives (1i–l) the yields were around Scheme 3 – Chart B), whereas α-chloro cyclohexanone
50% (products 7ia–7la), probably due to the primary 1s showed a much lower reactivity (only 13% of 2a
radical intermediate, as already mentioned. However, consumption after 24 h; data not shown). These
exactly for this reason, these results are valuable. In findings highlighted a superior reactivity of cyclic
fact, many radical alkenylation protocols do not work aromatic ketones (R4 =Ar) with respect to cyclic
on α-halo aceto-derivatives.[35b,67a,68a] As expected, we aliphatic ketones (R4 =Alk). Lastly, it was evident that
achieved superior yields (92–96%, products 7ga, 7ma, the olefin substituents (R1 and R2) had a remarkable
7na) with α-methyl α-bromoketones (1g, 1m–n), role in directing the transformation towards 3 or 7. It
bearing both aliphatic or aromatic substituents. Aiming was already reported that the alkene electronic effects
to expand our library of β,γ-alkenyl ketones 7, we significantly affect the outcome of similar
reacted some α-bromoketones with different olefins transformations[35c] and some authors justified their
obtaining the expected products in good yields (7ge, results considering that electron-donor substituents
7gf, 7gr, 7ne and 7mr). α-Methylstyrene 2g provided favor the radical oxidation[70] and the following double
high conversion, however, the β,γ-alkenyl ketone 7gg bond formation. Our results aligned with those already
was obtained in mixture with the γ,δ-alkenyl ketone
10gg. The trisubstituted alkene 2n was also tested: the
reaction with 2-bromo-1-phenyl-1-propanone 1g did
not proceed, whereas 2-bromoacetophenone 1i fur-
nished the expected product 7in although in low yield.
These findings confirm a significant impact of the
steric hindrance on the radical addition to the olefin.
We proceeded by reacting 2-bromo-1-phenyl-1-prop-
anone 1g with two different 1,1-dialkylethylenes. In
the presence of 1,1-dicyclohexylethylene 2p the trans-
formation did not take place even after 72 hours.
Conversely, a peculiar behavior was shown by 1,1-
dibutylethylene 2o providing the corresponding sub-
stituted tetralone as the main reaction product (53%)
(see Supporting Information). Lastly, we confirmed the
Scheme 4. Substrate-dependent chemodivergent transformation.
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reported. Although a single EDG was tolerated (3ab ingly obtained the desired product in quantitative yield
and 3ac, Scheme 2), two EDGs on the olefin (2f) (93%). In general, the reactions involving these
triggered the formation of a considerable amount of substrates (1o–q) were slow (72 hours), probably
β,γ-unsaturated ketone (37% of 7af). Moreover, a because the steric hindrance around the radical carbon
quantitative α-alkenylation was obtained reacting β- slowed the addition to the olefin. However, we
ketoester 1b with this highly electron-rich olefin (2f), observed a higher reactivity for α-EWG-substituted
whereas the same β-ketoester provided only dihydro- ketones (1o, 1p and 1r vs 1q), which could generate
furan when reacted with less electron-rich 1,1-diphe- more electrophilic and reactive radicals.
nylethylene 2a (7bf vs 3ba, respectively).
Mechanistic investigations. The study of processes
As last remark, we applied our photocatalytic involving oxidation states modifications is known to
protocol to α,α-disubstituted α-haloketones 1o–r be a challenging task, due to the formation of reactive
(Scheme 5). With these compounds the final proton- intermediates with short life-times.[76] To better under-
elimination leading to dihydrofurans 3 was not stand the reaction mechanism of our photoredox Ir-
possible, therefore, we expected the formation of the catalysed transformations, we decided to set up some
corresponding β,γ-alkenyl derivatives 7, as experimen- properly designed experiments and to confirm the
tally observed by many authors.[49,51,68d,69] Conversely, existence of the proposed intermediates with DFT
all the tested quaternary α-haloketones subjected to our calculations.
reaction conditions generated the cyclic hemiketal 6 as
First, were carried out a series of reactions in
the only reaction product, characterized by a tetrahy- different conditions, to demonstrate the visible light-
drofuran skeleton with three quaternary carbons promoted radical pathway of our reaction (Table 2).
(Scheme 5).
The crucial role of both the photocatalyst and light was
These highly substituted cyclopentyl hemiketals (6) confirmed, since in their absence the reactants were
are useful synthetic intermediates,[71] in particular for completely unreactive (entries 2–3, Table 2). A prom-
the preparation of materials[72] and medicinally relevant inent role for the excited photocatalyst fac-Ir(ppy)3 as
molecules.[73] Our approach represents a particularly initiator of a radical chain propagation mechanism was
straightforward synthesis of these scaffolds, which also excluded. In fact, the overall amount of cyclic
were obtained for the first time in high yield by radical products (3aa+6aa) obtained after two hours of
addition of ketones to olefins.[74] Among the obtained irradiation (entry 4) almost exactly matched with the
compounds, 2-acetyl-2-chlorocyclohexan-1-one 1o yield of the product 3aa obtained after 22 hours of
provided the spiro product 6oa in good yield (56%) as further stirring in the dark (entry 5, see Supporting
single diastereoisomer, and 2-chloro-2,2-difluoroaceto- Information for a detailed study). Moreover, the
phenone 1r quantitatively furnished the fluorinated measured photoreaction quantum yield was 0.24,
hemiketal 6ra. Only Konno and co-workers obtained reasonably confirming a closed catalytic cycle (Φ<1)
products with a similar substituents distribution but and ruling out a radical chain propagation mechanism
exploiting a much longer synthetic pathway.[72,75]
(see Supporting Information for details).[33b] The
Supposing a significant role of water in the radical inhibitor TEMPO completely stopped the
formation of these compounds, we repeated the syn- reaction (entry 6), thus suggesting an electron transfer-
thesis of 6qa in MeCN/H2O mixture and we gratify- triggered radical pathway. Furthermore, a high reso-
lution mass spectrometry (HRMS) study allowed us to
Table 2. Investigations on the reaction mechanism.
Entry Reaction conditions
modification
t [h]
Yield [%][b]
3aa 6aa 7aa
[a]
1
2
3
4
5
6
7
–
24
24
24
2
84
–
–
–
–
–
4
–
–
–
–
–
–
–
–
–
10
No catalyst
No light
–
Light+dark
TEMPO (2 eq.)
No freeze pump thaw 24
12
2+22 17
24
–
46
Scheme 5. For optimized reaction conditions see Scheme 2.
1
NMR yields determined by H NMR spectroscopic analysis of
[b]
[a] For optimized reaction conditions see Scheme 2.
Deter-
the crude mixture using triphenylmethane as internal standard
and integrating the signals of the products. Yields after flash
mined by 1H NMR spectroscopic analysis of the crude
mixture using triphenylmethane as internal standard and
integrating the signals of the products. TEMPO=2,2,6,6-
tetramethylpiperidine-1-oxyl.
[a]
[b]
chromatography reported in brackets. Reaction time: 72 h.
The mixture MeCN/H2O (1/4) was used as solvent without
base. [c] Reaction time: 24 h.
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detect the adduct between TEMPO and β-ketoester, detected, even in the absence of base or in the presence
supposed to generate the first radical intermediate (see of an excess of LiCl as carbocation quencher[60,62] (see
Supporting Information for details). At last, we proved Supporting Information for details). These findings
that the presence of oxygen, a well-known quencher of might suggest that the atom-transfer does not occur.
the excited state of many transition-metal polypyridyl However, the reaction of the intermediate halide might
compounds,[77] actually made the transformation less be so fast that it cannot be detected.
efficient, providing dihydrofuran 3aa in lower yield
(46%) together with some by-products (entry 7).
Based on the experimental evidences so far
obtained and on previous literature reports, a reason-
Second, Stern-Volmer luminescence quenching ex- able mechanistic rationale for our photoredox Ir-
periments (see Supporting Information) demonstrated catalyzed transformation was formulated, as shown in
that the quenching of excited fac-Ir(ppy)3 was accom- Schemes 6 and 7. Under visible light irradiation,
IV/III*
plished by the α-chloro substrate 1a’, supporting the IrIII(ppy)3 is photoexcited to [IrIII(ppy)3]* (E1/2
=
postulated SET in generating the first α-keto radical À 1.73 V),[42] which undergoes a single electron transfer
intermediate.
(SET) process in the presence of α-halo ketone 1,[78]
Finally, to evaluate the possible occurrence of an generating Ir(IV)+XÀ species and the electrophilic
atom-transfer reaction eventually followed by the radical A. This intermediate adds to electron-rich
1
elimination of HX, we analyzed by H-NMR, GC-MS olefin 2 providing radical B, which, in principle, can
and HRMS the crude mixtures deriving from ketoester follow two different reaction pathways (Schemes 6 and
1a’ and ketone 1g. No organic halide had ever been 7). In the first possible path (Scheme 6), radical B is
oxidized (E1/2ox = +0.23 V vs SCE for 2a and 2n, E1/
ox = +0.16 V vs SCE for 2g, E1/2ox = +0.37 V vs SCE
2
for 2j and 2m, E1/2ox = +0.09 V vs SCE for 2o)[79] by
Ir(IV) species (E1/2IV/III = +0.77 V),[42] restoring the
Ir(III)-complex and generating carbocation C. This
highly reactive intermediate may directly afford prod-
uct 7 by base-promoted elimination, or may undergo a
polar cyclization providing the cyclic cationic inter-
mediate D. This species differently behaves depending
on the substitution pattern. When a hydrogen is present
at α-position of the ketone (R6 =H), the reactive
intermediate D preferentially evolves through a base-
assisted proton-elimination leading to dihydrofuran 3.
Conversely, if no hydrogen is present at the α-position
(R6 ¼ H), hemiketal 6 is formed by interception of
cation D by traces of water present in the reaction
mixture. Indeed, the generation of hemiketal 6 is
increased in the presence of a large amount of water as
a reagent (entry 7, Table 1; product 6qa, Scheme 5).
Concerning dihydrofurans 3, we observed a com-
pletely different stability depending on the electronic
properties of the substituent R5, in particular under
slightly acidic conditions. Stable dihydrofurans are
obtained starting from ketones 1 substituted at the α-
position with EWGs, while the methyl-substituted
dihydrofuran 3ga converted spontaneously to the β,γ-
unsaturated ketone 7ga over silica gel or in CDCl3.
These experimental findings led us to postulate that the
β,γ-unsaturated ketones 7 were formed from the
corresponding dihydrofurans 3, through an acid-medi-
ated oxygen protonation followed by ring-opening and
proton-elimination (Scheme 6).[48,51,58,80] This hypothe-
sis was also supported by separate experiments
conducted by treating the obtained dihydrofurans 3
with the acidic species generated during the reaction
(see Supporting Information for details).
Scheme 6. Polar cyclization pathway.
Although the most popular mechanisms invoked for
similar radical transformations support almost com-
Scheme 7. Radical cyclization pathway.
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pletely the above mentioned mechanistic rationale Me, R5 =CO2Me, R6 =H) deriving from 1a or 1a’
(Scheme 6), we cannot completely rule out the with alkene 2a in the presence of 2,6-lutidine as the
possibility of a radical cyclization pathway, as reported base (Table 1, Entry 9, see Supporting Information for
in Scheme 7. In this second possible path, radical B details). The complete calculated energy profile for
directly cyclizes, providing the oxygen-substituted this transformation at the M06-2X/6-31+G(d,p)//
radical F, which in turn is oxidized by Ir(IV)+XÀ M06-2X/cc-pvtz using CH3CN as the solvent, afford-
species (E1/2IV/III = +0.77 V).[42] According to a radical- ing either 3aa or 7aa, is depicted in Figure 3. The
polar crossover transformation, the IrIII(ppy)3 photo- initial radical addition to give intermediate Ba resulted
catalyst would be regenerated by oxidation of radical F in a very favorable exergonic reaction (ΔG298 =À 21.7/
to carbocation D, which then evolves as already À 24.0 kcal·molÀ 1), characterized by a low-lying tran-
described (Scheme 6). However, the oxidation of oxy- sition state (TS1, ΔG� =5.8/3.4 kcal·molÀ 1). On the
genated radical F should be less favored than the contrary, the direct radical cyclization of Ba to afford
oxidation of radical B.[79b,81] Many papers report both Fa was a rather endergonic reaction (ΔG298 =12.1/
mechanisms (polar and radical cyclizations) as 14.6 kcal·molÀ 1), with a considerably large activation
possible,[8c,15,16,34,52c] and some authors believe the energy (TS2, ΔG� =27.4/28.0 kcal·molÀ 1). To assess
radical cyclization to be more likely under certain the feasibility of the oxidation reaction of radical Ba to
reaction conditions.[13c,17,25b,38,50e,57,82] Aiming to learn the carbocation Ca by Ir(IV) species, the correspond-
more about the mechanism of our photocatalytic ing oxidation potential was calculated according to the
process, we performed some DFT computational procedure recently reported by Nicewicz,[78c] by fully
investigations comparing the polar cyclization optimizing the relevant structures at the M06-2X/6-31
(Scheme 6) and the radical cyclization (Scheme 7) +G(d,p) and using CH3CN as the solvent (see
pathways. Moreover, we also tried to get a deeper Supporting Information for details). The calculated
insight on the chemodivergent behavior of α-EWG- oxidation potential (E°1/2 = +0.37 V vs SCE, CH3CN)
substituted and α-unsubstituted/alkyl-substituted halo was comparable with the values experimentally ob-
ketones 1.
tained for analogous benzhydryl derivatives[79] and it
DFT calculations. Given the reasonable existence accounts for a thermodynamically favored oxidation
of the radical A in the postulated mechanism, we reaction (ΔG298 =À 24.9 kcal·molÀ 1). The so obtained
started by modeling the reaction of radical Aa (R4 = carbocation Ca may now follow two distinct reaction
Figure 3. Complete free energy profile (kcal·molÀ 1) for the reaction between radical Aa and olefin 2a to afford alkene 7aa or
dihydrofuran (DHF) 3aa in the gas-phase at the M06-2X/6-31+G(d,p) level of theory. Energies in parentheses are relative to single
point calculations at the M06-2X/cc-pvtz level of theory in CH3CN. LUT=2,6-lutidine. Energies of Ca, TS4 and Da are scaled by
adding 2,6-lutidine calculated energy.
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pathways, either a lutidine-promoted elimination to the case of 1g and a larger elimination barrier both for
afford β,γ-unsaturated ketone 7aa (Figure 3, bottom TS7 vs TS3 and for TS8 vs TS5 – the two profiles
left) or a cationic cyclization to cation Da, followed were qualitatively similar. Once more, the formation of
again by a lutidine-promoted elimination to give the cyclic product 3ga seems to be favored also in the
dihydrofuran 3aa (Figure 3, bottom right). All in- case of ketone 1g, contrary to what was experimentally
volved reactions are favorable exergonic transforma- found.
tions with low activation energies. However, the
Summarizing the results of DFT calculations, Ir(IV)
cationic cyclization resulted slightly favored over the species are able to easily oxidize radicals B to the
competing elimination reaction (TS4/TS3, ΔΔG� = corresponding carbocations C, fostering a very favor-
À 1.2/À 1.3 kcal·molÀ 1), qualitatively accounting for able cationic cyclization pathway, ultimately leading to
the experimentally obtained results (Table 1, Entry 9: the formation of dihydrofurans 3, excluding a relevant
3aa/7aa=82/18), also considering that the subsequent contribution of a direct elimination reaction in the
elimination reaction to 3aa via TS5 resulted an almost formation of β,γ-unsaturated ketones 7 from cations C
barrierless transformation.
(Scheme 6). Moreover, the radical cyclization pathway
The analogous energy profile for the reaction of (Scheme 7) resulted considerably more energetically
radical Ag (R4 =Ph, R5 =Me, R6 =H) deriving from demanding than the cationic one, therefore it probably
1g, a ketone lacking the EWG at the α-position, with doesn’t play a relevant role in the overall reaction
alkene 2a in the presence of 2,6-lutidine as the base is mechanism. Finally, DFT calculations confirmed that
depicted in Figure 4. Given the similar oxidation the chemodivergent behavior of ketones not possessing
potential value obtained also for the oxidation of an EWG at the α-position is a direct consequence of
radical Bg to cation Cg by Ir(IV) species, (E°1/2 = + the experimentally determined lower stability of the
0.31 V vs SCE, CH3CN; ΔG298 =À 26.3 kcal·molÀ 1), corresponding dihydrofurans 3, rather than the result of
the radical cyclization pathway was not calculated in a competing reaction pathway. According to our
this case and the cationic pathway was postulated to be hypothesis (Scheme 6), we supposed that the proto-
once again the most favorable one. Even if some nated base present in the reaction mixture could act as
differences resulted by comparing the energy profiles an acid additive, triggering a base-assisted ring open-
relative to the reactions between 1a’ or 1g with 2a À ing of the alkyl-substituted (or not substituted) dihy-
most notably a true barrierless cationic cyclization in drofuran and promoting the formation of the observed
Figure 4. Complete free energy profile (kcal·molÀ 1) for the reaction between radical Ag and olefin 2a to afford alkene 7ga or
dihydrofuran (DHF) 3ga in the gas-phase at the M06-2X/6-31+G(d,p) level of theory. Energies in parentheses are relative to single
point calculations at the M06-2X/cc-pvtz level of theory in CH3CN. LUT=2,6-lutidine. Energies of Cg and Dg are scaled by
adding 2,6-lutidine calculated energy.
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alkenylation product 7. This ring opening pathway through an acid-promoted transformation (Scheme 6)
may be less efficient in the presence of an EWG (R5) and not from the cationic intermediate C, as reported
both depleting the endocyclic oxygen of electron by many authors.[9a,49,54a,56,57,68a,c,d,69c]
density and competing for the hydrogen-bonding with
the protonated base. Confirming this last hypothesis, it
is worth mentioning that the lutidinium cation in the
Conclusion
final calculated structure 3ga/LUTH+ moved consid- In summary, we have developed the first example of
erably away from the initial deprotonation position, to visible light-promoted photoredox catalytic reaction
bind the dihydrofuran endocyclic oxygen (Figure 5b), between α-halo ketones 1 and alkenes 2 showing a
while it remained almost in the same position in the predictable chemodivergent outcome. 2,3-Dihydrofur-
case of 3aa/LUTH+, stabilized by a hydrogen bond ans 3 or β,γ-unsaturated ketones 7 were obtained
interaction with the ester moiety at the α-position mainly depending on the substrate substitution pattern.
(Figure 5a).
However, the role played by the reaction conditions
To further support this mechanistic hypothesis was disclosed thanks to the identification of a plausible
experimentally, we performed some reactions in the reaction mechanism, based on careful experimental
presence of two equivalents of 2,6-lutidine as a soluble investigations and DFT calculations. Concerning the
base (Scheme 8).
proposed mechanistic hypothesis, two features of this
By minimizing the enol oxygen protonation, the transformation deserve to be emphasized: i) the
photocatalytic process furnished dihydrofurans 3 as the process is configured as a radical-polar crossover
main products also starting from alkyl- or phenyl- reaction, in which radical species are initially gener-
substituted α-halo ketones 1. These experimental ated and then converted into reactive cationic inter-
findings, together with the results of DFT calculations, mediates, ii) the transformation is redox-neutral, acting
confirmed that in our reaction conditions β,γ-unsatu- the Ir-catalyst as both reductant and oxidant in two
rated ketones 7 are formed from dihydrofurans 3 different steps of the process. The mild reaction
conditions and the redox-neutral nature of the trans-
formation make it particularly sustainable avoiding the
use of both sacrificial reactants and stoichiometric
strong oxidants, sometimes expensive, potentially
environmentally unfriendly and/or source of side-
reactions.
The developed protocol represents the first example
of photoredox catalytic coupling between α-haloke-
tones and unfunctionalized olefins providing variably
substituted β,γ-alkenyl ketones in good yields, avoid-
ing their rearrangement into the α,β-unsaturated deriv-
atives. Moreover, our approach offers a particularly
straightforward synthesis of cyclic hemiketals (6),
characterized by a tetrahydrofuran skeleton with three
quaternary carbons, which were obtained for the first
time in high yield by radical addition of ketones to
olefins.
Figure 5. DFT optimized structures of the final products 3aa/
LUTH+ (a) and 3ga/LUTH+ (b).
Experimental Section
General Information
All the commercial chemicals were purchased from Sigma-
Aldrich, VWR, Alfa Aesar, or TCI-Chemicals and used without
additional purifications. The 1H and 13C NMR spectra were
recorded on a Varian INOVA 400 NMR instrument with a
5 mm probe. All chemical shifts have been quoted relative to
residue solvent signal; chemical shifts (δ) are reported in ppm
and coupling constants (J) are reported in hertz (Hz). HPLC
analyses were performed on an Agilent Technologies HP1100
instrument. A Phenomenex Gemini C18 3 μm (100×3 mm)
column was employed for the chromatographic separation:
mobile phase H2O/CH3CN, gradient from 30% to 80% of
CH3CN in 8 min, 80% of CH3CN until 22 min, then up to 90%
Scheme 8. Reaction conditions: 1 (1.2 eq.), 2a (0.1 mmol),
Ir(ppy)3 (1 mol%), 2,6-lutidine (2 eq.), MeCN (1 mL), blue
LED (465 nm), freeze pump thaw (1 cycle), rt, 24 h. NMR
yields determined by H NMR spectroscopic analysis of the
crude mixture using triphenylmethane as internal standard and
integrating the signals of the products.
1
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of CH3CN in 2 min, flow rate 0.4 mLminÀ 1. Low-resolution
MS (LRMS) ESI analyses were performed on an Agilent
Technologies MSD1100 single-quadrupole mass spectrometer.
Mass spectrometric detection was performed in the full-scan
mode from m/z 50 to 2500, with a scan time of 0.1 s in the
positive ion mode, ESI spray voltage of 4500 V, nitrogen gas
pressure of 35 psi, drying gas flow rate of 11.5 mLminÀ 1 and
fragmentor voltage of 30 V. High-resolution MS (HRMS) ESI
analyses were performed on a Xevo G2-XS QTof (Waters) mass
spectrometer. Mass spectrometric detection was performed in
the full-scan mode from m/z 50 to 1200, with a scan time of
0.15 s in the positive ion mode, cone voltage: 40 V, collision
energy: 6.00 eV. ESI: capillary: 3 kV, cone: 40 V, source
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°
°
temperature: 120 C, desolvation temperature: 600 C, cone gas
flow: 50 L/h, desolvation gas flow: 1000 L/h. Melting point
(m.p.) measurements were performed on Bibby Stuart Scientific
SMP3 apparatus. Flash chromatography purifications were
carried out using VWR silica gel (40–63 μm particle size).
Thin-layer chromatography was performed on Merck 60 F254
plates.
Typical Procedure for the Photoredox Synthesis of
Products 3, 6 and 7
All reactions were performed on 0.1 mmol scale of olefin 2 (or
halogenated compound 1 when an excess of alkene was used).
A 4 mL screw cap septum vial equipped with a magnetic
stirring bar was charged with the olefin 2 (0.1 mmol), MeCN
(1 mL), the halogenated compound
1 (1.2 equivalents),
Na2HPO4 (1 equivalent) and Ir(ppy)3 (1 mol%). The vial was
closed and the oxygen was removed by one cycle of the freeze-
pump-thaw procedure, then the vial was filled with argon. The
reaction mixture was irradiated under strong stirring using blue
LED stripes (465 nm) for 24 h unless otherwise stated.
Eventually, the inorganic solid was filtered through a cotton
plug and the solvent was removed under reduced pressure. The
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1
crude mixture was analyzed by H NMR spectroscopy using
triphenylmethane (0.1 mmol) as an internal standard. The
product was then purified by flash chromatography on silica
gel.
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For the reactions carried out in the presence of water, the work-
up was as follows: EtOAc (1 mL) was added and the two
phases were separated. The aqueous phase was extracted two
more times with EtOAc (2×2 mL), the combined organic
phases were collected, dried over Na2SO4 and filtered. The
solvent was evaporated under reduced pressure.
Acknowledgements
We acknowledge Ministero dell’Università e della Ricerca
(PRIN2017 – 20174SYJAF_001, SURSUMCAT) and University
of Bologna (RFO) for the financial support.
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FULL PAPER
Chemodivergent Photocatalytic Synthesis of Dihydrofurans
and β,γ-Unsaturated Ketones
Adv. Synth. Catal. 2021, 363, 1–17
A. Quintavalla*, R. Veronesi, D. Carboni, A. Martinelli, N.
Zaccheroni, L. Mummolo, M. Lombardo*