Photoredox propargylation of aldehydes catalytic in titanium

Article abstract of DOI:10.1021/acs.joc.1c00521

A practical and effective photoredox propargylation of aldehydes promoted by 10 mol % of [Cp₂TiCl₂] is presented. No stoichiometric metals or scavengers are used for the process. A catalytic amount of the cheap and simply prepared or

Full text of DOI:10.1021/acs.joc.1c00521

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Photoredox Propargylation of Aldehydes Catalytic in Titanium
Francesco Calogero, Andrea Gualandi,* Marco Di Matteo, Simone Potenti, Andrea Fermi,
Giacomo Bergamini, and Pier Giorgio Cozzi*
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ABSTRACT: A practical and effective photoredox propargylation
of aldehydes promoted by 10 mol % of [Cp2TiCl2] is presented.
No stoichiometric metals or scavengers are used for the process. A
catalytic amount of the cheap and simply prepared organic dye
3DPAFIPN is used as the reductant for titanium. The reaction
displayed a broad scope, and no traces of allenyl isomers were
detected for simple propargyl bromide, whereas mixtures of
propargyl and allenyl isomers were observed for substituted
propargyl bromides.
Preliminarily, we have also mentioned that the propargyla-
tion reaction of aldehydes was also accessible by the dual
photoredox-mediated catalysis with titanium,9,16 and herein we
illustrate the potentiality, cleanness, and simplicity of the
propargylation reaction conducted under photoredox con-
ditions by the use of propargyl bromide.
n just a few years, photoredox catalysis has reached an
Iextraordinary level of advancement, introducing new and
exciting methodologies in organic chemistry.1 Besides electron
transfer, many interesting reactions can also be promoted by
photocatalytic methodologies using energy transfer (EnT) to
reach a reactive transition state in molecules or complexes.2
Now, dual photoredox catalysis,3 that is the combination of
metal-promoted processes with photoredox cycles, is in
continuous development.4 From the application of synergistic
dual photoredox catalysis to cross-coupling reactions, metal-
catalyzed processes were addressed to radical to polar cross-
over reactions (RPC),5 with the aim of developing important
C−C bond-forming reactions.6 In this context, allylation
methodologies were introduced with chromium,7 nickel,8 and
titanium.9 Particularly, the earth-abundant titanium can give
important advantages in terms of sustainability and eco-
Starting by employing hydrocinnamic aldehyde 1a, we have
optimized the model propargylation reaction using propargyl
bromide, and in general, it was found that the reaction was
promoted by the organic dyes 3DPAFIPN, affording the
product 3a in good yields. 4CzIPN17 and 3CzClIPN18 were
also tested in the model reactions and gave inferior results
(Table 1, entries 3 and 4, respectively). All reactions were
performed with the cheap and commercially available
[Cp2TiCl2]. As reported in our allylation reaction,9a the use
of THF, with a substrate concentration of 0.05 M, was
important to allow the desired transformation due to the
strong overlap in the absorbance of the photocatalyst and the
titanium complex. The optimized conditions are in line with
the photophysical observation because the concentration of the
red titanium complex (ε455nm ≈ 250 M−1 cm−1) allows a
significant absorption of the blue photons by 3DPAFIPN
(ε455nm ≈ 2900 M−1 cm−1) to promote the photoinduced
electron transfer. Hantzsch’s ester was found to be the best
choice as the stoichiometric reductant since various sacrificial
reductants (i.e., different amines) were proved to be not suited
for the propargylation reaction. This is in part related to the
friendliness of the process,10 and its use in combination with
11
̈
photoredox catalysis was first explored by Gansauer. In
addition, the interesting photophysical properties of titanium
complexes make the further exploration of their chemistry in
the excited state even more intriguing.12 We recently have
reported the allylation reaction of aldehydes, employing 10 mol
% of the inexpensive [Cp2TiCl2], in the presence of an organic
dye, 3DPAFIPN,13 and Hantzsch’s ester as the stoichiometric
reductant.9 Quite recently, Glorius has reported an interesting
carbonyl propargylation14 via dual chromium/photoredox
catalysis, taking advantage of a catalytic radical three
components coupling of 1,3-enynes, aldehydes, and radical
precursors, in the presence of CrCl3 and visible light.15
However, the direct use of propargylic halides or alkynes for
the generation of propargyl chromium species is still not
reported by means of the emerging dual photoredox catalytic
system.
Received: March 4, 2021
Published: April 22, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.1c00521
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Table 1. Propargylation Reaction of Hydrocinnamaldehyde
and Variation of Some Reaction Parameters
Scheme 1. Dual Photoredox Propargylation of Aromatic
Aldehydes
a
b
entry
deviations from standard conditions
yield (%)
c
1
none
>99(98)
2
3
4
5
1.0 mmol scale, 48 h, 3 mol % of 3DPAFIPN
4CzIPN instead of 3DPAFIPN
3CzClIPN instead of 3DPAFIPN
no Light
>99(93)
62
57
0
6
7
8
9
10
11
12
no Hantzsch’s ester
no [Cp2TiCl2]
no degassed solvent
no photocatalyst, with irradiation at 456 nm
in the presence of TEMPO (1 equiv)
DMF instead of THF
0
0
homopropargylic alkoxide. As a matter of fact, the protonated
pyridine derivative obtained by the oxidation of the Hantzsch’s
ester behaves as a scavenger for the reaction, enabling the
desired turnover of the employed titanium complex. As was
observed for the allylation reaction, also in the photoredox
propargylation reaction, 10 mol % of the [Cp2TiCl2] complex
gave the optimal catalyst concentration. In all reported
examples with aromatic aldehydes, no traces of the possible
75
0
10
traces
55
CH3CN instead of THF
a
Reactions performed on a 0.1 mmol scale irradiating with a 40W
Kessil lamp, 456 nm. Determined by H NMR analysis. Values in
parentheses represent the yield after chromatographic purification.
Reaction performed on a 0.2 mmol scale.
b
1
1
allenylic product were detected by H NMR analysis of the
c
crude reaction mixture. The reaction is also quite effective with
aliphatic aldehydes (3q−v), and excellent results were
obtained (Scheme 2). Branched aliphatic aldehydes were
lack of stability of [Cp2TiCl2] in the presence of different
amines under irradiation.16 The propargylation reaction was
quite sensitive to traces of oxygen and water, and low yields
were isolated, performing the reaction in the presence of
oxygen (Table 1, entry 8). It is worth noting that the
photocatalyst does not decompose during the photoreaction
and can be easily recovered at the end of the reaction by flash
chromatography.
Scheme 2. Dual Photoredox Propargylation of Aliphatic
Aldehydes
It was possible to scale the reaction up to 1.0 mmol,
increasing the reaction time to 48 h without observing an
appreciable decrease of the yield (Table 1, entry 2).
The selected reaction conditions were employed to test the
scope of the reaction with aromatic and aliphatic aldehydes. As
evident by the data reported in Scheme 1, aromatic and
heteroaromatic aldehydes are suitable substrates for the
reaction. Yields are, in general, from good to moderate. The
presence of electron-withdrawing groups on the aromatic ring
reduced the yield of the reaction. Sterical hindrance in the
ortho-position does not hamper the reactivity, with either
activating or deactivating groups. Although the oxidized
product of Hantzsch’s ester (the corresponding protonated
pyridinium) is strongly acidic and could favor undesired
reaction pathways involving the indole ring, indole substrates
are reactive in the propargylation reaction, giving much better
yields compared to what was observed for the allylation
reaction.9a Variously substituted thiophene carboxaldehydes
are suitable substrates for the transformation. As already noted
in the allylation reaction, no additives or scavengers are
required for the release of the desired homopropargylic alcohol
with the concomitant restoration of the titanium complex from
found to be reactive substrates, furnishing the respective
homopropargylic alcohols in good yields. In addition, aliphatic
aldehydes with acidic protons, whose propargylation products
can suffer from undesired water elimination pathways, are
suitable substrates. No modifications in the conditions were
made to perform the reaction with aliphatic aldehydes with
respect to aromatic substrates.
In general, the reactions ran smoothly without any
significant inconveniences. Also, with aliphatic aldehydes, the
reactions favored the propargylic derivatives in all examined
cases.
We have briefly investigated the outcome of the reaction in
the case of different propargylic bromides (Scheme 3).
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We have already reported9 that Hantzsch’s ester and
[Cp2TiCl2] are effective quenchers of the photocatalyst. It is
also worth mentioning that we have also established that the
pyridine salt formed in the reaction is not a quencher at any
concentration. In the case of propargylation, the absence of
quenching with propargylic bromide suggests the mechanism
illustrated in Figure 1. The oxidative quenching of
Scheme 3. Dual Photoredox Propargylation of Aliphatic
Aldehydes
Figure 1. Proposed catalytic cycle.
*3DPAFIPN is responsible for the formation of [Cp2TiCl]
and 3DPAFIPN•+. The latter is a strong oxidant (E(PC•+/PC)
= +1.30 vs SCE),13 and the photoredox cycle is closed by the
Hantzsch’s ester (E(HE•+/HE) = +1.0 vs SCE), which reduces
the 3DPAFIPN•+ back to 3DPAFIPN. The reaction produces
the strong reductant HE•+ that can participate in further
electron transfer events,21 generating the rearomatized
Hantzsch’s ester, in the form of its pyridinium salt.
Furthermore, the oxidative quenching of the photocatalyst in
its excited state by the titanium complex [Cp2TiCl2] generates
the [Cp2TiCl] species. A radical-mediated addition22 of
[Cp2TiCl] to the propargyl bromide gave the corresponding
allenylic/propargylic titanium reagents. Subsequent reaction of
the allenylic species with aldehydes gave the titanium-alkoxy
derivatives that are transformed into the corresponding
alcohols by acidic protons available from the oxidized
Hantzsch’s ester pyridinium salt. In fact, the latter is an acidic
compound, and it features a low pKa compared to other
reagents used as scavengers in the catalytic redox reaction
promoted by titanium chemistry (such as collidine·HCl).23
In summary, we have described a direct photoredox
propargylation reaction mediated by a cheap and not toxic
titanium complex that affords the desired homopropargylic
alcohols in good yields with both aromatic and aliphatic
aldehydes. Further studies about metal photoredox-mediated
reactions24 are in progress in our laboratory.
Interestingly, the presence of aliphatic or aromatic substituents
on the propargylic moiety favors the allenylic product,
probably due to the major sterical hindrance of the allenylic
titanium intermediate, compared to the propargylic. The
synthesis and structural characterizations of allenyl titanocene-
(IV) and propargyl titanocene(IV) were reported in
literature.19 These compounds are involved in fast metal-
lotropic allenyl−propargyl equilibria in solution prior to the
electrophilic quenching,20 as confirmed by DFT calculations.
Therefore, the reactivity of differently substituted propargylic
halides are controlled by the different energy barriers in
transition states relative to the reaction of the propargyl and
allenyl titanium(IV) precursors with carbonyls via SE2
mechanism and not by the metallotropic equilibria.19
The reaction with secondary propargyl bromides gave
unsatisfactory simple diastereoselection; in this case, the result
could be imputable to the absence of control in the formation
of the allenyl titanium intermediate. We have conducted the
Stern−Volmer analysis of the reaction, similarity to our
previous study of allylation, by simply varying the concen-
tration of propargyl bromide added to the 3DPAFIPN. As
illustrated in Figure S3B (see Supporting Information), in air-
equilibrated solution, the emission intensity of 3DPAFIPN is
barely decreasing upon increasing the concentration of
propargyl bromide, thus highlighting a slow diffusional
quenching (kq 1.0 × 108 M−1 s−1).
The same conclusions can be drawn by observing the
negligible changes in the emission lifetime in the presence of
propargyl bromide at concentrations up to ca. 0.13 M (Figure
S3C). In degassed solutions, the long-excited state lifetime of
pristine 3DPAFIPN (172 μs) is decreasing to 41 μs upon the
addition of propargyl bromide at high concentrations (ca. 0.11
M). The estimated quenching constant is 3 orders of
magnitude lower than that determined for [Cp2TiCl2] in the
same experimental conditions (kq ≈ 105 and 5.2 × 108 M−1 s−1,
respectively;8 see Figure S4B), pointing out that a photo-
induced electron transfer is more likely to occur to the latter.
EXPERIMENTAL SECTION
■
1
General Methods and Materials. H NMR, 13C NMR, and 19F
NMR spectra were recorded on a Varian Mercury 400 spectrometer.
The residual protic signal of the solvent for the H and 13CDCl3
1
signals for 13C were used as references for spectra recorded in CDCl3
(7.26 and 77.16 ppm, respectively). The trifluoroacetic acid signal
(−76.55 ppm) was used as a reference for 19F NMR spectra.
Chemical shifts are reported in parts per million (ppm) of the δ scale
1
relative to TMS for H and 13C NMR spectra and CFCl3 for 19F
NMR spectra. Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, dd = doublet of doublet, ddd =
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doublet of doublet of doublet, td = triplet of doublet, m = multiplet),
coupling constants (Hz). Chromatographic purifications were
performed with 240−400 mesh silica gel. HPLC-MS analyses were
performed on an Agilent Technologies HP1100 instrument coupled
with an Agilent Technologies MSD1100 single-quadrupole mass
spectrometer using a Phenomenex Gemini C18 3 μm (100 mm × 3
mm) column; mass spectrometric detection was performed as follows:
in full-scan mode from m/z 50 to 2500, scan time 0.1 s in positive ion
mode, ESI spray voltage 4500 V, nitrogen gas 35 psi, drying gas flow
rate 11.5 mL min−1, and fragmentor voltage 30 V. HRMS was
performed on a Waters Xevo G2-XS QTof, ESI+, cone voltage 40 V,
Capillary 3KV, with a source temperature of 120 °C. All reactions
were set up under an argon atmosphere in oven-dried glassware
(borosilicate) using standard Schlenk techniques. The reaction
mixture was irradiated with a Kessil PR160L@456 nm. Lamp
technical specifications are available on the manufacturer’s web
site.25 The reaction vessel was placed 10 cm approximately from the
lamp, and the temperature was maintained at room temperature by
cooling with a PR160 ring w/fan kit.26 3DPAFIPN,13 4CzIPN,13
3CzClIPN,13 and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicar-
boxylate (Hantzsch’s Ester)27 were prepared following literature
procedures.
Standard Procedure for Photoredox Titanium-Catalyzed
Propargylation of Aldehydes. All reactions were performed on a
0.2 mmol scale of aldehyde. A dry 10 mL Schlenk tube, equipped with
a Rotaflo stopcock, magnetic stirring bar, and argon supply tube, was
first charged under argon with the organic photocatalyst 2,4,6-
tris(diphenylamino)-5-fluoroisophthalonitrile 3DPAFIPN (5 mol %,
0.010 mmol, 6.4 mg), [Cp2TiCl2] catalyst (10 mol %, 0.02 mmol, 5.0
mg), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,
i.e. Hantzsch’s ester (2 equiv, 0.4 mmol, 100 mg). Inhibitor-free dry
THF (4 mL, in order to obtain a 0.05 M solution of aldehyde) was
then added, the reaction mixture was further subjected to a freeze−
pump−thaw procedure (three cycles), and the vessel was refilled with
argon. Then, propargyl bromide derivative 2a−d (0.6 mmol, 3 equiv)
and the substrate 1a−v (0.2 mmol) were added. The reaction was
irradiated under vigorous stirring for 14 h. After that, the reaction
mixture was quenched with H2O (approximately 5 mL) and extracted
with AcOEt (4 × 5 mL). The combined organic layers were dried
over anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The crude was subject of flash column chromatography
(SiO2) to afford the products 3a−v, 4a−c, and 5a−b in the stated
yields.
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.29
1-(2-Chlorophenyl)but-3-yn-1-ol (3c): brown oil, 76% (0.15
mmol, 27 mg). The general procedure was applied using 1c (0.2
mmol, 22.4 μL) previously distilled and 2a (solution 80% v/v in
toluene, 0.6 mmol, 56 μL, 3 equiv). The title compound was isolated
by flash column chromatography (100% DCM). Spectroscopic data
were in agreement with those reported in literature.28
1-(4-Fluorophenyl)but-3-yn-1-ol (3d): brown oil, 78% (0.16
mmol, 22.3 mg). The general procedure was applied using 1d (0.2
mmol, 22 μL) previously distilled and 2a (solution 80% v/v in
toluene, 0.6 mmol, 56 μL, 3 equiv). The title compound was isolated
by flash column chromatography (100% DCM). Spectroscopic data
were in agreement with those reported in literature.30
1-(4-(Trifluoromethyl)phenyl)but-3-yn-1-ol (3e): brown oil,
40% (0.08 mmol, 18 mg). The general procedure was applied using
1e (0.2 mmol, 28 μL) previously distilled and 2a (solution 80% v/v in
toluene, 0.6 mmol, 56 μL, 3 equiv). The title compound was isolated
by flash column chromatography (100% DCM). Spectroscopic data
were in agreement with those reported in literature.31
1-(Naphthalen-2-yl)but-3-yn-1-ol (3f): brown oil, 71% (0.14
mmol, 28 mg). The general procedure was applied using 1f (0.2
mmol, 32 mg) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.8
1-Phenylbut-3-yn-1-ol (3g): brown oil, 58% (0.12 mmol, 18
mg). The general procedure was applied using 1g (0.2 mmol, 20.4
μL) previously distilled and (solution 80% v/v in toluene, 0.6 mmol,
56 μL, 3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.32
1-([1,1′-Biphenyl]-4-yl)but-3-yn-1-ol (3h): brown oil, 68%
(0.14 mmol, 30.2 mg). The general procedure was applied using 1h
(0.2 mmol, 36 mg) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56
μL, 3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.33
1-(4-(tert-Butyl)phenyl)but-3-yn-1-ol (3i): brown oil, 50% (0.1
mmol, 20.2 mg). The general procedure was applied using 1i (0.2
mmol, 32 μL) previously distilled and 2a (solution 80% v/v in
toluene, 0.6 mmol, 56 μL, 3 equiv). The title compound was isolated
by flash column chromatography (100% DCM). Spectroscopic data
were in agreement with those reported in literature.34
Procedure for 1 mmol Scale. A dry 50 mL Schlenk tube,
equipped with a magnetic stirring bar and argon supply tube, was first
charged under argon with the organic photocatalyst 3DPAFIPN 2,4,6-
tris(diphenylamino)-5-fluoroisophthalonitrile (3 mol %, 0.03 mmol,
19 mg), [Cp2TiCl2] catalyst (8 mol %, 0.08 mmol, 0.020 g), and
diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, namely,
Hantzsch’s ester (2 equiv, 2 mmol, 0.500 g). Inhibitor-free dry
THF (20 mL in order to obtain a 0.05 M solution of aldehyde) was
then added, the reaction mixture was further subjected to a freeze−
pump−thaw procedure (four cycles), and the vessel refilled with
argon. Then, propargyl bromide 2a (80% v/v in toluene, 3 mmol, 3
equiv, 0.280 mL) and the substrate 1a (1 mmol, 0.134 g, 0.132 mL)
were added. The reaction was irradiated under vigorous stirring for 48
h. After that, the solvent was removed under reduced pressure. The
crude was subjected to flash column chromatography (SiO2) to afford
the products 3a in 93% yield (0.93 mmol, 0.162 g).
1-Phenylhex-5-yn-3-ol (3a): brown oil, 98% (0.195 mmol, 34
mg). The general procedure was applied using 1a (0.2 mmol, 26 μL)
previously distilled and 2a (solution 80% v/v in toluene, 0.6 mmol, 56
μL, 3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.28
1-(4-Chlorophenyl)but-3-yn-1-ol (3b): brown oil, 86% (0.17
mmol, 31 mg). The general procedure was applied using 1b (0.2
mmol, 28 mg) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
1-(4-Methoxyphenyl)but-3-yn-1-ol (3j): brown oil, 56% (0.11
mmol, 19 mg). The general procedure was applied using 1j (0.2
mmol, 26 μL) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.35
1-(3-Methoxyphenyl)but-3-yn-1-ol (3k): brown oil, 71% (0.14
mmol, 25 mg). The general procedure was applied using 1k (0.2
mmol, 26 μL) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.29
1-(2-Methoxyphenyl)but-3-yn-1-ol (3l): brown oil, 62% (0.12
mmol, 22 mg). The general procedure was applied using 1l (0.2
mmol, 26 μL) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.31
1-(Benzo[d][1,3]dioxol-5-yl)but-3-yn-1-ol (3m): brown oil,
67% (0.13 mmol, 25 mg). The general procedure was applied using
1m (0.2 mmol, 38 mg) and 2a (solution 80% v/v in toluene, 0.6
mmol, 56 μL, 3 equiv). The title compound was isolated by flash
column chromatography(100% DCM). Spectroscopic data were in
agreement with those reported in literature.29
1-(Thiophen-3-yl)but-3-yn-1-ol (3n): brown oil, 75% (0.15
mmol, 23 mg). The general procedure was applied using 1n (0.2
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mmol, 18 μL) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.36
1-(Thiophen-2-yl)but-3-yn-1-ol (3o): brown oil, 40% (0.08
mmol, 12 mg). The general procedure was applied using 1o (0.2
mmol, 18 μL) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL,
3 equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.32
toluene, 0.6 mmol, 56 μL, 3 equiv). The title compound was isolated
by flash column chromatography (100% DCM). In analogy with the
reported data in literature for similar compounds,39 it was possible to
distinguish the syn and the anti isomer. The diastereoisomeric ratio
1
was calculated, considering the H NMR spectrum of the reaction
crude, comparing the integral of the signal at 3.77 ppm for the syn
product and at 3.49 for the anti product. 3vsyn 1H NMR (401 MHz,
CDCl3): δ 7.33−7.18 (m, 5H, overlapped with the residual peak of
the solvent and peaks related to the other isomer aromatic protons),
3.77 (s, 1H), 3.09−2.97(m, 1H), 2.52−2.39 (m, 1H), 2.05 (t, J =
12.0, 2.6 Hz, 2H), 1.93−1.83 (m, 3H), 1.33−1.29 (m, 3H). 13C NMR
(101 MHz, CDCl3): δ 146.9, 128.6 (2H), 127.1(2H), 126.2, 80.8,
70.9, 68.0, 44.6, 36.5, 27.9, 23.1. 3vanti 1H NMR (401 MHz, CDCl3):
δ 7.33−7.18 (m, 5H, overlapped with the residual peak of the solvent
and peaks related to the other isomer aromatic protons), 3.49 (s, 1H),
2.96−2.87(m, 1H), 2.37−2.20 (m, 1H), 2.02 (t, J = 12.0, 2.6 Hz, 2H),
1.82−1.74 (m, 3H), 1.28−1.24 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 146.3, 128.5 (2H), 126.8 (2H), 126.1, 80.6, 70.8, 67.7,
44.5, 36.4, 27.4, 22.0. HRMS (ESI/Q-TOF) m/z: [M-H2O + H]+
calcd for C13H15, 171.1174; found, 171.1160.
1-(4-Chlorophenyl)-2-phenylbuta-2,3-dien-1-ol and 1-(4-
Chlorophenyl)-4-phenylbut-3-yn-1-ol (4a−4a′): brown oil, 76%
(0.14 mmol, 36 mg) as a mixture regioisomers 4a/4a′ (91:9). The
general procedure was applied using 1b (0.2 mmol, 28 mg) and 2b
(0.6 mmol, 117 mg, 3 equiv). The ratio of regioisomer was calculated
considering the 1H NMR spectrum of the reaction crude and
comparing the integral of the signal at 5.71 ppm for 4a and at 4.91
ppm for 4a′. The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.40
tert-Butyl 3-(1-Hydroxybut-3-yn-1-yl)-2-methyl-1H-indole-
1-carboxylate (3p): brown oil, 68% (0.14 mmol, 41 mg). The
general procedure was applied using 1p (0.2 mmol, 52 mg) and 2a
(solution 80% v/v in toluene, 0.6 mmol, 56 μL, 3 equiv). The title
compound was isolated by flash column chromatography (100%
1
DCM). H NMR (401 MHz, CDCl3): δ 8.10 (d, J = 8.0 Hz, 1H),
7.77 (d, J = 7.6 Hz, 1H), 7.30−7.16 (m, 2H overlapped with the
residual peak of the solvent), 5.22 (dd, J = 7.9, 6.2 Hz, 1H), 2.96
(ddd, J = 16.7, 8.2, 2.4 Hz, 1H), 2.68 (ddd, J = 16.7, 5.8, 2.4 Hz, 1H),
2.60 (s, 3H), 2.35 (s, 1H), 2.06 (t, J = 2.3 Hz, 1H), 1.68 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3): δ 150.6, 136.0, 134.2, 127.3,
123.5, 122.4, 119.4, 118.4, 115.4, 83.9, 80.9, 70.5, 67.1, 28.2, 27.4,
14.2. HRMS (ESI/Q-TOF): m/z [M-Boc-H2O + H]+ calcd for
C13H11N, 181.0891; found, 182.0961. HRMS (ESI/Q-TOF): m/z [M
+ Na]+ calcd for C18H21NO3Na, 322.1419, found, 322.1409.
(Z)-Dodec-9-en-1-yn-4-ol (3q): yellow oil, 99% (0.2 mmol, 36
mg). The general procedure was applied using 1q (0.2 mmol, 34 μL)
and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL, 3 equiv). The
title compound was isolated by flash column chromatography (100%
1
DCM). H NMR (401 MHz, CDCl3): δ 5.50−5.19 (m, 2H), 3.80−
3.71 (m, 1H), 2.43 (ddd, J = 16.7, 4.7, 2.6 Hz, 1H), 2.31 (ddd, J =
16.7, 6.7, 2.6 Hz, 1H), 2.11−1.98 (m, 5H), 1.97−1.85 (m, 1H),
1.57−1.51 (m, 2H), 1.44−1.35 (m, 3H), 1.25 (m, 1H), 0.95 (td, J =
7.5, 2.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 131.8, 128.8,
80.8, 70.7, 69.8, 36.1, 29.6, 27.3, 26.9, 25.2, 20.5, 14.3. ESI-MS: m/z
198.2 [M + NH4]+. HRMS (ESI/Q-TOF): m/z [M + NH4]+ calcd
for C12H24NO, 198.1858; found, 198.1853.
Pentadec-1-yn-4-ol (3r): brown oil, 65% (0.13 mmol, 25 mg).
The general procedure was applied using 1r (0.2 mmol, 32 μL) and
2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL, 3 equiv). The title
compound was isolated by flash column chromatography (100%
DCM). Spectroscopic data were in agreement with those reported in
literature.37
1-Phenylpent-4-yn-2-ol (3s): brown oil, 87% (0.17 mmol, 28
mg). The general procedure was applied using 1s (0.2 mmol, 23 μL)
and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL, 3 equiv). The
title compound was isolated by flash column chromatography (100%
DCM). Spectroscopic data were in agreement with those reported in
literature.38
1-Cyclohexylbut-3-yn-1-ol (3t): brown oil, 85% (0.17 mmol, 26
mg). The general procedure was applied using 1t (0.2 mmol, 22 μL)
and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL, 3 equiv). The
title compound was isolated by flash column chromatography (100%
DCM). Spectroscopic data were in agreement with those reported in
literature.29
1,1-Diphenylpent-4-yn-2-ol (3u): brown oil, 76% (0.15 mmol,
36 mg). The general procedure was applied using 1u (0.2 mmol, 39.2
mg) and 2a (solution 80% v/v in toluene, 0.6 mmol, 56 μL, 3 equiv).
The title compound was isolated by flash column chromatography
(100% DCM). 1H NMR (401 MHz, CDCl3): δ 7.41 (dd, J = 8.2, 1.0
Hz, 2H), 7.37−7.18 (m, 8H), 4.54 (ddd, J = 8.7, 6.3, 4.5 Hz, 1H),
4.13 (d, J = 8.7 Hz, 1H), 2.46 (ddd, J = 16.9, 4.3, 2.7 Hz, 1H), 2.30
(ddd, J = 16.9, 6.4, 2.7 Hz, 1H), 2.17−2.08 (m, 1H), 2.04 (s, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 141.7, 140.6, 128.8 (3C), 128.7
(2C), 128.6 (2C), 128.2, 126.8, 126.9, 80.6, 71.7, 71.1, 56.9, 25.3.
HRMS (ESI/Q-TOF) m/z: [M-H2O + H]+ calcd for C17H15N,
219.1174, found, 219.1164.
1-(4-Chlorophenyl)-2-methylbuta-2,3-dien-1-ol and 1-(4-
chlorophenyl)pent-3-yn-1-ol (4b−4b′): brown oil, 46% (0.1
mmol, 18 mg) as a mixture of regioisomers 4b/4b′ (66:34). The
general procedure was applied using 1b (0.2 mmol, 28 mg) and 2c
(0.6 mmol, 52 μL, 3 equiv). The regioisomeric ratio was calculated
considering the 1H NMR spectrum of the reaction crude and
comparing the integral of the signal at 5.10 ppm for 4b and at 4.77
ppm for 4b′. The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.41
4-Methyl-1-phenylhexa-4,5-dien-3-ol and 1-phenylhept-5-
yn-3-ol (4c−4c′): brown oil, 90% (0.18 mmol, 34 mg) as a mixture
of regioisomers 4c/4c′ (71:29). The general procedure was applied
using 1v (0.2 mmol, 26 μL) and 2c (0.6 mmol, 52 μL, 3 equiv). The
regioisomeric ratio was calculated considering the 1H NMR spectrum
of the reaction crude and comparing the integral of the signal at 4.81
ppm related for 4c and at 4.72 ppm for 4c′. The title compound was
isolated by flash column chromatography (100% DCM). Spectro-
scopic data were in agreement with those reported in literature.42
1-(4-Chlorophenyl)-2-methylbut-3-yn-1-ol and 1-(4-
chlorophenyl)penta-2,3-dien-1-ol (5a−5a′): brown oil, 80%
(0.16 mmol, 31 mg) as a mixture of regioisomers and
diastereoisomers 5a/5a′ of 97:3, 5asyn/5aanti dr of 1:1. The
regioisomeric ratio was calculated considering the 1H NMR spectrum
of the reaction crude and comparing the integrals of the signal at 4.71
ppm for 5a and at 5.29 ppm for 5a′. The diastereoisomeric ratio was
1
calculated considering the H NMR spectrum of the reaction crude
comparing the integral of the signal at 4.71 ppm for the product 5asyn
and at 4.51 ppm for the product 5aanti. The general procedure was
applied using 1b (0.2 mmol, 28 mg) and 2d (0.6 mmol, 79 mg, 3
equiv). The title compound was isolated by flash column
chromatography (100% DCM). Spectroscopic data were in agreement
with those reported in literature.43
4-Methyl-1-phenylhex-5-yn-3-ol and 1-phenylhepta-4,5-
dien-3-ol (5b−5b′): brown oil, 94% (0.19 mmol, 35 mg) as a
mixture of regioisomers and diastereoisomers of 5b/5b′ of 92:8,
5bsyn/5banti dr of 18:82. The regioisomeric ratio was calculated,
1
considering the H NMR spectrum of the reaction crude, comparing
6-Phenylhept-1-yn-4-ol (3v): brown oil, 55% (0.11 mmol, 20
mg) as a syn/anti mixture, dr of 1:1. The general procedure was
applied using 1v (0.2 mmol, 29.6 mg) and 2a (solution 80% v/v in
the integral of the signal at 3.49 ppm for 5b and at 4.80 ppm for 5b′.
1
The diastereoisomeric ratio was calculated, considering the H NMR
7006
https://doi.org/10.1021/acs.joc.1c00521
J. Org. Chem. 2021, 86, 7002−7009

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
spectrum of the reaction crude, comparing the integral of the signal at
3.54 ppm related to the product 5bsyn and the multiplet (1H) at 3.49
ppm related to the product 5banti. The general procedure was applied
using 1a (0.2 mmol, 26 μL) and 2d (0.6 mmol, 79 mg, 3 equiv). The
title compound was isolated by flash column chromatography (100%
DCM). Spectroscopic data were in agreement with those reported in
literature.44
ACKNOWLEDGMENTS
■
Prof. P. Ceroni and Dr. M. Marchini are acknowledged for
helpful discussions. National project (PRIN 2017 ID:
20174SYJAF) SURSUMCAT “Raising up Catalysis for
Innovative Developments” is acknowledged for financial
support of this research.
Photophysical and Mechanistic Studies. All photophysical
analyses were carried out in air-equilibrated tetrahydrofuran at 298 K
unless otherwise specified. UV−vis absorption spectra were recorded
with a PerkinElmer λ40 spectrophotometer using quartz cells with an
optical path length of 1.0 cm. Degassed solutions are obtained by
means of repeated pump−freeze−thaw cycles (ca. 4 × 10−6 mbar) in
sealed quartz cuvettes. Luminescence spectra were performed with a
PerkinElmer LS-50, a Varian Cary Eclipse, or an Edinburgh FLS920
spectrofluorimeter equipped with a Hamamatsu R928 phototube.
Lifetimes shorter than 10 μs were measured by the above-mentioned
Edinburgh FLS920 spectrofluorimeter equipped with a TCC900 card
for data acquisition in time-correlated single-photon counting
experiments (0.5 ns time resolution). The estimated experimental
errors are 2 nm on the band maximum, 5% on the molar absorption
coefficient, and luminescence lifetime.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00521.
Photos of reaction setup, copies of NMR spectra, and
photophysical study results (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
̀
Andrea Gualandi − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
Bologna, Italy; orcid.org/0000-0003-2403-4216;
Email: andrea.gualandi10@unibo.it
̀
Pier Giorgio Cozzi − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
Bologna, Italy; orcid.org/0000-0002-2677-101X;
Email: piergiorgio.cozzi@unibo.it
Authors
̀
Francesco Calogero − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
Bologna, Italy
̀
Marco Di Matteo − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
(4) Zhang, H. H.; Chen, H.; Zhu, C.; Yu, S. A Review of
Enantioselective Dual Transition Metal/Photoredox Catalysis. Sci.
China: Chem. 2020, 63 (5), 637−647.
Bologna, Italy
(5) Pitzer, L.; Schwarz, J. L.; Glorius, F. Reductive Radical-Polar
Crossover: Traditional Electrophiles in Modern Radical Reactions.
Chem. Sci. 2019, 10 (36), 8285−8291.
̀
Simone Potenti − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
Bologna, Italy; Scuola Normale Superiore, 56126 Pisa, Italy;
orcid.org/0000-0002-6300-3124
(6) Wiles, R. J.; Molander, G. A. Photoredox-Mediated Net-Neutral
Radical/Polar Crossover Reactions. Isr. J. Chem. 2020, 60 (3−4),
281−293.
̀
Andrea Fermi − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
(7) (a) Schwarz, J. L.; Schäfers, F.; Tlahuext-Aca, A.; Luckemeier, L.;
̈
Bologna, Italy
Glorius, F. Diastereoselective Allylation of Aldehydes by Dual
Photoredox and Chromium Catalysis. J. Am. Chem. Soc. 2018, 140
(40), 12705−12709. (b) Mitsunuma, H.; Tanabe, S.; Fuse, H.;
Ohkubo, K.; Kanai, M. Catalytic Asymmetric Allylation of Aldehydes
with Alkenes through Allylic C(sp3)-H Functionalization Mediated by
Organophotoredox and Chiral Chromium Hybrid Catalysis. Chem.
Sci. 2019, 10 (12), 3459−3465. (c) Schwarz, J. L.; Huang, H. M.;
Paulisch, T. O.; Glorius, F. Dialkylation of 1,3-Dienes by Dual
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̀
Giacomo Bergamini − Alma Mater Studiorum, Universita di
Bologna, Dipartimento di Chimica “G. Ciamician”, 40126
Bologna, Italy; orcid.org/0000-0002-2135-4073
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00521
Notes
The authors declare no competing financial interest.
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https://doi.org/10.1021/acs.joc.1c00521
J. Org. Chem. 2021, 86, 7002−7009

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