Cp2TiCl2-Catalyzed Photoredox Allylation of Aldehydes with Visible Light

Article abstract of DOI:10.1021/acscatal.0c00348

A Barbier-type Cp₂TiCl₂-mediated (10 mol %) photoredox allylation of aldehydes under irradiation with visible light (blue light-emitting diodes (LEDs), 450 nm) and in the presence of an organic dye (3DPAFIPN, 5 mol %) with allylbromides is described.

Full text of DOI:10.1021/acscatal.0c00348

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Article
Cp2TiCl2-CATALYZED PHOTOREDOX ALLYLATION
OF ALDEHYDES WITH VISIBLE LIGHT
Andrea Gualandi, Francesco Calogero, Martino Mazzarini, Simone
Guazzi, Andrea Fermi, Giacomo Bergamini, and Pier Giorgio Cozzi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00348 • Publication Date (Web): 28 Feb 2020
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Cp TiCl -CATALYZED PHOTOREDOX
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ALLYLATION OF ALDEHYDES WITH VISIBLE
LIGHT
Andrea Gualandi,* Francesco Calogero, Martino Mazzarini, Simone Guazzi, Andrea Fermi,
Giacomo Bergamini,* and Pier Giorgio Cozzi*
Dipartimento di Chimica “Giacomo Ciamician”, Alma Mater Studiorum – Università di
Bologna, Via Selmi 2, 40126, Bologna, Italy
E-mail: andrea.gualandi10@unibo.it; giacomo.bergamini@unibo.it; piergiorgio.cozzi@unibo.it
KEYWORDS Titanium • allylation • photoredox catalysis • aldehydes • Hantzsch Ester
ABSTRACT A Barbier-type Cp TiCl -mediated (10 mol%) photoredox allylation of aldehydes
2
2
under irradiation with visible light (blue LEDs, 450 nm) and in the presence of an organic dye
(3DPAFIPN, 5 mol%) with allylbromides is described.
Allylation of carbonyls is a key strategy for the preparation of functionalized building blocks
1
in the total synthesis of natural products. In particular, allylation reaction realized under Barbier
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conditions can give access to transient organometallic reactive allylating species. Normally,
over-stoichiometric amount of sacrificial reductant such as metallic manganese or zinc, in the
presence of an active redox metal complex is necessary. In Barbier type allylation performed
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with catalytic amount of titanium or chromium (Nozaki-Hiyama-Kishi reaction), the use of a
scavenger able to liberate the active metal from the organic product is mandatory for sustaining
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the catalytic cycle. Pioneering studies reported by Fürstner and Gansäuer have introduced the
practice of catalytic redox cycle in Organic Synthesis, further developed into interesting
stereoselective variants.8
Photoredox catalysis, by the use of metal complexes, dyes, or semiconductors, can give
9
interesting approaches to radical species by electron transfer (ET) or energy transfer. The
combination of photoredox catalytic cycle with other catalytic cycles, working cooperatively,
opens the way to new reaction pathways.10 Metallaphotoredox catalysis, i.e. metal catalysis
merged with photoredox catalysis, is a new and rapidly growing research area.11 Now,
photoredox catalysis is starting to explore the possibility to use a clean and rapid access to
1
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radicals for generating nucleophilic reagents. This concept, that combines radical and polar
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chemistry, in a so-called reductive radical-polar crossover (RRPC) was recently reviewed. In
this approach, a suitable alkyl radical is converted into a nucleophile by reduction or by capture
with a suitable transition metal complex. These so formed nucleophilic species can then react
with electrophiles such as carbonyls or imines.
Glorius and Kanai have recently reported RRPC photoredox allylation methodologies based on
14
chromium (Figure 1). In these radical reactions, photogenerated allyl radicals are converted
into a traditional nucleophilic Cr(III)allyl reagents by means of a single electron reduction
carried out by the Cr(II) present in the reaction mixture. The Cr(II) used in catalytic amount was
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re-generated by the photocatalytic cycle. Importantly, these new transformations are still in their
infancy, although high enantiomeric excesses can be obtained.14b,c
A (2018).
O
OH
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H
R
Cr Ir
Ni
+
R
R = electron-rich aryl,heteroaryl, amino d.r. >19:1
to 11:1; up to 95% yield
B (2019).
O
Ni
OH R2
H
R1
Cr PC
Mg L*
*
*
R4
+
R3
R4
R2
R1
R3
1
2
3
4
PC = organophotocatalyst, L* = BOX, R , R , R , R = alkyl
d.r. 20:1, ee 85-99%, up to 97% yield
C (2020).
O
R
OH
*
R'
R'
Cr PC
Ni
*
+
+
Me
N
H
Me
R
PC = organophotocatalyst, L* = BOX, R = alkyl, R' = COOEt, CN
d.r. 2.3:1-9:1, ee 84-96%, up to 93% yield
This work: simple and general titanium/photoredox allylation of aldehydes
O
OH
Ti PC
X +
R
Hantzsch ester
R
R = H, Me, Ph
X = Cl, Br
Ni
up to 94:6 d.r.,
up to 98% yield
Figure 1. Photoredox synergistic allylations of aldehydes; A, see ref. 14a; B, see ref. 14b; C, see
ref. 14c.
In this paper, we report a practical and straightforward radical-polar crossover photoredox
allylation of aldehydes mediated by titanium complexes, that give access to a wide range of
homoallylic alcohols in high yields. Moreover, the reaction uses 1,3-dicyano-5-fluoro-2,4,6-
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tris(diphenylamino)-benzene (3DPAFIPN) as the photocatalyst, a cheap and easily prepared
organic dye, in the presence of the readily available Hantzsch’s ester as sacrificial reductant and
scavenger for the titanium complexes.
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Recently, we have reported a nickel based dual photoredox approach in the allylation of
aldehydes, with a broad scope and functional groups compatibility, by the use of commercially
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available or easily prepared allylacetates. However, we want to explore the use of affordable
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green metals and mild reaction conditions. In particular, the use of Cp Ti(III)Cl, the Nugent-
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Rajanbabu reagent, in Barbier-type allylation reactions, is particularly attractive, as titanium
is considered non-toxic, environmentally friendly, and abundant.19
Methodologies based on the employment of Cp (III)TiCl in catalytic conditions, in the
2
presence of stoichiometric amounts of active metals (Mn) and in combination with 2,4,6-
collidine and Me SiCl added more interest in this chemistry, leading to the discover of new
3
2
0
transformations. In addition, recently Gansäuer reported an interesting study on the photoredox
titanium mediated reactions of epoxides, combining Cp Ti(III)Cl catalysis with photoredox
2
catalysis bypassing the requirement of metallic reductants and stoichiometric acidic additives.21
Shi and co-workers have recently reported another synergistic utilization of
titanocene/photoredox dual catalysis in the radical opening/spirocyclization of epoxyalkynes in
the presence of 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as a photocatalyst and
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Hantzsch’s ester. Based on our, Gansäuer and Shi studies, we have settled a new photoredox
allylation of aldehydes mediated by catalytic amount of titanium complex, and in Table 1 some
key observations about the reaction conditions are reported.
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Table 1. Allylation reaction and variation of some reaction parameters.
[
3
Cp2TiCl2], 10 mol%
DPAFIPN, 5 mol%
O
OH
3a
Br
Ph
+
Ph
THF 0.05 M, Blue LEDs
1a
2a, 3 equiv.
rt, 14h
Hantzsch ester, 2 equiv.
NPh2
NC
CN MeOOC
COOMe
Ph N
NPh2
DPAFIPN
N
2
H
F
3
Hantzsch ester
Entrya Deviations from standard conditions
Yield (%)b
1
none
>99 (98)c
®
>99 (98)c
2
40W Kessil lamp 456 nm, 6 h
®
>99 (97)c
3
40W Kessil lamp 456 nm, 14 h, 0.7 mmol scale
4d
5
40W Kessil lamp 456 nm, 48 h, 5 mmol scale
®
>99 (96)c
4CzIPN instead then 3DPAFIPN
45
96
0
6e
7e
8
{Ir[dF(CF )ppy] (dtbbpy)}(PF ) instead of 3DPAFIPN
3
2
6
[Ru(bpy) ]Cl instead of 3DPAFIPN
3
2
No Hantzsch ester
0
9
Allylchloride instead of allylbromide
No [Cp TiCl ]
92
0
1
1
1
1
1
0
2
2
1
2
3
4
No light
0
No degassed solvent
0
No photocatalyst, with irradiation at 380 nm
Toluene instead of THF
0
60
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a
b
c
Reactions performed on 0.1 mmol scale. Determined by 1H-NMR analysis. Isolated yield
d
after chromatographic purification. The reaction was performed using 8 mol% of Cp TiCl and
mol % of 3DPAFIPN. 1% of the photocatalyst was used.
2
2
e
3
Hydrocinnamic aldehyde (1a) was used in the model reaction, and in general it was found that
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the reaction was promoted by various photocatalysts (entries 5-6 Table 1, and Table S7), LED
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sources (entries 1-2, Table 1), with the organic dyes 3DPAFIPN affording good conversions
and extremely clean reactions. Other organic dyes were found to be less efficient in promoting
the transformation. Different titanium complexes and salts were employed (see Table S3),
demonstrating their inferior ability to promote the reaction compared to the cheap and available
Cp TiCl . Reaction conditions were carefully optimized bringing out that THF with a substrate
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concentration of 0.05 M was crucial. It is also important the role played by the Hantzsch’s ester
since a series of different sacrificial reductants were found not suitable for the reaction (see
Table S5). In this regard, we firstly checked the stability of Cp TiCl in the presence of different
2
2
amines (See Figure S15). The addition of 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-
benzo[d]imidazole (BIH), quinuclidine and other aliphatic amines to a mM solution of Cp TiCl
2
2
causes changes in the absorption spectrum attributable to ligand exchange. The bulky
triphenylamine (TPA) did not interact with the titanium complex in the ground state, but
absorption changes have been observed under visible light irradiation. However, addition of
amines was found deleterious, giving practically no conversion (see Table S6). From a practical
point of view, the reaction was quite sensitive to traces of oxygen and water. 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. By the use of a Kessil® LED lamp at 456 nm
(
40 W, for 6 hours, Table 1 entry 2), it was possible to considerably reduce the reaction time and
to scale the reaction up to 5 mmol without observing lower conversion and yield (Table 1 entries
3 and 4).
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The wide applicability of our initial finding was confirmed with a variety of aromatic and
aliphatic aldehydes, and Schemes 1 and 2 illustrate the salient results obtained. As evident by the
data reported in Scheme 1, aromatic, and heteroaromatic aldehydes are suitable substrates for the
reaction. Yields are good to moderate as a function of the presence of electron-withdrawing
groups, that have an impact on the isolated yields. As the Hantzsch ester is oxidized under the
reaction conditions to the corresponding protonated pyridinium salt, with concomitant formation
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+
of H , acid sensitive substrates such as pyrrole or indole gave lower yields due to decomposition
promoted by the presence of Brønsted acids.
Scheme 1. Synergistic allylation reaction of aromatic aldehydes.
OH
O
[
Cp2TiCl2], 10 mol%
3DPAFIPN, 5 mol%
Br
+
Ar
Ar
b-p
(2 x 0.1 mmol)
THF 0.05 M, Blue LEDs,
rt, 14-48h
Hantzsch ester, 2 equiv.
1
2a, 3 equiv.
3b-p
OH
OH
OH
OH
3b, 90%
tBu
3c, 77% Ph
3d, 86%
OH
3e, 83%
OH
Cl
OH
OH
3f, 85%
3g, 41%
3g, 52%
CF3
3h, 70%
3i, 49%
a 3i, 48%
Cl
NC
a
OH
OH
OH
MeOOC
3j, 68%
Me2N(O)C
OH
3k, 63%
MeO
3l, 75%
OH
OH
OH
O
O
S
S
Ph
3m, 65%
3n, 71%
3o, 47%
N
3p, 21%
Boc
a
reaction performed with Kessill lamp 456 nm, reaction time 4 h
Hindered aromatic substrates were found less reactive. In comparison to the published titanium
mediated allylation reaction, a minor percentage of titanium (10 vs 20 mol%) it is necessary. No
further scavengers or bases are necessary for the titanium as the proton derived from the
oxidation of the Hantzsch’s ester is able to restore the catalytic cycle acting as a scavenger.
Differently substituted linear aliphatic aldehydes are quite suitable substrates as illustrated in
Scheme 2 (see Scheme S2 for further substrates studied).
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Scheme 2. Synergistic allylation reaction of aliphatic aldehydes.
[
3
Cp2TiCl2], 10 mol%
DPAFIPN, 5 mol%
OH
O
Br
+
R
R
THF 0.05 M, Blue LEDs,
rt, 14-48h
1
q-y
2a, 3 equiv.
3q-y
(2 x 0.1 mmol)
Hantzsch ester, 2 equiv.
OH
OH
OH
6
4
3
q, 73%
3r, 40%
3s, 60%
OH
OH
OH
O
O
BnO
TBSO
3
3
3t,79%
3u, 69%
3v, 60%
OH
OH
TsHN
OH
2
[
a]
3w, 60%
3x, 84%
rac-3y, 90%, 1.2:1 syn:anti
[
a]
reaction performed with Kessill lamp 456 nm, reaction time 14 h
Hindered aromatic substrates were found less reactive. In comparison to the published titanium
®
irradiation with powerful Kessil lamp is necessary for hindered cyclohexane carboxaldehyde. In
the case of pyvalic aldehyde, the reaction gave only low yields (see Scheme S2). Reaction with
chiral aldehydes 1y gave quite moderate diastereoisomeric ratio, in favor of a Felkin-controlled
allylation product. The reaction is quite tolerant to functional groups including halides, CF3,
esters, nitriles, ethers. Interestingly, acidic NH groups were also tolerated although aliphatic or
aromatic amines cannot be used.
Allyl bromide bearing substituents in three position can be employed with good
regioselectivity in favor of the branched products and with moderate to good yields (Scheme 3).
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Scheme 3. Synergistic allylation reaction with crotyl bromoderivative.
Br 2b, 3 equiv.
1
1
1
1
1
1
1
1
1
1
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2
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O
OH
OH
[Cp TiCl ], 10 mol%
2
2
3DPAFIPN, 5 mol%
Ph
Ph
+
Ph
THF 0.05 M, Blue LEDs, rt, 48h
Hantzsch ester, 2 equiv.
1a
rac-3aa
3aa'
(
2 x 0.1 mmol)
rac- >99:1, anti:syn d.r. 91:9, 50%
3aa:3aa'
Br 2b, 3 equiv.
O
OH
OH
[Cp2TiCl2], 10 mol%
3DPAFIPN, 5 mol%
+
THF 0.05 M, Blue LEDs, rt, 48h
Hantzsch ester, 2 equiv.
1e
rac-3ea
3ea:3ea'
3ea'
(
2 x 0.1 mmol)
rac-
84:16, anti:syn d.r. 94:6, 82%
Allyl substituted reagents are in general less reactive to respect allylbromide under our
photoredox condition, as indicated by the preliminary results obtained (Scheme 4) with cinnamyl
bromide (2c) and in the presence of prenyl bromide (2d).
Scheme 4. Synergistic allylation reaction with substituted allyl bromoderivatives.
Ph
Br 2c, 3 equiv.
[Cp2TiCl2], 10 mol%
O
OH
OH
3DPAFIPN, 5 mol%
+
Ph
Ph
Ph
2 x 0.1 mmol)
Ph
THF 0.05 M,
Kessil lamp 456 nm, rt, 14h
Hantzsch ester, 2 equiv.
1a
Ph
3ac
3ac'
(
3
ac:3ac' 93:7, anti:syn 85:15, 25%
Br 2d, 3 equiv.
[
3
Cp2TiCl2], 10 mol%
DPAFIPN, 5 mol%
O
OH
OH
+
Ph
Ph
Ph
THF 0.05 M,
1a
2 x 0.1 mmol)
Kessil lamp 456 nm, rt, 14h
Hantzsch ester, 2 equiv.
3ad
3ad'
(
3ad:3ad' 69:31, 27%
Ketones showed a quite reduced reactivity in this reaction compared to aldehydes, and the
corresponding products were isolated in low yields, even using Kessil® lamp (see Scheme S2).
In order to evaluate the photoinduced mechanism of the reaction we investigated the quenching
of the photocatalyst’s luminescence by each of the components of the reaction (see SI). As
observed for similar substituted isophthalonitriles,15,23 3DPAFIPN is particularly suitable in
photocatalysis because possesses a very long emission lifetime in degassed solutions at room
temperature (0.130 ms in THF at λ 520 nm, see SI for details). Interestingly, no change in the
em
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intensity and decay of the 3DPAFIPN emission was observed upon addition of the allyl bromide
and hydrocinnamic aldehyde (at the same concentrations used to perform the reaction). On the
other hand, the addition of Hantzsch’s ester and Cp TiCl induces strong changes in the emission
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intensity of the photocatalyst. In particular, the quenching constants, determined from Stern-
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-1 -1
8
-1 -1
Volmer experiments, are 1.5 x 10 M s for the Hantzsch’s ester and 5.2x10 M s for the Ti
complex in degassed solutions (as in the employed photoreaction conditions described above). It
is worth noting that the two Stern-Volmer plots have been obtained using the ratio of the lifetime
(0/) for the quenching relative to Ti, because it re-absorbs the light emitted by 3DPAFIPN, and
the ratio of the emission intensity (I /I) in the case of Hantzsch’s ester because of the
0
superposition of its emission with pulsed laser source at 405 nm (see SI). To evaluate a possible
role of the pyridine, produced by the oxidation of the Hantzsch’s ester, in the photoinduced
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processes, we also test the quenching of 3DPAFIPN emission by this compound. No quenching
of the excited state of 3DPAFIPN was measured at any concentration of pyridine added (Figure
S20). The optimized reaction conditions are in line with the photophysical observation, because
the amount of 3DPAFIPN should be enough to absorb significant blue photons to promote the
photo induced electron transfer. However, the cost, availability and sustainability of these two
players, make the present approach extremely competitive for large scale application. The
determination of the quantum yield carried out gave a value of 1.3 % (see SI for full details).
Based on the results of the photophysical investigation, and although we cannot exclude short
radical chains, the tentative catalytic cycle is depicted in Figure 2. The oxidative quenching of
●+
3
DPAFIPN induces the formation of Cp Ti(III)Cl. The 3DPAFIPN is a strong oxidant
2
15
(
E3DPAFIPN●+/3DPAFIPN = + 1.30 vs SCE) and is reduced by the Hantzsch’s ester (EHE●+/ = +1.0
HE
vs SCE).25 The reaction is producing HE●+ that can participate in further electron transfer
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events25 and is a strong reductant. As suggested by Cuerva and Oltra, two molecules of
3
Cp Ti(III)Cl are necessary for the formation of the allyl titanium specie. Two possible scenarios
2
could be envisioned. The two molecules of Cp Ti(III)Cl are generated by two oxidative
2
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quenching of two molecules of *3DPAFIPN. In the other hand, one molecule of Cp TiCl is
2
2
●+
reduced by the *3DPAFIPN and another by the formed HE . In experiments carried out with
crotyl, cinnamyl, and prenyl reagents (Schemes 3 and 4) we have observed a prevalent -
regioselectivity. It is well-known that both crotyl–Ti(IV) and prenyl–Ti(IV) reagents react with
carbonyl favoring the -position.26 As is illustrated in Figure 2, the reaction is probably
proceeding through the radical coupling between allyl radicals and Cp Ti(III)Cl, that forms the
2
allylating Ti(IV) reagents. The protonated re-aromatized Hantzsch ester possesses a low pKa
(
see Scheme S3 for reactions induced by this Brønsted acid), compared to other reagents used as
scavengers in the catalytic redox reaction promoted by titanium chemistry (such as collidine and
Me SiCl), and it is efficient in restoring the catalytic cycle by protonation of the titanium-alkoxy
3
bond.
Figure 2. Proposed mechanism for the reaction.
3DPAFIPN
*3DPAFIPN
HE
2 X
or
X and HE
2 [Cp2TiX]
+ 2 X-
X
R1
SET
1
ET
HE
[3DPAFIPN]
COOMe
R1
[
Cp2TiX2]+ Cp2XTi
MeOOC
2
[Cp2TiX2]
O
R
N
OH
H
OTiCp2X
1
R
R
H+ + e-
Cp
H
+
R1
R
H+ + X-
Ti
Cp
O
1R
R
HE = Hantzsch ester; X = Cl, Br
H
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In summary, we have reported a novel allylation photoredox methodology based on the use of
Cp TiCl complex. From the point of view of a green chemistry perspective, the abundance and
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low toxicity of titanium make the procedure attractive for organic synthesis.20,27 Careful
mechanistic studies has shed light of the application on 3DPAFIPN or parent organic dyes in
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accessing Cp Ti(III)Cl reagent, avoiding the use of stoichiometric metal, such as Mn or Zn. The
2
Hantzsch’s ester used as stoichiometric reductant is unique for the titanium(III) chemistry, and
its oxidized and protonated form is beneficial for the turn-over of the titanium catalyst. Further
2
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studies to expand these radical-polar crossover reaction and to use other redox reactive metals
are in progress and will be reported in due time.
AUTHOR INFORMATION
Corresponding Author
*
Prof. P. G. Cozzi Alma Mater Studiorum – Università di Bologna, Via Selmi 2, 40126,
piergiorgio.cozzi@unibo.it
Author Contributions
A.G., G. B. and P. G. C. conceived the study. Photoredox reactions were carried out by A. G., F.
C, and M. M.. S. G and A. F. carried out the photophysical investigations, supervised by G. B..
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
National project (PRIN 2017 ID: 20174SYJAF) SURSUMCAT ”Raising up Catalysis for
Innovative Developments” is acknowledged for financial support of this research.
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Supporting Information. The following files are available free of charge.
Reaction optimization studies. Synthetic procedures for allylation reaction and preparation of
substrates and photocatalysts. Spectroscopic data for new compounds, and copies of NMR
spectra. Photophysical studies for the model reaction and Stern-Volmer plot.
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ACKNOWLEDGMENT
Prof. P. Ceroni and Dr. M. Marchini are acknowledged for helpful discussions.
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