Organocatalytic Enantioselective Alkylation of Aldehydes with [Fe(bpy)3]Br2 Catalyst and Visible Light

Article abstract of DOI:10.1021/acscatal.5b01573

Catalytic amounts (2.5 mol %) of [Fe(bpy)₃]Br₂ complex in the presence of visible light and the MacMillan catalyst 3 (20 mol %) are highly effective in promoting an enantioselective organocatalytic photoredox alkylation of aldehydes

Full text of DOI:10.1021/acscatal.5b01573

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Letter
Organocatalytic Enantioselective Alkylation of
Aldehydes with [Fe(bpy)3]Br2 Catalyst and Visible Light.
Andrea Gualandi, Marianna Marchini, Luca Mengozzi, Mirco
Natali, Marco Lucarini, Paola Ceroni, and Pier Giorgio Cozzi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01573 • Publication Date (Web): 02 Sep 2015
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Organocatalytic Enantioselective Alkylation of Aldehydes with
[Fe(bpy)3]Br2 Catalyst and Visible Light.
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Andrea Gualandi,† Marianna Marchini,† Luca Mengozzi,† Mirco Natali,⊥,‡ Marco Lucarini,† Paola Ceroni,*,†,‡ and Pier
Giorgio Cozzi*,†
†Dipartimento di Chimica “G. Ciamician” ALMA MATER STUDIORUM, Università di Bologna, Via Selmi 2, 40126,
Bologna, Italy. Emails: paola.ceroni@unibo.it; piergiorgio.cozzi@unibo.it
⊥Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Ferrara, Italy.
‡Centro Inter Universitario per la Conversione Chimica dell'Energia Solare (SOLAR-CHEM)
ABSTRACT: Catalytic amounts (2.5 mol%) of [Fe(bpy)3]Br2 complex in the presence of visible light, and the MacMillan
catalyst 3 (20 mol%), are highly effective in promoting an enantioselective organocatalytic photoredox alkylation of alde-
hydes with various α-bromo carbonyl compounds. Reaction yields of isolated compounds and enantioselectivities are very
good and comparable to the ones obtained by [Ru(bpy)3]2+, organic dyes, or semiconductors, in the presence of the same
organocatalysts. The use of first row abundant and cheap metals in photocatalyzed reactions can open new perspectives
in stereoselective organic synthesis.
KEYWORDS Photocatalysis, [Fe(bpy)3]Br2, Organocatalysis, Stereoselective alkylations, Aldehydes, Radicals.
Due to the mild reaction conditions and the high enan-
tiomeric excesses obtained, asymmetric catalysis promot-
ed by visible light, a sustainable and economical source of
energy, is emerging as an active new field of investiga-
tion.1 There are basically three leading strategies to pro-
mote enantioselective chemical reactions by light with
enamine organocatalysts and bromo derivatives,2 and all
of them are based on photoinduced electron transfer (ET)
processes.3 In 2008, MacMillan’s group reported the first
example of merging visible light induced photoredox ca-
talysis in asymmetric organocatalysis by using
[Ru(bpy)3]2+as photosensitizer (Figure 1, A).4 Chiral
enamines formed in situ as nucleophilic partners are able
to intercept the radical species generated by the photore-
dox event. Similarly, radical species can be generated by
other photosensitizers as organic dyes,5 semiconductors,6
or chiral iridium complexes.7 A variant for the generation
FIGURE 1. Strategies in stereoselective photocatalytic addi-
tion of bromo derivatives: A, asymmetric photocatalysis with
Ru(bpy)32+; B, asymmetric photocatalysis induced by EDA
complex; C, enamine photo-induced electron transfer.
of radical species was disclosed by Melchiorre, that used
chiral enamines able to form electron donor-acceptor
(EDA) complexes with benzyl halides electrophiles. The
resulting EDA complexes are capable of absorbing visible
light and inducing a charge transfer (Figure 1, B).8 Melchi-
orre was also reporting that quite nucleophilic enamines9
can photoreduce species that are not forming with them
EDA complexes (Figure 1, C).10 In all these processes three
general events are occurring in order to drive the chemi-
cal reaction: i) a photo driven-initiation step; ii) the elec-
tron transfer (ET) involving the photosensitizer (or the
EDA complexes, or enamine); iii) the oxidation of gener-
ated α-amino radicals to iminium ions (Figure 1).
Most commonly employed photosensitizers are based on
rare and expensive ruthenium and iridium complexes, alt-
hough interesting processes based on copper11,12 and
chromium13 photosensitizers have been described. The
discovery and employment of metal complexes as alterna-
tive, earth-abundant, first-row transition metals for pho-
toinduced synthetic organic transformations13 would be a
major advance in the area of photocatalysis. Particularly,
the use of iron(II) complexes would be in fact quite at-
tractive for photocatalytic stereoselective reactions as iron
is inexpensive, and very abundant.
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Photophysical properties of iron(II) tris(bipyridine) com-
Page 2 of 15
plexes were fully investigated.14 The prototypical
[Fe(bpy)3]2+ complex displays a metal-to-ligand charge-
transfer (MLCT) band in the visible region. The lowest
energy excited state is a metal-centered (MC) state, which
is formed within a hundred femtoseconds from the MLCT
excited states and it is not luminescent, due to fast non-
radiative decay to the ground state (ca. 650 ps lifetime).14f
[Fe(bpy)3]2+Is not a good candidate for dynamic electron-
transfer processes because of the extremely short lifetime
of the lowest energy excited state. Nevertheless, iron(II)
polypyridyl complexes have been reported as photosensi-
tizers of TiO2 demonstrating ultrafast electron injection.15
In this communication, we report that the combination of
2.5 mol% of [Fe(bpy)3]Br2 and visible light can effectively
replace [Ru(bpy)3]2+ or other photosensitizers in practical
and effective organocatalytic stereoselective reactions.
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SCHEME 2. Scope of the stereoselective alkylation pro-
moted by [Fe(bpy)3]Br2.
In addition, we have investigated the practical use of pho-
toinduced iron(II) reaction to access useful synthetic in-
termediates. The addition of bromo ester 2e to hydrocin-
namic aldehydes 1a,g,h (see SI for preparation) gave in a
straightforward manner the lactons 13-15, key intermedi-
ates for the synthesis of biologically active compounds.
SCHEME 1. Optimized conditions for the [Fe(bpy)3]Br2
photocatalyzed reaction.
In order to investigate the possibility to use iron(II)
polypyridyl complexes in photocatalysis we have selected,
as benchmark reaction, the α-alkylation of aldehydes de-
veloped by MacMillan (Scheme 1).4a Various Fe(II) com-
plexes were tested in the model reaction with chiral (ra-
cemic and enantiopure) organocatalysts (see SI for de-
tails). We discovered that [Fe(bpy)3]Br2 used in catalytic
amount (2.5 mol%) was a compelling and effective photo-
sensitizer for promoting the reaction between hydrocin-
namaldehyde and dimethyl bromomalonate, in the pres-
ence of 20 mol% of the organocatalyst 3 (Scheme 1) and
upon irradiation with visible light.
Isolated yields and enantiomeric excesses obtained were
comparable to the reaction promoted by [Ru(bpy)3]2+. No
decomposition of the photosensitizer was observed at the
end of the reaction, as monitored by the absorption band
in the visible region (Figure S11). Among all the iron com-
plexes investigated (see SI) [Fe(bpy)3]Br2gave the maxi-
mum yields, and from various solvent investigated, DMF
was the solvent of choice; enantioselectivity was optimal
at room temperature. The reaction was investigated in
detail with various aldehydes and bromo derivatives. The
salient results are reported in Scheme 2. In general, a
good scope for the reaction was observed. It was possible
to employ in the reaction various bromo-substituted car-
bonyl compounds as the reaction tolerates various func-
tional and protecting groups. No side reaction is observed
with aldehydes bearing alkene functional groups.
SCHEME 3. Preparation of enantioenriched lactones via
alkylation of aldehydes and synthesis of (-)-
isodehydroxypodophyllotoxin.
The lacton 15 was transformed into the natural product 16
by a straightforward transformation as illustrated in
Scheme 3.16,17,18
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To clarify mechanistic details about our reaction, we con-
ducted some control experiments. As CFL lamp emits also
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in the UV region (Figure S14) where reagents absorb light
(green line in Figure S12 is the reaction mixture without
the photosensitizer), we ruled out a UV-induced mecha-
nism by testing the reaction upon visible irradiation (λ>
420 nm) (Table S6), where only the photosensitizer
[Fe(bpy)3]Br2 absorbs light and effectively promotes the
reaction.19 On the other hand, in the presence of the iron
sensitizer and in the absence of light, the reaction does
not proceed. (Table S6).
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In order to prove the formation of radical species under
the combined action of light and [Fe(bpy)3]Br2we under-
took the study of the formation of radicals with EPR, in
the presence of a radical trap.20,21 The spin trap experi-
ments were performed in the presence of PBN (see
Scheme 4). In order to get a good EPR signal for the cor-
rect characterization of the spin adduct, we initially irra-
diated the reaction mixture with light containing also
near UV (λ > 320nm). Actually, irradiation at these wave-
lenghts of a deoxygenated DMF solution containing bro-
momalonate 2a (0.5 M), [Fe(bpy)3]Br2(10 mol%) and PBN
(0.1 M), resulted in a strong EPR signal consisting of a
characteristic doublet of triplets (Figure 2a). The spec-
trum was attributed to spin adduct 17 (Scheme 4), result-
ing from addition of malonate alkyl radical to PBN, as
suggested by the values of the EPR parameters22 (aN= 14.95
G, aH = 4.75 G, g = 2.0057) which are typical for PBN ad-
ducts with alkyl radicals having carbonyl groups in α-
position.17
FIGURE 2. EPR spectra of spin adduct 17 generated in DMF
in the presence of dimethyl bromomalonate 2a (0.5 M) and
PBN (0.1 M) as the spin trap at room temperature. Reaction
conditions: a) [Fe(bpy)3]Br2(10 mol%), irradiation with UV-
visible light (λ>320 nm); b) [Fe(bpy)3]Br2(10 mol%), irradia-
tion with visible light (λ>420 nm); c) [Fe(bpy)3]Br2(10 mol%)
no irradiation.
From these experiments it is clear that visible light and
[Fe(bpy)3]Br2 are necessary to drive the reaction to com-
pletion. Furthermore, EPR studies with a radical trap evi-
dence the formation of a radical and the reaction is com-
pletely shut down in the presence of TEMPO (20 mol%
and 100 mol%). To get more insights onto the mecha-
nism, an experiment with light turned off and on (Figures
S1-2) was performed and showed that reaction is proceed-
ing also when light is switched off, suggesting the exist-
ence of a radical chain mechanism.24 The photosensitizer
is capable of promoting, upon excitation, a chain radical
reaction in which the photochemical event is only the
starting step (Figure 3),10,19 in agreement with the results
obtained by femtosecond laser absorption spectroscopy
(see SI for details).22
R
t
Bu
tBu
R
N
O
N
O
PBN
17, R = CH(COOMe)2
18,
R = CH2COOCH2CF3
SCHEME 4. A Radical trap experiment demonstrates the
formation of radical induced by iron and visible light.
We then repeated the same experiment by employing vis-
ible light (λ > 420 nm), thus mimicking the synthetic re-
action conditions (Figure 2b). Also in this case the signal
due to the radical adduct 17 was clearly detected although
the intensity of the signals was weaker with respect to
that recorded in the presence of UV-visible light. No sig-
nals were observed in the absence of light or after irradia-
tion of a solution containing only the photosensitizer and
the spin trap (Figure 2c).
We also examined if the proposed chain process would
proceed through enamine catalysis with a radical clock-
containing aldehydes. If an α-cyclopropylcarbinyl radical
is formed during the iron(II) induced photocatalytic pro-
cess by ET, the aldehyde 1i, containing a cis-cyclopropane
ring, will be leading to the more stable trans-cyclopropyl
product 20 by opening-closure of the cyclopropyl ring.
The formation of only cis-20 provides a strong evidence
that an enamine addition mechanism is operating
(Scheme 5).
A similar trend was also observed in the presence of bro-
moester 2e (Figure S15). The PBN-adduct (18) was charac-
terized by slightly different EPR parameters: aN = 14.85 G,
aH = 5.55 G, g = 2.0057. In this case, however, the intensi-
ties of EPR spectra were lower if compared to those ob-
served in the spectra recorded with bromomalonate 2a
under the same experimental conditions. This indicates
that the formation of the less stable alkyl radical from 2e
is more difficult.23
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ASSOCIATED CONTENT
Page 4 of 15
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Supporting Information. Screening tests, and light effect
tests. Photophysical measurements and EPR studies. De-
tailed procedures. Copies of NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
SCHEME 5.Alkylation reaction performed in the presence
*Dipartimento di Chimica “G. Ciamician” ALMA MATER
STUDIORUM, Università di Bologna Via Selmi 2, 40126,
Bologna, Italy. Email: piergiorgio.cozzi@unibo.it.
of a radical-clock.
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Therefore, we propose that the reaction is proceeding
through a radical chain propagation pathway (see Figure
3).10 The addition of the radical III to enamine II is the
enantio-discriminating step.
Author Contributions
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript. A. G. was involved in the discovery and de-
velopment of the photochemical reaction. A. G. and L. M.
performed the experiments. M. M., M. N. and P. C. designed
and performed the photophysical measurements. M. L. de-
signed and performed the EPR experiments. P. G. C. con-
ceived and directed the project and wrote the manuscript
with contributions from all the authors.
Funding Sources
Bologna University, Fondazione Del Monte, SLAMM project
are acknowledged for financial support to A G. and L. M., P.
C. and M. M. acknowledge the European Commission ERC
Starting Grant (PhotoSi, 278912).
ACKNOWLEDGMENT
Sandro Gambarotta is acknowledged for sharing unpublished
result and for a fruitful discussion.
ABBREVIATIONS
Bpy, 2,2’-bipyridine; DCM, dichloromethane; DMF, N,N-
dimethylformamide; PBN, N-tert-butyl-α-phenylnitrone;
TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy.
FIGURE 3. Suggested catalytic cycle for the Fe(II) alkylation.
The [Fe(bpy)3]Br2 photosensitizer acts as a reductant for
initiating the chain mechanism, as proposed in Figure 3.
The ability of the amidoalkyl radical IV to behave as
strong reducing agent26 induces the reduction of bromo-
malonate, regenerating the radical III.27,28
REFERENCES
(1) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.; Chem.
Rev. 2013, 113, 5322-5363; (b) Narayanam, J. M. R.; Stephenson, C.
R. J. Chem. Soc. Rev. 2011, 40, 102-113; (c) Skubi, K. L.; Yoon, T. P.
Nature 2014, 515, 45-46; (d) Brimioulle, R.; Lenhart, D.; Maturi,
M. M.; Bach, T. Angew. Chem. Int. Ed. 2015, 54, 3872-3890; (e)
Meggers, E. Chem. Comm. 2015, 51, 3290-3301.
(2) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471-5569.
(3) N. Zhan, S. R. Samanta, B. M. Rosen, V. Percec, Chem. Rev.
2014, 114, 5848-5958.
(4)(a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322,
77-80; (b) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 10875-10877; (c) Shih, H.-W.; Vander Wal,
M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc.2010,
132, 13600-13603. (d) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc.
2012, 134, 8094-8097. (e) Tarantino, K. T.; Liu, P.; Knowles, R. R.
J. Am. Chem. Soc. 2013, 135, 10022-10025. (f) Du, J.; Skubi, K. L.;
Schultz, D. M.; Yoon, T. P. Science 2014, 344, 392-396.
(5) Neumann, M.; Füldner, S.; König, B.; Zeitler, K. Angew.
Chem. Int. Ed. 2011, 50, 951-954.
In conclusion, we discovered another class of valuable
photosensitizers based on first-row transition metals in
the arena of light-activated catalysis for synthetic trans-
formations. To our knowledge, this work represents the
first report of the use of [Fe(bpy)3]Br2 complex being ap-
plied in stereoselective photocatalysis. Not only this work
opens new perspectives in the area of asymmetric trans-
formations, but raises new questions about the use of co-
balt, and manganese complexes as alternative photosensi-
tizers based on earth-abundant metals. Further synthetic
applications in photocatalysis of iron complexes, and oth-
er first row metals will be reported in due course.
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(6) (a) Cherevatskaya, M.; Neumann, M.; Füldner, S.; Har-
idazolidinone 3 are quite poor catalyst for this reaction giving
low yields after prolonged reaction time (see SI published by
Melchiorre, ref. (10), for details).
(20) (a) Julià, L.; Bosch, M. P.; Rodriguez S.; Guerrero, A. J.
Org. Chem. 2000, 65, 5098-5103; (b) Mileo, E.; Benfatti, F.; Cozzi,
P.G.; Lucarini, M. Chem. Commun. 2009, 469-470.
(21) Zhang, J.; Campolo, D.; Dumur, F.; Xiao, P.; Fouassier, J.
P.; Gigmes, D.; Lalevée, J. J. Polym. Sci. A Polym. Chem. 2015, 53,
42-49.
(22) An iterative least squares fitting procedure based on the
systematic application of the Monte Carlo method was per-
formed in order to obtain the experimental spectral parameters
of the radical adducts. (a) Franchi, P.; Mezzina, E.; Lucarini, M. J.
Am. Chem. Soc. 2014, 136, 1250-1252; (b) Valgimigli, L.; Lucarini,
M.; Pedulli, G.F.; Ingold, K.U. J. Am. Chem. Soc. 1997, 119, 8095-
8096.
(23)The C-H bond dissociation energies in H-CH2COOEt and
H-CH(COOMe)2 are 96 and 90.5 kcal mol-1, respectively (Luo,
Y.-R. in “Bond Dissociation Energies in Organic Compounds”,
2003, CRC Press), p 67 and 68, respectively.
(24) For an important study concerning the off-on experi-
ments, and photochemical processes, see: Cismesia, M. A.; Yoon,
T. P. Chem. Sci. 2015; DOI: 10.1039/C5SC02185E.
1
2
3
4
5
6
7
8
lander, C.; Kümmel, S.; Dankesreiter, S.; Pfitzner, A.; Zeitler, K.;
König, B. Angew. Chem. Int. Ed. 2012, 51, 4062-4066. (b) Riente,
P.; Mata Adams, A.; Albero, J.; Palomares, E.; Pericàs, M. A. An-
gew. Chem. Int. Ed. 2014, 53, 9613-9616.
(7) H. Huo, X. Shen, C. Wang, L. Zhang, P. Röse, L.-A. Chen,
K. Harms, M. Marsch, G. Hilt, E. Meggers, Nature 2014, 515, 100-
103.
(8) (a) Arceo, E.; Jurberg, I. D.; Álvarez-Fernández, A.;
Melchiorre, P. Nat. Chem. 2013, 5, 750-756. b) Arceo, E.;
Bahamonde, A.; Bergonzini, G.; Melchiorre, P. Chem. Sci. 2014, 5,
2438-2442.
(9) For the nucleophilicity of enamines, see: Mayr, H.;
Lakhdar, S.; Maji, B.; Ofial, A. R. Beil. J. Org. Chem. 2012, 8, 1458-
1578; and ref. therein.
(10) Silvi, M.; Arceo, E.; Jurberg, I. D.; Cassani, C.; Melchiorre,
P. J. Am. Chem. Soc. 2015, 137, 6120-6123.
(11) Kern, J.-M; Sauvage, J.-P. J. Chem. Soc. Chem. Commun.
1987, 546-548.
(12)For reviews on Cu photocatalysis in synthesis, see: Paria,
S.; Reiser, O. ChemCatChem 2014, 6, 2477-2483.
(13) Stevenson, S. M.; Shores, M. P.; Ferreira, E. M. Angew.
Chem. Int. Ed. 2015, 54, 6506-6510.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) (a) Creutz, C.; Chou, M.; Netzel, T. L.; Okumura, M.;
Sutin, N. J. Am. Chem. Soc. 1980, 102, 1309-1319; (b) Kober, E. M.;
Meyer, T. J. Inorg. Chem. 1983, 22, 1614-1616; (c) Juban, E. A.;
Smeigh, A. L.; Monat, J. E.; McCusker, J. K. Coord. Chem. Rev.
2006, 250, 1783-1791; (d) Bressler, C.; Milne, C.; Pham, V.-T.;
ElNahhas, A.; van der Veen, R. M.; Gawelda, W.; Johnson, S.;
Beaud, P.; Grolimund, D.; Kaiser, M.; Borca, C. N.; Ingold, G.;
Abela, R.; Chergui, M. Science 2009, 323, 489-492; f) Cannizzo,
A.; Milne, C. J.; Consani, C.; Gawelda, W.; Bressler, C.; Van
Mourik, F.; Chergui, M. Coord. Chem. Rev. 2010, 254, 2677-2686.
(15) (a) Ferrere, S. Chem. Mater. 2000, 12, 1083-1089; (b) Fer-
rere, S.; Gregg, B. A. J. Am. Chem. Soc. 1998, 120, 843-844.
(16) Kuhn, M.; Von Wartbung, A. Helv. Chim. Acta 1967, 50,
1546-1565.
(17) For precedent enantioselective synthesis of isodeoxy-
podophyllotoxin see: (a) Itoh, T.; Chika, J.; Takagi, Y.; Nishiyama,
S. J. Org. Chem. 1993, 58, 5717-5723; (b) Bode, J. W.; Doyle, M. P.;
Protopopova, M. N.; Zhou, Q.-L. J. Org. Chem. 1996, 61, 9146-
9155.
(18) For a photocatalytic approach to lactones, see: Welin, E.
R.; Warkentin, A. A.; Conrad, J. C.; MacMillan, D. W. C. Angew.
Chem. Int. Ed. 2015, 54, 9668-9672.
(25)We were unable to detect by ultrafast spectroscopy the
electron transfer quenching of the iron complex excited state in
the presence of enamine and bromomalonate at different con-
centrations. However, the uncertainty accompanying the ultra-
fast measurements, in particular in the sub-ps region (i.e., in the
time scale of the MLCT lifetime), suggests that the quenching
process takes place with a rather low efficiency (5% or even less).
For a detailed discussion, see SI.
(26)Ismaili, H.; Pitre, S. P.; Scaiano, J. C. Catl. Sci. Technol.
2013, 3, 935-937.
(27) An atom transfer mechanism, in which the α-aminoalkyl
radical is abstracting a bromine atom, has been also suggested as
key step for ruthenium catalyzed reaction, see ref 26. In this al-
ternative mechanism, the α-amidoalkyl radical after abstraction
of the bromine is forming a α-bromo amine adduct, that is de-
composed to the iminium ion pair.
(28) The [Fe(bpy)3]Br2 is not decomposed or oxidized during
the reaction. As possible steps for the reduction of Fe(III) to
Fe(II) we propose that the α-aminoalkyl radical produced after
the addition of the malonate, or the oxidation of sacrificial
enamine are the compelling reductants. For SOMO chemistry
performed with Fe polypyridyl complexes in which Fe(III) com-
plexes are used as stoichiometric oxidants of enamines, see:
Comito, R. J.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2013, 135, 9358-9361.
(19) Although enamines derived from Hayashi-Jørgensen cata-
lyst are able to promote the stereoselective alkylation reaction
with bromo-malonates (rif (10)) in absence of any photosensitiz-
ers, the less nucleophilic enamines derived from MacMillan im-
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SYNOPSIS TOC
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Strike the iron…while is hot! Iron tris(bipyridyl) complexes are efficient catalysts (2.5 mol%) for the
photocatalytic synergistic enantioselective alkylation of aldehydes performed with a MacMillan catalyst
(20 mol%). The application of low cost and abundant metals will be next frontier in organic photocatal-
ysis for ET, radical reactions, and photoinduced mediated organic processes.
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Strategies in stereoselective photocatalytic addition of bromo derivatives: A, asymmetric photocatalysis with
Ru(bpy)32+; B, asymmetric photocatalysis induced by EDA complex; C, enamine photo-induced electron
transfer
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EPR spectra of spin adduct 17 generated in DMF in the presence of dimethyl bromomalonate 2a (0.5 M) and
PBN (0.1 M) as the spin trap at room temperature. Reaction conditions: a) [Fe(bpy)3]Br2 (10 mol%),
irradiation with UVꢀvisible light (λ>320 nm); b) [Fe(bpy)3]Br2 (10 mol%), irradiaꢀtion with visible light
(λ>420 nm); c) [Fe(bpy)3]Br2 (10 mol%) no irradiation.
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Suggested catalytic cycle for the Fe(II) alkylation.
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Optimized conditions for the [Fe(bpy)3]Br2 photocatalyzed reaction.
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