Intermolecular radical addition to carbonyls enabled by visible light photoredox initiated hole catalysislena

Article abstract of DOI:10.1021/jacs.7b08086

Herein, we present a novel strategy for the utilization of simple carbonyl compounds, aldehydes and ketones, as intermolecular radical acceptors. The reaction is enabled by visible light photoredox initiated hole catalysis and the in situ Br?nsted acid activation of the carbonyl compound. This regioselective alkyl radical addition reaction does not require metals, ligands or additives and proceeds with a high degree of atom economy under mild conditions. The proposed mechanism is supported by both experimental and theoretical studies.

Full text of DOI:10.1021/jacs.7b08086

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Communication
Intermolecular Radical Addition to Carbonyls Enabled
by Visible Light Photoredox Initiated Hole Catalysis
Lena Pitzer, Frederik Sandfort, Felix Strieth-Kalthoff, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08086 • Publication Date (Web): 17 Sep 2017
Downloaded from http://pubs.acs.org on September 17, 2017
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Intermolecular Radical Addition to Carbonyls Enabled by Visi-
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Lena Pitzer†, Frederik Sandfort†, Felix Strieth-Kalthoff and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
† These authors contributed equally.
Supporting Information Placeholder
ABSTRACT: Herein, we present a novel strategy for the utili-
zation of simple carbonyl compounds, aldehydes and ketones,
as intermolecular radical acceptors. The reaction is enabled by
visible light photoredox initiated hole catalysis and the in situ
Brønsted acid activation of the carbonyl compound. This regi-
oselective alkyl radical addition reaction does not require met-
als, ligands or additives and proceeds with a high degree of
atom economy under mild conditions. The proposed mecha-
nism is supported by both experimental and theoretical studies.
Over the last decade photo(redox) catalysis has emerged as a
powerful platform for organic chemists to develop valuable
transformations proceeding via radical pathways.1,2 Concomi-
tant with the rapid growth of the field is an ever-present need
for the continued expansion of the scope of amenable radical
precursors and acceptors. Addressing this, our group recently
developed a screening method for the identification of new
quenchers.3 However, the scope of radical acceptors is still lim-
ited and exploration of a broader acceptor pool remains an on-
going challenge.4 In general, C–C double bonds represent the
most commonly used radical π-acceptors. C–N double bonds
have also been shown to act as acceptors, but generally activa-
tion via electron deficient substituents on the nitrogen is re-
quired.5 Notably, C–O double bonds, specifically substituted al-
dehydes or ketones, have to the best of our knowledge, only
Figure 1. Concept of applying carbonyls as radical π-acceptors.
In situ Brønsted acid activation facilitates ET to an alkoxy radical.
been used once as intermolecular radical acceptors.6-8
The intermolecular addition of radicals to alkenes is known to
Considering this, we sought to develop a process based on hole
catalysis induced by a combination of common photoredox
chemistry with Brønsted or Lewis acid coordination.12 We hy-
pothesized the formation of an alkyl radical via quenching of a
photoredox catalyst with a suitable substrate. This alkyl radical
could then add to an activated, e.g. protonated, carbonyl. The
formed alkoxy radical cation would be able to engage in ET due
to its enhanced oxidation potential, contrary to an alkoxy radi-
cal (see Figure 1).
proceed irreversibly to yield carbon centered radicals. In con-
trast, addition to carbonyls is a reversible process due to the for-
mation of a thermodynamically unfavorable alkoxy radical.9
Upon formation, these radicals preferably decay via homolytic
cleavage, i.e. C–C β-scission, to form a more stable radical spe-
cies.10 Therefore, successful radical addition is only possible if
the alkoxy radical can be intercepted via a subsequently fast
event, e.g. electron transfer (ET). As Studer and Curran recently
emphasized, electron or hole catalysis can offer such possibili-
ties by controlling the selectivity of competing radical reac-
tions.11 In this context, C–C β-scission could be suppressed by
using Brønsted or Lewis acid coordination to form an alkoxy
radical cation, which allows for hole catalysis. This coordina-
tion would concurrently provide a greater thermodynamic driv-
ing force for the desired forward reaction while kinetically en-
hancing the rate of the ET step (see Figure 1).
Inspired by Nicewicz’s work, we became interested in alkenes
as alkyl radical precursors.15 The oxidation of an alkene to form
a radical cation, followed by trapping of the cation with a protic
nucleophile, would not only generate the alkyl radical, but also
liberate a proton for the required activation of the carbonyl. The
highly oxidizing and poorly reducing photoredox catalyst 9-me-
red
sityl-10-methylacridinium tetrafluoroborate (1) (E1/2
= -0.57 V vs SCE)2b, which has already been applied in such
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oxidations, would furthermore ensure the exclusion of a con- recognized immediate bleaching of the solution, which is pro-
posed to be caused by catalyst decomposition.17 Isolation of a
modified catalyst species and submission to the standard condi-
tions without 1 still resulted in moderate product formation.16
Furthermore, the UV-visible absorption spectrum of this spe-
cies revealed significant absorption only until 410 nm. Conse-
quently, the light source was changed to blue LEDs with a λmax
of 400 nm, which increased the yield of the product to 73%.
Control experiments also showed the necessity of using both
light and the photocatalyst. Performing the reaction under air
resulted in only a slight decrease in yield. The regioselectivity
of the addition reaction was fully confirmed by X-ray analysis
of products 4g and 4h.16
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trary reaction pathway proceeding via reduction of the car-
bonyl. Interestingly, carbonyls in photoredox catalysis have
only ever been used as radical donors even though they possess
a largely negative reduction potential (e.g. E1/2red = −1.93 V vs
SCE for benzaldehyde)13).14
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Figure 2. Standard reaction conditions.
Studies began by irradiating a mixture containing photocatalyst
1, the inexpensive and easily available starting materials 4-
fluorobenzaldehyde (2a) and alkene 3a in the presence of meth-
anol as a nucleophile in dichloromethane (see Figure 2) with
blue LEDs (λmax = 455 nm). Pleasingly, under these conditions
we observed the formation of the desired product 4a in 20%
yield.16 As reported in other reactions performed with 1, we also
This reaction is proposed to proceed via the photoexcitation of
1, followed by reductive quenching with 3a to form radical cat-
ion I (see Figure 3A). Nucleophilic trapping of the cation by
methanol and proton transfer to the carbonyl delivers II as a
hydrogen-bonded adduct consisting of the alkyl radical and the
activated carbonyl.16 Subsequent radical addition via a six-
membered transition state forms radical cation III. ET with 3a
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0
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Figure 3. A. Mechanistic proposal. B. Mechanistic studies: 1) UV-vis spectra of 2a (green), 3a (pink), reaction mixture without 1 (orange),
reaction mixture (red), reaction mixture after 60 s of irradiation (blue), 2) Stern-Volmer quenching study with 3a (red) and 2a (blue), 3)
Radical trapping experiment adding TEMPO to standard conditions, 4) Radical clock experiment using benzoylcyclopropane 5a as radical
acceptor (yields determined via 1H NMR spectroscopy using CH2Br2 as internal standard).
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generates the product and the initial radical cation I, thus com-
pleting the hole catalysis cycle. The product can also potentially
be formed via oxidation of the reduced photocatalyst by III.
through carbonyl reduction.16 Given that the lower limit ap-
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proximation of the chain length was determined to be 7, the
photoredox initiation cycle should be completed and performed
more than once to account for the yield of >70% (4a, Figure 3).
Lastly, DFT calculations suggest the formation of the six-mem-
bered transition state following II.16 The key ET between III
and 3a should also be thermodynamically favorable according
to calculated redox potentials (E(III)1/2ox ≥ +1.70 V vs SCE and
This mechanistic proposal is based on several experimental and
theoretical studies (see Figure 3B and SI), which support the
different steps or intermediates. UV-visible spectroscopy en-
sured that only 1 absorbs light at λ = 400 nm. Therefore, a direct
excitation of the carbonyl compound is unlikely. Furthermore,
Stern-Volmer quenching studies support ET from the styrene to
1*. An alternative pathway, proceeding via energy transfer
from 1* to the carbonyl as an indirect excitation of the carbonyl
is also unlikely, due to no observable quenching of 1* by the
carbonyl. Radical trapping with TEMPO provided evidence for
the formation of the alkyl radical derived from the alkene after
nucleophilic trapping with methanol. Thus, the formation of a
theoretical radical anion derived from the aldehyde could be
dismissed. Moreover, kinetic isotope experiments suggested
that proton transfer to the carbonyl is not the rate determining
step.16 It is however of high importance, as no reactivity was
observed in the presence of a base (e.g. 2,6-lutidine) or in the
presence of a non-protic nucleophile, e.g. when using NaOMe
instead of methanol as a nucleophile.16 A radical clock experi-
ment using benzoylcyclopropane (5a) as radical acceptor pro-
vided evidence for the regioselective addition to the C-terminus
of the C–O double bond, as no obvious ring opened side prod-
ucts could be detected. Thus, we assume that a C-centered rad-
ical (derived from 5a) is not formed and an alternative pathway,
proceeding via reduction of the protonated carbonyl and subse-
quent radical coupling with the alkyl radical, is unlikely. Addi-
tionally, experiments to determine the reaction quantum yield
and chain length suggest the possibility of the ET between III
and 3a and further oppose the probability of a radical coupling
ox
E(3a)1/2 = +1.22 V vs SCE)16. Without proton coordination,
this ET would not be feasible (E(IIIdeprotonated
)
ox ≤ -0.25 V vs
1/2
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SCE (calculated).16
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Scope and limitation studies were then performed with a variety
of aromatic aldehydes, ketones, alkenes and alcohols (Figure
3). In general, aldehydes provided higher yields of the respec-
tive products than ketones. For both carbonyl classes we de-
tected increased yields when electron withdrawing substituents
at the aromatic ring were present compared to electron donating
substituents (e.g. 79%, 4h vs 63%, 4m). Apart from monoaryl
ketones, diaryl ketones and electron deficient aliphatic ketones
were also found to be viable radical acceptors (e.g. 6i, 43%, 6h,
31%). Regarding the alkene scope, no specific order of reactiv-
ity can be attributed to the electronic influence based on the per-
formed examples. Aliphatic alkenes also gave the correspond-
ing products in acceptable yields (4q, 52%). Variation of the
alcohol was well tolerated (74%, 4w, 86%, 4u), though more
steric hindrance resulted in lower yields (4v, 51%). Scaling up
the reaction to 2.5 mmol did not cause any decrease in yield (4c,
90%). An additive-based robustness screen was also performed,
showing in average minimal adverse effects of different addi-
tives on the reaction yield, indicating high functional group tol-
erance;18 good functional group preservation was also ob-
served.16
Figure 4. Scope of the intermolecular radical addition to carbonyls. Standard conditions: Aldehyde (0.3 mmol), alkene (0.45 mmol), 1
(0.015 mmol), ROH (0.9 mmol), CH2Cl2, isolated yields given as a sum of the two separated diastereomeres, d.r. generally 1:1.2. a) 0.1 M
(3.0 mL CH2Cl2) b) Reaction performed on a 2.5 mmol scale. c) 0.75 mmol of alkene + 1.5 mmol of MeOH used. d) 0.2 M (1.5 mL CH2Cl2).
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Synthesis 2008, 21, 3509. b) Tiecco, M.; Testaferri, L.; Marini, F.;
In conclusion, a strategy for the intermolecular trapping of alkyl
radicals with simple carbonyl compounds, including substituted
aldehydes and ketones, has been developed. The reaction uti-
lizes visible light photoredox smart initiated hole catalysis to
facilitate the key in situ Brønsted acid activation of the car-
bonyl. The mechanistic proposal is based on several experi-
mental and theoretical studies. In future work it is hoped that
this Brønsted acid coordination strategy will enable the stereo-
chemically controlled formation of C–C bonds. No metals, lig-
ands or additives were necessary, leading to a high degree of
atom economy. The reactions displayed high functional group
tolerance, were performed with inexpensive starting materials
and under mild conditions. Overall, this work constitutes a pow-
erful new strategy for the longstanding challenge of using car-
bonyls as intermolecular radical acceptors.
Sternativo, S.; Santi, C.; Bagnoli, L.; Temperini, A. Tetrahedron 2007, 63,
5482. c) Sugi, M. Tetrahedron 2002, 58, 3171. d) Devin, P.; Fensterbank,
L.; Malacria, M. Tetrahedron Lett. 1998, 39, 833. e) Rodríguez, J. R.;
Castedo, L.; Mascareñas, J. L. Org. Lett. 2001, 3, 1181. f) Chang, S.-Y.;
Shao, Y.-F.; Chu, S.-F.; Fan, G.-T.; Tsai, Y.-M. Org. Lett. 1999, 1, 945. g)
Beckwith, A. L. J. J. Am. Chem. Soc. 1989, 111, 2674. h) Tsang, R.; Fraser-
Reid, B. J. Am. Chem. Soc. 1986, 108, 2116. i) Che, C.; Huang, Q.; Zheng,
H.; Zhu, G.; Horaguchi, T.; Stephens, W. P.; Liu, J.; Lei, A.; Liang, Y.-M.
Chem. Sci. 2016, 7, 4134.
(9) a) Wilsey, S.; Dowd, P.; Houk, K. N. J. Org. Chem. 1999, 64, 8801. b)
Curran, D. P.; Diederichsen, U.; Palovich, M. J. Am. Chem. Soc. 1997, 119,
4797.
(10) For selected reviews, see: a) Salamone, M.; Bietti, M. Synlett 2014, 25,
1803. b) Hartung, J.; Gottwald, T.; Špehar, K. Synthesis 2002, 11, 1469.
(11) For selected reviews of "electron/ hole catalysis", see: a) Studer, A.;
Curran, D. P. Nat. Chem. 2014, 6, 765. b) Julliard, M.; Chanon, M. Chem.
Rev. 1983, 83, 425. c) Bauld, N.; Bellville, D. J.; Harirchian, B.; Lorenz, K.
T.; Pabon, R. A.; Reynolds, D. W.; Wirth, D. D.; Chiou, H. S.; Marsh, B.
K. Acc. Chem. Res. 1987, 20, 371.
(12) Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2016, 55, 58.
(13) Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Synlett 2016, 27, 714.
(14) For selected examples, see: a) Nakajima, M.; Fava, E.; Loescher, S.;
Jiang, Z.; Rueping, M. Angew. Chem. Int. Ed. 2015, 54, 8828. b) Huo, H.;
Shen, X.; Wang, C.; Zhang, L.; Röse, P.; Chen, L.-A.; Harms, K.; Marsch,
M.; Hilt, G.; Meggers, E. Nature 2014, 515, 100. c) Rono, L. J.; Yayla, H.
G.; Wang, D. Y.; Armstrong, M. F.; Knowles, R. R. J. Am. Chem. Soc.
2013, 135, 17735. d) Petronijevic, F. R.; Nappi, M.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2013, 135, 18323.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website
AUTHOR INFORMATION
*glorius@uni-muenster.de
(15) For selected examples, see: a) Wilger, D. J.; Grandjean, J.-M. M.;
Lammert, T. R.; Nicewicz, D. A. Nat. Chem. 2014, 6, 720. b) Perkowski,
A. J.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 10334. c) Hamilton,
D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012, 134, 18577. d) Nguyen, T.;
Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 9588.
ORCID
Frank Glorius: 0000-0002-0648-956X
Notes
The authors declare no competing financial interests.
(16) For further information see Supporting Information.
(17) Romero, N. A.; Nicewicz, D. A. J. Am. Chem. Soc. 2014, 136, 17024.
ACKNOWLEDGMENT
(18) Gensch, T.; Teders, M.; Glorius, F.
10.1021/acs.joc.7b01139.
J
Org. Chem. 2017,
We thank Tobias Wagner for experimental support and Michael
Teders, Dr. Michael James, Dr. Lisa Candish and Felix Klauck for
helpful discussions. Financial support from the Deutsche For-
schungsgemeinschaft (Leibniz Award) is acknowledged.
REFERENCES
(1) For selected reviews from the special issue in Acc. Chem. Res. 2016:
Photoredox Catalysis in Organic Chemistry, see: a) Gentry, E. C.;
Knowles, R. R. Acc. Chem. Res. 2016, 49, 1546. b) Hopkinson, M. N.;
Tlahuext-Aca, A.; Glorius, F. Acc. Chem. Res. 2016, 49 , 2261. c) Tellis, J.
C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A.
Acc. Chem. Res. 2016, 49, 1429. d) Margrey, K. A.; Nicewicz, D. A. Acc.
Chem. Res. 2016, 49, 1997. e) Staveness, D.; Bosque, I.; Stephenson, C. R.
J. Acc. Chem. Res. 2016, 49, 2295. f) Yoon, T. P. Acc. Chem. Res. 2016,
49, 2307.
(2) For selected reviews, see: a) Twilton, J.; Le, C.; Zhang, P.; Shaw, M.
H.; Evans, R. W.; MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 52. b)
Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. c) Skubi, K.
L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035.
(3) a) Hopkinson, M. N.; Gómez-Suárez, A.; Teders, M.; Sahoo, B.;
Glorius, F. Angew. Chem. Int. Ed. 2016, 55, 4361. b) Teders, M.; Gòmez-
Suàrez, A.; Pitzer, L.; Hopkinson, M. N.; Glorius, F. Angew. Chem. Int. Ed.
2017, 56, 902.
(4) Yang, W.-C.; Dai, P.; Luo, K.; Ji, Y.-G.; Wu, L. Adv. Synth. Catal. 2017,
359, 2390.
(5) For selected reviews, see: a) Hideto, M.; Ueda, M.; Naito, T. Synlett
2004, 7, 1140. b) Friestad, G. K. Tetrahedron 2001, 57, 5461.
(6) a) Clerici, A.; Porta, O.; Zago, P. Tetrahedron 1986, 42, 561. b) Clerici,
A.; Porta, O. J. Org. Chem. 1989, 54, 3872.
(7) For selected examples using formaldehyde as radical acceptors, see: a)
Humphreys, R. W. R. J. Org. Chem. 1983, 48, 1483. b) Sanderson, J. R.;
Yeakey, E. L.; Lin, J. J.; Duranleau, R.; Marquis, E. T. J. Org. Chem. 1987,
52, 3243. c) Sanderson, J. R.; Lin, J. J.; Duranleau, R. G.; Yeakey, E. L.;
Marquis, E. T. J. Org. Chem. 1988, 53, 2859. d) Fuller, G.; Rust, F. F. J.
Am. Chem. Soc. 1958, 80, 6148. e) Oyama, M. J. Org. Chem. 1965, 30,
2429. f) Kawamoto, T.; Fukuyama, T.; Ryu, I. J. Am. Chem. Soc. 2012, 134,
875.
(8) For selected examples using C–O double bonds as intramolecular radi-
cal acceptors, see: a) Gansäuer, A.; Piestert, F.; Huth, I.; Lauterbach, T.
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