Deaminative Strategy for the Visible-Light-Mediated Generation of Alkyl Radicals

Article abstract of DOI:10.1002/anie.201706896

A deaminative strategy for the visible-light-mediated generation of alkyl radicals from redox-activated primary amine precursors is described. Abundant and inexpensive primary amine feedstocks, including amino acids, were converted in a single step into redox-active pyridinium salts and subsequently into alkyl radicals by reaction with an excited-state photocatalyst. The broad synthetic potential of this protocol was demonstrated by the alkylation of a number of heteroarenes under mild conditions.

Full text of DOI:10.1002/anie.201706896

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Accepted Article
Title: Deaminative Strategy for the Visible Light-Mediated Generation
of Alkyl Radicals
Authors: Felix Klauck, Michael James, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706896
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10.1002/anie.201706896
Angewandte Chemie International Edition
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Deaminative Strategy for the Visible Light-Mediated Generation of
Alkyl Radicals
Felix J. R. Klauck+, Michael J. James+ and Frank Glorius*
Abstract: A deaminative strategy for the visible light-mediated
generation of alkyl radicals from redox-activated primary amine
precursors is described. Abundant and inexpensive primary amine
feedstocks, including amino acids, were converted in a single step into
redox-active pyridinium salts and subsequently into alkyl radicals by
reaction with an excited-state photocatalyst. The broad synthetic
potential of this protocol was demonstrated in the alkylation of a
number of heteroarenes under mild and operationally simple
conditions.
could be generated following a single-electron reduction of a
Katritzky salt II (E1/2 = −0.93 V vs. SCE in DMF)[13] and the
fragmentation of the resultant dihydropyridine radical V, a process
driven by the reformation of the aromatic pyridine ring. This work
would represent a significant advance in the field of photoredox
catalysis, as while alkyl radicals can be prepared from a variety of
different precursors, the photocatalytic generation of an alkyl
radical species via the cleavage of a C‒N bond is still a
conceptually limited process.[14,15] Thus, a general method for the
deaminative formation of alkyl radicals would enable a powerful
new retrosynthetic disconnection that would allow inexpensive
primary amine precursors to be converted into complex high-
value compounds.
Methods for the generation of alkyl radicals are highly important
processes that enable the formation of new C–C and C–X bonds
in ways that would not be possible by traditional two-electron
pathways.[1] Furthermore, methods which can use naturally
abundant and inexpensive feedstocks to generate alkyl radicals
are of high interest in modern synthetic organic chemistry.[2] In
particular, decarboxylative methods using carboxylic acids as
radical precursors have been the focus of recent attention,[3]
especially with redox-active NHPI esters I (Scheme 1A);[4] these
bench stable solids have enabled a range of powerful cross-
coupling reactions to be performed under nickel catalyzed
conditions.[5]
Primary amines are another feedstock of similar natural
abundance to carboxylic acids,[6] and so naturally, a number of
methods have been developed to exploit them as synthetic
intermediates in two-electron processes.[7] Primary amines also
feature prominently in numerous biologically active natural
products[8] and drug molecules,[9] and as such, a range of
methods exist for their synthesis.[10] All of these features
strengthen demand to utilize this functionality as a synthetic
handle in single-electron C–C and C–X bond forming reactions.
To this end, Watson and co-workers recently reported that bench
stable Katritzky salts II,[11] which are readily formed in one step by
the condensation of a primary amine with a commercially
available pyrylium salt, can engage in elegant nickel catalyzed
cross-coupling reactions with boronic acids (Scheme 1A, II →
III).[12] While this cross-coupling reaction is presumed to proceed
via the formation of an alkyl radical species, the open-shell
intermediate is inaccessible for direct functionalization as it is
immediately captured by the nickel catalyst in a formal oxidative
addition process (II → IV).
Scheme 1. a) Previous work on nickel catalyzed cross-coupling reactions; b)
Inspired by this work, we envisioned that Katritzky salts could also
be used to generate reactive alkyl radicals under visible light-
mediated conditions (Scheme 1B). Here, an open-shell species
The deaminative visible light-mediated generation of alkyl radicals.
Herein, we describe the realization of this approach for the
deaminative generation of alkyl radicals from redox-activated
primary amines under mild, visible light-mediated conditions. The
feasibility of this approach and the synthetic utility of the resultant
alkyl radicals was demonstrated by a number of C–C bond
forming heteroarene alkylation reactions.
[*]
F. J. R. Klauck[+], Dr. M. J. James[+], Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
[+]
These authors contributed equally to this work.
Our studies began with the condensation of cyclohexylamine 1
with 2,4,6-triphenylpyrylium tetrafluoroborate
cyclohexyl Katritzky salt 3a on a gram-scale after a simple
2
to afford
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201706896
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filtration. Katritzky salt 3a was then submitted to luminescence
quenching studies with several common photocatalysts (see
supporting information),[16] of which iridium-based photocatalysts
fac-Ir(ppy)3 and [Ir(ppy)2(dtbbpy)]PF6 were most efficiently
quenched (>99% and 83% respectively).
FID analysis using mesitylene as internal standard. [c] Isolated yield on a 0.3
mmol scale in parentheses.
With the optimized conditions in hand, we sought to establish the
generality of this strategy for the generation of alkyl radicals and
their application in C–C bond forming reactions. Thus, a wider
range of Katritzky salts was prepared for examination as in
scheme 2. To our delight, a range of cyclic, acyclic and
heterocyclic Katritzky salts could all be used to form alkylated
isoquinolines 5a–i in generally excellent yield (scheme 3). Other
substituted heterocycles were also well-tolerated in this process,
with alkylated isoquinolines 5j–l and quinolines 5m–q afforded in
typically good yield. The synthetic value of these reactions was
further demonstrated with the efficient formation of
imidazopyridazine derivative 5r (related derivatives have
undergone clinical trials against myeloproliferative diseases).[19]
Prominent ligand architectures were also efficiently alkylated with
this method, such as in phenanthridine and phenanthroline
derivatives 5s and 5t.[20]
Scheme 2. Synthesis of cyclohexyl Katritzky salt 3a.
Having established that Katritzky salt 3a could effectively quench
the luminescence of an excited-state photocatalyst, we sought to
develop an appropriate reaction to establish a proof of concept
and to demonstrate the synthetic utility of this method. Thus, we
turned our attention towards the formation of a C–C bond between
the nucleophilic cyclohexyl radical and an electron-deficient
heteroarene, such as isoquinoline 4a.[17] Pleasingly, after
optimization studies (see supporting information), the desired
alkylated product 5a could be prepared in excellent yield by
irradiating a solution of isoquinoline 4a with just 1.2 equivalents of
the cyclohexyl Katritzky salt 3a and [Ir(ppy)2(dtbbpy)]PF6 (2.5
mol%) in DMA (N,N-dimethylacetamide, 0.2 M) with visible light
for 48 h (λmax = 455 nm, blue LEDs)[18] (table 1, entry 1). A shorter
reaction time was insufficient to effectively form the product 5a
(entry 2), as was using the more efficiently quenched
photocatalyst, fac-Ir(ppy)3 (entry 3), suggesting that the formation
of the alkyl radical might be hindered by a competing back
electron transfer process. Minimal reaction was also observed in
the absence of a photocatalyst or light (entries 4 & 5) and all
reactivity was completely suppressed with the addition of TEMPO
((2,2,6,6-tetramethylpiperidin-1-yl)oxyl, entry 6). A TEMPO-alkyl
radical adduct was also detected by ESI-MS analysis during these
studies, strongly suggesting that an alkyl radical intermediate is
indeed formed in this reaction (for further mechanistic studies,
including Stern-Volmer quenching studies and quantum yield
determination see supporting information).
Table 1. Visible light-mediated deaminative C‒H alkylation of isoquinoline 4a.
Entry
Variation from standard conditions[a]
Yield [%][b]
1
2
3
4
5
6
none
16 h reaction time
88 (83)[c]
Scheme 3. Scope of the deaminative C‒H alkylation of heteroarenes.
Reactions performed on a 0.30 mmol scale in 1.5 mL of solvent. [a] Performed
with 3.0 equiv. of 3.
62
<5
9
fac-Ir(ppy)3 instead of [Ir(ppy)2(dtbbpy)]PF6
no photocat.
Having demonstrated the effectiveness of this approach for the
generation of relatively simple cyclic and acyclic alkyl radicals, we
sought to challenge this process for the generation of more
complex alkyl radical species using one of the most well-known
naturally abundant feedstocks – amino acids. Amino acids have
previously been used as radical precursors in photoredox
no light
0
TEMPO (2.0 equiv.)
0
[a] Conditions: 4a (0.10 mmol), 3a (0.12 mmol), and [Ir(dtbbpy)(ppy)2]PF6 (2.5
mol%) and DMA (0.2 M) under argon. [b] Yields determined by calibrated GC-
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10.1002/anie.201706896
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COMMUNICATION
catalyzed decarboxylative processes (Scheme 4, VI → VII),[21]
and as such, a deaminative protocol (VI → VIII) would offer a
powerful complementary approach for the chemoselective
generation of alkyl radicals from the same precursors.
should be noted that these reactions also failed to proceed in the
absence of photocatalyst or light, excluding SN mechanisms for
the formation of the observed products (see supporting
information).
In conclusion, we have developed a mild and efficient visible light-
mediated protocol for the deaminative generation of alkyl radicals.
Highly abundant primary alkyl amines, including amino acids,
were readily converted into redox-active Katritzky salts, which
were subsequently used as radical precursors for the alkylation of
both electron-rich and -deficient heteroarenes. We believe this
work will be of significant interest to the synthetic community and
will enable the formation of new C–C and C–X bonds from a
significantly enlarged source of alkyl radicals.
Acknowledgements
Scheme 4. Overview of amino acids as radical precursors in photoredox
catalysis.
This work was supported by the Alexander von Humboldt
Foundation (M.J.J.) and the Fonds der Chemischen Industrie
(F.J.R.K.). We also thank Lena Pitzer and Christian Breuers for
experimental support and Dr. Lisa Candish, Dr. Adrián Gómez-
Suárez, Michael Teders, Lena Pitzer, Aleyda Garza-Sanchéz,
Adrian Tlahuext-Aca and Mirco Fleige for helpful discussions.
Consequently, a variety of natural and unnatural amino acid
methyl esters were converted into the required Katritzky salts 3.
Pleasingly, our previously developed conditions were still
sufficient to generate the desired electrophilic radicals, which
were capable of alkylating electron-rich heteroarenes (Scheme
5).[22,23] Thus, with minor modifications to the reaction
stoichiometry (see supporting information) a number of C2-
alkylated indole products 6a–g was prepared in modest to good
yield. The scope of this reaction with respect to the heteroarene
was also investigated with an alanine derived Katritzky salt, which
was used to successfully form C2/3-alkylated indoles 6h–j and
C2-alkylated pyrrole 6k without any additional optimization. It
Keywords: alkyl radicals • deamination • redox-active •
photoredox catalysis • amino acids
Scheme 5. Scope of the amino acid-based deaminative C‒H alkylation of heteroarenes. Reactions performed on a 0.30 mmol scale in 1.5 mL of solvent.
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[14] Current methods for the generation of carbon centered radicals via the
cleavage of C–N bonds are mostly limited to the single-electron reduction
of aryl diazonium salts. For examples, see: a) Y. Su, L. Zhang, N. Jiao,
Org. Lett. 2011, 13, 2169; b) D. P. Hari, P. Scholl, B. König, J. Am. Chem.
Soc. 2012, 134, 2958; c) B. Sahoo, M. N. Hopkinson, F. Glorius, J. Am.
Chem. Soc. 2013, 135, 5505; d) A. Tlahuext-Aca, M. N. Hopkinson, B.
Sahoo, F. Glorius, Chem Sci. 2016, 7, 89.
[1]
For selected reviews on visible light photoredox catalysis: a) J. M. R.
Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40, 102; b) J.
Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828; Angew. Chem.
2012, 124, 6934; c) J. W. Tucker, C. R. J. Stephenson J. Org. Chem.
2012, 77, 1617; d) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org.
Chem. 2016, 81, 6898.
[15] For a related example of N–N bond cleavage, see: T. W. Greulich, C. G.
Daniliuc, A. Studer, Org. Lett. 2015, 17, 254.
[2]
[3]
a) G. J. S. Dawes, E. L. Scott, J. Le Nôtre, J. P. M. Sanders, J. H. Bitter,
Green Chem. 2015, 17, 3231; b) G. Yang, C. Zhu, X. Zou, L. Zhou, Sci.
Rep. 2016, 6, 29711.
[16] a) M. N. Hopkinson, A. Gomez-Suarez, M. Teders, B. Sahoo, F. Glorius,
Angew. Chem. Int. Ed. 2016, 55, 4361; Angew. Chem. 2016, 128, 4434;
b) M. Teders, A. Gomez-Suarez, L. Pitzer, M. N. Hopkinson, F. Glorius,
Angew. Chem. Int. Ed. 2017, 56, 902; Angew. Chem. 2017, 129, 921.
[17] For selected examples of related Minisci-type C–H alkylations, see: a) Y.
Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder, D. D. Dixon, R. A.
Rodriguez, R. D. Baxter, B. Herle, N. Sach, M. R. Collins, Y. Ishihara, P.
S. Baran, Nature 2012, 492, 95; b) D. A. DiRocco, K. Dykstra, S. Krska,
P. Vachal, D. V. Conway, M. Tudge, Angew. Chem. Int. Ed. 2014, 53,
4802; Angew. Chem. 2014, 126, 4902; c) J. Jin, D. W. C. MacMillan,
Nature 2015, 525, 87; d) G.-X. Li, C. A. Morales-Rivera, Y. Wang, F. Gao,
G. He, P. Liu, G. Chen, Chem. Sci. 2016, 7, 6407; e) J. K. Matsui, D. N.
Primer, G. A. Molander, Chem. Sci. 2017, 8, 3512; f) W.-M. Cheng, R.
Shang, Y. Fu, ACS Catal. 2017, 7, 907; g) R. A. Garza-Sanchez, A.
Tlahuext-Aca, G. Tavakoli, F. Glorius, ACS Catal. 2017, 7, 4057.
[18] We believe that the use of visible light sources minimizes absorption by
the substrates and allows a mild reaction protocol with a broad functional
group tolerance (for absorption spectra of the catalysts see supporting
information).
a) L. Chu, C. Ohta, Z. Zuo, D. W. C. MacMillan, J. Am. Chem. Soc. 2014,
136, 10886; b) S. Ventre, F. R. Petronijevic and D. W. C. MacMillan, J.
Am. Chem. Soc. 2015, 137, 5654; c) J. D. Griffin, M. A. Zeller, D. A.
Nicewicz, J. Am. Chem. Soc. 2015, 137, 11340; d) C. P. Johnston, R. T.
Smith, S. Allmendinger, D. W. C. MacMillan, Nature 2016, 536, 322; e)
L. Candish, L. Pitzer, A. Gómez-Suárez, F. Glorius, Chem. Eur. J. 2016,
22, 4753; f) L. Candish, E. A. Standley, A. Gómez-Suárez, S. Mukherjee,
F. Glorius, Chem. Eur. J. 2016, 22, 9971.
[4]
a) K. Okada, K. Okamoto, N. Morita, K. Okubo, M. Oda, J. Am. Chem.
Soc. 1991, 113, 9401; b) M. J. Schnermann, L. E. Overman, Angew.
Chem. Int. Ed. 2012, 51, 9576; Angew. Chem. 2012, 124, 9714; c) L.
Candish, M. Teders, F. Glorius, J. Am. Chem. Soc. 2017, 139, 7440; d)
W. F. Petersen, R. J. K. Taylor, J. R. Donald, Org. Lett. 2017, 19, 874; e)
A. Tlahuext-Aca, R. A. Garza-Sanchez, F. Glorius, Angew. Chem. Int.
Ed. 2017, 56, 3708; Angew. Chem. 2017, 129, 3762; f) D. Hu, L. Wang,
P. Li, Org. Lett. 2017, 19, 2770.
[5]
a) T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura,
B. D. Maxwell, M. D. Eastgate, P. S. Baran, Science 2016, 352, 801; b)
K. M. M. Huihui, J. A. Caputo, Z. Melchor, A. M. Olivares, A. M. Spiewak,
K. A. Johnson, T. A. DiBenedetto, S. Kim, L. K. G. Ackerman, D. J. Weix,
J. Am. Chem. Soc. 2016, 138, 5016; c) J. T. Edwards, R. R. Merchant,
K. S. McClymont, K. W. Knouse, T. Qin, L. R. Malins, B. Vokits, S. A.
Shaw, D.-H. Bao, F.-L. Wei, T. Zhou, M. D. Eastgate, P. S. Baran, Nature
2017, 545, 213; d) C. Li, J. Wang, L. M. Barton, S. Yu, M. Tian, D. S.
Peters, M. Kumar, A. W. Yu, K. A. Johnson, A. K. Chatterjee, M. Yan, P.
S. Baran, Science 2017, DOI: 10.1126/science.aam7355; e) N. Suzuki,
J. L. Hofstra, K. E. Poremba, S. E. Reisman, Org. Lett. 2017, 19, 2150.
E. Scott, F. Peter, J. Sanders, Appl. Microbiol. Biotechnol. 2007, 75, 751.
a) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564; b) Q.
Wang, Y. Su, L. Li, H. Huang, Chem. Soc. Rev. 2016, 45, 1257.
T. P. T. Cushnie, B. Cushnie, A. J. Lamb, Int. J. Antimicrob. Agents 2014,
44, 377.
[19] J. J. Douglas, K. P. Cole, C. R. J. Stephenson, J. Org. Chem. 2014, 79,
11631.
[20] A. C. Edwards, A. Geist, U. Müllich, C. A. Sharrad, R. Pritchard, R.
Whitehead, L. M. Harwood, Chem. Commun. 2017, 53, 8160.
[21] a) Z. Zuo, D. W. C. MacMillan, J. Am. Chem. Soc. 2014, 136, 5257; b) Z.
Zuo, H. Cong, W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan, J. Am. Chem.
Soc. 2016, 138, 1832; c) W.-M. Cheng, R. Shang, Y. Fu, ACS Catal.
2017, 7, 907.
[22] a) L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker, C. R. J.
Stephenson, Org. Lett. 2010, 12, 3104; b) J. J. Devery III, J. J. Douglas,
J. D. Nguyen, K. P. Cole, R. A. Flowers II, C. R. J. Stephenson, Chem.
Sci. 2015, 6, 537; c) E. C. Swift, T. M. Williams, C. R. J. Stephenson,
Synlett 2016, 27, 754.
[6]
[7]
[8]
[9]
[23] Minimal reaction was observed when the amino acid-derived Katritzky
salts were reacted with isoquinoline, presumably due to the
incompatibility of electrophilic radicals with electron-deficient
heteroarenes. For details, see: a) H. Fischer, L. Radom, Angew. Chem.
Int. Ed. 2001, 40, 1340; Angew. Chem. 2001, 113, 1380; b) F. De
Vleeschouwer, V. Van Speybroeck, M. Waroquier, P. Geerlings, F. De
Proft, Org. Lett. 2007, 9, 2721.
N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010, 87,
1348.
[10] a) J. Bariwal, E. Van der Eycken, Chem. Soc. Rev. 2013, 42, 9283; b) V.
Froidevaux, C. Negrell, S. Caillol, J.-P. Pascault, B. Boutevin, Chem. Rev.
2016, 116, 14181.
[11] A. R. Katritzky, U. Gruntz, D. H. Kenny, M. C. Rezende, H. Sheikh, J.
Chem. Soc., Perkin Trans. 1 1979, 430.
[12] C. H. Basch, J. Liao, J. Xu, J. J. Piane, M. P. Watson, J. Am. Chem. Soc.
2017, 139, 5313.
[13] J. Grimshaw, S. Moore, J. T. Grimshaw, Acta Chem. Scand. B. 1983, 37,
485.
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Felix J. R. Klauck+, Michael J. James+
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Deaminative Strategy for the Visible
Light-Mediated Generation of Alkyl
Radicals
Radical Cut. A deaminative strategy for the visible light-mediated generation of
alkyl radicals from redox-activated primary amine precursors is described.
Abundant and inexpensive primary amine feedstocks, including amino acids, were
converted in a single step into redox-active pyridinium salts and subsequently into
alkyl radicals by reaction with an excited-state photocatalyst. The broad synthetic
potential of this protocol was demonstrated in the alkylation of a number of
heteroarenes under mild and operationally simple conditions.
This article is protected by copyright. All rights reserved.