Visible-Light-Mediated Charge Transfer Enables C?C Bond Formation with Traceless Acceptor Groups

Article abstract of DOI:10.1002/chem.201901397

The development and application of traceless acceptor groups in photochemical C?C bond formation is described. This strategy was enabled by the photoexcitation of electron donor–acceptor (EDA) complexes with visible light. The traceless acceptors, which were readily prepared from amino acid and peptide feedstocks, could be used to alkylate a wide range of heteroarene and enamine donors under metal- and peroxide-free conditions. The crucial role of the EDA complexes in the mechanism of these reactions was explored through combined experimental and computational studies.

Full text of DOI:10.1002/chem.201901397

A Journal of
Accepted Article
Title: Visible-Light-Mediated Charge Transfer Enables C–C Bond
Formation with Traceless Acceptor Groups
Authors: Michael J. James, Felix Strieth-Kalthoff, Frederik Sandfort,
Felix Klauck, Felicitas Wagener, and Frank Glorius
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To be cited as: Chem. Eur. J. 10.1002/chem.201901397
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Visible-Light-Mediated Charge Transfer Enables C–C Bond
Formation with Traceless Acceptor Groups
Michael J. James, Felix Strieth-Kalthoff, Frederik Sandfort, Felix J. R. Klauck, Felicitas Wagener and
Frank Glorius*
Dedicated to Richard J. K. Taylor on the occasion of his 70th birthday
Abstract: The development and application of traceless acceptor
groups in photochemical C–C bond formation is described. This
strategy was enabled by the photoexcitation of electron donor-
compatible and traceless acceptors, which do not incorporate
unwanted (electron-deficient) arene moieties into the final
product, would significantly advance the scope and utility of this
acceptor (EDA) complexes with visible light. The traceless acceptors, synthetic strategy.
which were readily prepared from amino acid and peptide feedstocks, Herein, we describe the realization of this approach through the
could be used to alkylate a wide range of heteroarene and enamine
donors under metal- and peroxide-free conditions. The crucial role of
the EDA complexes in the mechanism of these reactions was
explored through combined experimental and computational studies.
photoexcitation of EDA complexes between pyridinium salt
acceptors and heteroarene or enamine donors with visible light
(Scheme 1b). The traceless pyridinium salt acceptors were all
readily prepared from abundant amino acid precursors following
established condensation chemistry with a pyrylium salt.[9]
The formation of C–C bonds continues to be one of the primary
challenges in organic synthesis.[1] To meet this challenge, a wide
range of powerful radical-based methods have been
developed.[2] Of particular note, methods which can utilize
abundant functional groups as alkyl radical precursors have
received significant attention from the synthetic community.[3]
Most prominently, a number of decarboxylative strategies
involving alkyl radicals have been developed to form C–C
bonds.[4] More recently, Watson and co-workers have elegantly
demonstrated that redox-activated amines can be used in
deaminative cross-coupling strategies.[5] However, the majority
of the aforementioned methods require the use of
(expensive/high catalyst loading) transition metal catalysts or
excess hazardous peroxides as oxidants. Thus, alternative
methods which avoid these common tropes are of significant
interest.
In recent years, a number of photochemical strategies have
been developed to circumvent these limitations.[6] In particular,
pioneering studies by Melchiorre and co-workers have shown
that photoexcited EDA complexes have significant potential to
enable C–C bond formation under mild metal- and peroxide-free
conditions.[7,8] Strategies using these complexes in synthesis are
typically operationally simple and can be readily performed with
simple organic precursors. For example, electron-rich indole
donors can be photochemically alkylated with highly electron-
deficient dinitrobenzyl bromide acceptors (Scheme 1a). However,
the scope of this strategy is generally restricted by the acceptors
and their required high electron affinity. Moreover, the synthetic
utility of these methods has remained limited by the fact that the
electron-deficient arene moiety of the acceptor is typically
incorporated into the final product. Thus, the design of broadly
Scheme 1. Photochemical C–C bond formation with EDA complexes.
Our studies in this area initiated during our previous work using
iridium photoredox catalysis to promote C–C bond formation
with Katritzky pyridinium salts.[10,11] In this work we observed that
colourless pyridinium salts derived from amino acids formed
strongly coloured solutions in the presence of indoles (Scheme
2). Furthermore, Aggarwal and co-workers,[12a] and our own
group,[12c] recently demonstrated that Katrizitky pyridinium salts
can be used as productive acceptors in EDA complexes for C–B
bond formation. Thus, based on this observation and our
previous work, we questioned whether we might promote the
photochemical alkylation of indole 1a with pyridinium salt [PyN]-
Ala-OMe 2a without the use of a photocatalyst. First, the solution
was irradiated with a light source covering a broad wavelength
range (white LEDs), but no product formation was observed.
However, upon addition of 2,6-lutidine small quantities of the
[*]
Dr. M. J. James, F. Strieth-Kalthoff, F. Sandfort, F. J. R. Klauck, F.
Wagener, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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desired product 3a were detected. Following further base
screening, a marked increase in reactivity was observed when
redox-active bases were used, of which morpholine was the
most effective. Further modification to the reaction conditions,
such as increasing the amount of [PyN]-Ala-OMe and
morpholine to 1.5 equivalents, decreasing the reaction
concentration (0.4 M) and using 5 W blue LEDs (λmax = 455 nm),
enabled the product 3a to be formed in 91% (NMR) yield (not
shown). At this stage we sought to determine if an EDA complex
was indeed formed in the reaction mixture using UV-Vis
spectroscopy. Interestingly, from these studies we observed two
1:1 complexes of both indole 1b and morpholine with [PyN]-Ala-
OMe 2a (Complex A and Complex B, respectively).[13] Benesi-
Hildebrand-type analysis revealed that both complexes had
comparable binding constants (KEDA) and thus likely exist as a
dynamic equilibrium in solution. However, their molar extinction
coefficients differed dramatically, which suggested that
Complex A was the most photochemically active species.
Furthermore, in the absence of light, only low levels of
conversion to the product were observed. All reactivity was also
completely suppressed in the presence of oxygen. These results
together strongly suggested that this reaction proceeds through
a radical process initiated by the photoexcitation of EDA
Complex A.
modest to high yields. Finally, a dipeptide derived acceptor
([PyN]-Phe-Gly-OEt) was also successfully used to form product
3m in modest yield. The yield of 3m was unusually low due to
the competing formation of an alkylated 2,4,6-triphenylpyridine
byproduct.
Scheme 3. Scope of amino acid-derived accpetors with indole 1b. Isolated
yields reported.
The scope of the donors with respect to [PyN]-Ala-OMe as the
standard acceptor was then explored (Scheme 4a). First, simple
3-methyl/phenyl substituted indole donors were both alkylated to
form the corresponding products 3a,n in excellent yields.
However, product 3a was formed in diminished yield when the
reaction was performed on a 1.0 mmol scale, suggesting that
this reaction protocol is highly sensitive to the light intensity.[15]
An N-benzyl protected indole donor could also be used to form
the desired product 3o in acceptable yield. Encouraged by these
results, we examined common indole natural product
frameworks and found that we could readily alkylate tryptohol,
Cbz-protected tryptamine and melatonin to form products 3p–r
in consistently good yields. A long-chain ester derivative 3s was
likewise prepared in excellent yield. Indole donors bearing
substituents on the 2-position could also be tolerated, as shown
with the formation of indole products 5a,b. Next, satisfied we
had demonstrated good compatibility with indole donors, we
sought to determine if other heteroarenes could also be
employed. Thus, inspired by the success of 2-/3-phenyl
substituted indoles we examined the reactivity of their
benzofuran analogues, which were both alkylated to afford
benzofurans 3t, 5c in good to excellent yields (Scheme 4b). In
an analogous fashion, 2-/3-substituted benzothiophene
Scheme 2. Initial observation, optimization and EDA complex characterization.
Yields were determined by 1H NMR spectroscopy against an internal standard
(1,3,5-trimethoxybenzene).
Next, having developed optimal reaction conditions and
concluded our preliminary EDA complex analysis, we began to
examine which other amino acid derived acceptors were
compatible with indole 1b (Scheme 3).[14] First, simple aliphatic
acceptor derivatives ([PyN]-Gly-OEt etc.) were converted into
the desired products 3b–f in consistently good yields. More
functionalized acceptors derived from protected lysine and
methionine precursors were similarly tolerated to afford products
3g,h in good yields. Next, a variety of phenylalanine and
tyrosine derivatives were used to prepare products 3i–l in
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derivatives were also alkylated to afford products 3u, 5d
(Scheme 4c). Although modest yielding, the formation of
borylated benzothiophene 3u, was particularly pleasing as it
illustrates the functional group tolerance and potential synthetic
utility of this method. It should also be noted that, to the best of
our knowledge, these are the first examples in which benzofuran
and benozothiophene derivatives have been used as donors in
productive EDA complexes. Finally, we tested the reactivity of
enamines as donors with [PyN]-Ala-OMe (Scheme 4d). Without
additional optimisation we found that cyclohexanone could be
alkylated in modest yield, simply by using our standard reaction
conditions with 2.5 equivalents of morpholine. Here, the in situ
formed enamine was alkylated to form product 6a as a mixture
of diastereoisomers in modest yield. Next, to establish the
feasibility of an organocatalytic approach, we showed that by
replacing morpholine with Et3N, pyrrolidine (20 mol%) could be
used to promote the organocatalytic alkylation of aliphatic
aldehydes to form products 6a–d as 1:1 mixtures of
diastereoisomers in modest yields. It should be noted that the
yields of these unoptimised reactions was likely reduced by the
rapid and facile oxidation of the aldehyde products to the
corresponding carboxylic acids.[15] However, these reactions
provide a clear proof of principle that an enantioselective variant
might later be realized.
Scheme 4. Scope of compatible donors with acceptor [PyN]-Ala-OMe 2a. Isolated yields reported.
To gain further insight into the mechanism of these reactions, we
elected to use indole 1b as a model substrate for both
experimental and computational analysis. First, based on the
UV-Vis spectra of the reaction mixture and its components, we
found no evidence for the potential formation of a ternary EDA
complex between [PyN]-Ala-OMe, 1b and morpholine (Scheme
5.1a). Thus, considering the greater molar extinction coefficient
and the established reactivity of Complex A with other non-
donor bases (see Scheme 2), we reaffirmed our initial
hypothesis that Complex A was most likely the photochemically
active complex that initiates a radical chain process. The validity
of this hypothesis was further reinforced by computational
studies using time-dependent density functional theory (TDDFT),
which clearly demonstrated that upon visible light excitation of
Complex A, a charge-transfer-type excited state is populated
through an excitation from an indole-centered π orbital to a
pyridinium-centered π* orbital (Scheme 5.1b).[16] Thus we
propose that following the photoexcitation of Complex A, a
small quantity of the excited complex dissociates and escapes
the solvent cage to initiate an exergonic radical chain process
(Scheme 5.2).[17] The dissociated pyridinyl radical 7 can then
irreversibly fragment to afford electrophilic radical 8, which
based on DFT analysis is the turnover-determining intermediate
of the radical chain.[15] This electrophilic radical then reversibly
adds to indole 1b to form benzylic radical 9. Here, the base is
proposed to facilitate the propagation of the radical chain by
enabling the thermodynamically unfavourable electron transfer
between 9 (Ecalc. = −0.48 V) and 2a (Ecalc. = −0.98 V) through a
concerted proton-coupled electron transfer (PCET) type pathway
(Scheme 5.3).[18]
Other alternative stepwise pathways
proceeding through homolytic aromatic substitution (HAS) or
base-promoted homolytic aromatic substitution (BHAS)
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processes were determined to be thermodynamically
unfeasible.[19] It is possible that this three-component concerted
electron transfer event could be assisted by the pre-coordination
of morpholine to the acceptor (through Complex B), which
would formally render this process a two-component collision.
Furthermore, this rationale could account for why a significant
increase in reactivity was observed when bases which can also
function as donors were used.
variety of donors with acceptors derived from abundant amino
acid and peptide feedstocks. We hope this work will facilitate the
development of other traceless acceptor systems with improved
atom economy and even broader donor compatibility. The
potential application of these acceptors in asymmetric protocols
is also an area of significant interest. Overall, this strategy is
expected to be of broad interest to the field of photochemical C–
C bond formation and will enable a number of products to be
selectively accessed using abundant precursors and
operationally simple conditions.
In summary, we have described the development of a traceless
acceptor group strategy to photochemically alkylate a wide
Scheme 5. Proposed mechansim and supporting studies. HAS: homolytic aromatic substitution. BHAS: base-promoted homolytic aromatic substitution. PCET:
proton-coupled electron transfer.
[2]
[3]
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;
c) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81,
6898; d) D. Ravelli, S. Protti, M. Fagnoni, Chem. Rev. 2016, 116, 9850;
e) A. Studer, D. P. Curran, Angew. Chem. Int. Ed. 2016, 55, 58; f) C.-S.
Wang, P. H. Dixneuf, J.-F. Soulé, Chem. Rev. 2018, 118, 7532.
Acknowledgements
This work was supported by the Alexander von Humboldt Foun-
dation (M.J.J.), the Deutsche Forschungsgemeinschaft (SFB
858, F.S.K.) and the Fonds der Chemischen Industrie (F.S.,
F.J.R.K.). We thank L. Pitzer, Dr Z. Nairoukh, M. P. Wiesenfeldt
and M. Teders for helpful discussions.
For selected examples, 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) J. Jin,
D. W. C. MacMillan, Nature 2015, 525, 87; c) W. Chen, Z. Liu, J. Tian, J.
Li, J. Ma, X. Cheng, G. Li, J. Am. Chem. Soc. 2016, 138, 12312; d) Á.
Gutiérrez-Bonet, J. C. Tellis, J. K. Matsui, B. A. Vara, G. A. Molander,
ACS Catal. 2016, 6, 8004; e) L. Pitzer, F. Sandfort, F. Strieth-Kalthoff,
F. Glorius, J. Am. Chem. Soc. 2017, 139, 13652; f) F. Xue, F. Wang, J.
Liu, J. Di, Q. Liao, H. Lu, M. Zhu, L. He, H. He, D. Zhang, et al., Angew.
Chem. Int. Ed. 2018, 57, 6667; g) R. R. Merchant, J. T. Edwards, T. Qin,
M. M. Kruszyk, C. Bi, G. Che, D.-H. Bao, W. Qiao, L. Sun, M. R. Collins,
et al., Science 2018, 360, 75; f) J. M. Smith, J. A. Dixon, J. N.
Keywords: Visible light • C–C bond formation • EDA complexes
• Amino Acids • Traceless acceptors
[1]
For reviews on C–C bond formation, see: a) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457; b) J. Magano, J. R. Dunetz, Chem. Rev.
2011, 111, 2177; c) C. C. C. Johansson Seechurn, M. O. Kitching, T. J.
Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51, 5062; d) C.-L.
Sun, Z.-J. Shi, Chem. Rev. 2014, 114, 9219.
DeGruyter, P. S. Baran,
10.1021/acs.jmedchem.8b01303.
J. Med. Chem.
2018, DOI
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[4]
For selected examples, see: a) Z. Zuo, D. W. C. MacMillan, J. Am.
Chem. Soc. 2014, 136, 5257; b) A. Noble, D. W. C. MacMillan, J. Am.
Chem. Soc. 2014, 136, 11602; c) J. Xuan, Z.-G. Zhang, W.-J. Xiao,
Angew. Chem. Int. Ed. 2015, 54, 15632; d) 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; e) 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; f) A. Tlahuext-Aca, R. A. Garza-Sanchez, F. Glorius,
Angew. Chem. Int. Ed. 2017, 56, 3708; g) 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, et al., Nature 2017, 545, 213;
h) M. Koy, F. Sandfort, A. Tlahuext-Aca, L. Quach, C. G. Daniliuc, F.
Glorius, Chem. Eur. J. 2018, 24, 4552; i) R. S. J. Proctor, H. J. Davis, R.
J. Phipps, Science 2018, 360, 419.
Zhang, S.-L. You, Org. Lett. 2018, 20, 4379; e) Q. Guo, M. Wang, H.
Liu, R. Wang, Z. Xu, Angew. Chem. Int. Ed. 2018, 57, 4747.
[9]
A. R. Katritzky, C. M. Marson, Angew. Chem. Int. Ed. 1984, 23, 420; b)
A. R. Katritzky, M. A. Kashmiri, G. Z. de Viile, R. C. Patel, J. Am. Chem.
Soc. 1983, 105, 90; c) D. Moser, Y. Duan, F. Wang, Y. Ma, M. J. O’Neill,
J. Cornella, Angew. Chem. Int. Ed. 2018, 57, 11035.
[10] F. J. R. Klauck, M. J. James, F. Glorius, Angew. Chem. Int. Ed. 2017,
56, 12336.
[11] For related reactions using Katritzky pyridinium salts in photoredox
catalysis, see: a) M. Ociepa, J. Turkowska, D. Gryko, ACS Catal. 2018,
8, 11362; b) F. J. R. Klauck, H. Yoon, M. J. James, M. Lautens, F.
Glorius, ACS Catal. 2019, 9, 236; c) Z.-F. Zhu, M.-M. Zhang, F. Liu,
Org. Biomol. Chem. 2019, 17, 1531.
[12] For deaminative borylation reactions using pyridinium salts, see: a) J.
Wu, L. He, A. Noble, V. K. Aggarwal, J. Am. Chem. Soc. 2018, 140,
10700; b) J. Hu, G. Wang, S. Li, Z. Shi, Angew. Chem. Int. Ed. 2018,
57, 15227; c) F. Sandfort, F. Strieth-Kalthoff, F. J. R. Klauck, M. J.
James, F. Glorius, Chem. Eur. J. 2018, 24, 17210.
[5]
a) C. H. Basch, J. Liao, J. Xu, J. J. Piane, M. P. Watson, J. Am. Chem.
Soc. 2017, 139, 5313; b) J. Liao, W. Guan, B. P. Boscoe, J. W. Tucker,
J. W. Tomlin, M. R. Garnsey, M. P. Watson, Org. Lett. 2018, 20, 3030;
c) W. Guan, J. Liao, M. P. Watson, Synthesis 2018, 50, 3231; d) S.
Plunkett, C. H. Basch, S. O. Santana, M. P. Watson, J. Am. Chem. Soc.
2019, 141, 2257.
[13] Indole 1b was used for UV-Vis spectroscopic analysis instead of indole
1a due to its comparable reactivity and more pleasant odour.
[14] During these studies the reaction time varied significantly (between 18–
48 h) with each acceptor and so the reaction time was increased to 48
h as standard for all reactions.
[6]
[7]
C. G. S. Lima, T. de M. Lima, M. Duarte, I. D. Jurberg, M. W. Paixão,
ACS Catal. 2016, 6, 1389.
a) E. Arceo, I. D. Jurberg, A. ꢀlvarez-Fernández, P. Melchiorre, Nat.
Chem. 2013, 5, 750; b) M. Nappi, G. Bergonzini, P. Melchiorre, Angew.
Chem. Int. Ed. 2014, 53, 4921; c) Ł Wozniak, J. J. Murphy, P.
Melchiorre, J. Am. Chem. Soc. 2015, 137, 5678; d) S. R. Kandukuri, A.
Bahamonde, I. Chatterjee, I. D. Jurberg, E. C. Escudero-Adán, P.
Melchiorre, Angew. Chem. Int. Ed. 2015, 54, 1485; e) A. Bahamonde, P.
Melchiorre, J. Am. Chem. Soc. 2016, 138, 8019; f) R.-B. Hu, S. Sun, Y.
Su, Angew. Chem. Int. Ed. 2017, 56, 10877; g) Z.-Y. Cao, T. Ghosh, P.
Melchiorre, Nat. Commun. 2018, 9, 3274; h) T. Morack, C. Mück-
Lichtenfeld, R. Gilmour Angew. Chem. Int. Ed. 2018, DOI
10.1002/anie.201809601.
[15] For further information see the Supporting Information.
[16] Further TDDFT studies suggest that Complex B could also initiate the
radical chain (see the Supporting Information for details).
[17] We considered an in solvent cage recombination event unlikely, as this
does not account for the essential role of the base in promoting these
reactions.
[18] a) D. R. Weinberg, C. J. Gagliardi, J. F. Hull, C. F. Murphy, C. A. Kent,
B. C. Westlake, A. Paul, D. H. Ess, D. G. McCafferty, T. J. Meyer,
Chem. Rev. 2012, 112, 4016; b) E. C. Gentry, R. R. Knowles, Acc.
Chem. Res. 2016, 49, 1546.
[19] A. Studer, D. P. Curran, Nat. Chem. 2014, 6, 765.
[8]
For examples of EDA complexes in trifluormethylation reactions, see: a)
Y. Cheng, X. Yuan, J. Ma, S. Yu, Chem. Eur. J. 2015, 21, 8355; b) Y.
Cheng, S. Yu, Org. Lett. 2016, 18, 2962; c) H.-Y. Tu, S. Zhu, F.-L. Qing,
L. Chu, Chem. Commun. 2018, 54, 12710; d) M. Zhu, K. Zhou, X.
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Michael J. James, Felix Strieth-Kalthoff,
Frederik Sandfort, Felix J. R. Klauck,
Felicitas Wagener and Frank Glorius*
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Visible-Light-Mediated Charge
Transfer Enables C–C Bond
Formation with Traceless Acceptor
Groups
The development and application of traceless acceptor groups in photochemical C–
C bond formation is described. This strategy was enabled by the photoexcitation of
electron donor-acceptor (EDA) complexes with visible light. The traceless
acceptors, which were readily prepared from amino acid and peptide feedstocks,
could be used to alkylate a wide range of heteroarene and enamine donors under
metal- and peroxide-free conditions. The crucial role of the EDA complexes in the
mechanism of these reactions was explored through combined experimental and
computational studies.
This article is protected by copyright. All rights reserved.