Asymmetric visible-light photoredox cross-dehydrogenative coupling of aldehydes with xanthenes

Article abstract of DOI:10.1021/acscatal.7b02659

We report a methodology for the catalytic asymmetric cross-coupling of two C(sp³)-H bonds employing visible light as an economical and environmentally benign source of energy. Photoredox catalysis is used for the oxidation of a diarylmethane to the corresponding cation, which is then trapped by an enamine intermediate generated in situ from an aldehyde reactant and a secondary amine organocatalyst. Notably, this mild method is an ideal synthetic approach from the green chemistry point of view. It does not require preinstallation of functional groups, thereby constituting an atom economical, efficient transformation, and it allows the formation of a C-C bond with simultaneous installation of one or two new stereocenters in a highly enantio- and diastereoselective manner. Mechanistic studies by experimental and computational methods aid to clarify the origin of the observed enantioselectivity.

Full text of DOI:10.1021/acscatal.7b02659

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Letter
Asymmetric Visible-Light Photoredox Cross-
Dehydrogenative Coupling of Aldehydes with Xanthenes
Evgeny Larionov, Marco M Mastandrea, and Miquel A. Pericàs
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02659 • Publication Date (Web): 19 Sep 2017
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Asymmetric Visible-Light Photoredox Cross-Dehydrogenative Cou-
pling of Aldehydes with Xanthenes.
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Evgeny Larionov,† Marco M. Mastandrea,† and Miquel A. Pericàs*,†,‡
† Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Avda. Països Cat-
alans, 16, 43007 Tarragona, Spain
‡ Department de Química Organica, Universitat de Barcelona, 08080 Barcelona, Spain
Supporting Information Placeholder
great progress in enantioselective photoredox α-alkylation of alde-
ABSTRACT: We report a methodology for the catalytic asym-
hydes using alkyl bromides,[10] there are few reports on the corre-
sponding photoredox CDC reactions with non-functionalized
C(sp3)-H bonds.[11] We envisioned that the combination of enamine
and photoredox catalysis would enable an asymmetric coupling be-
tween diarylsubstituted CH2 units and aldehydes (Figure 1c).
metric cross-coupling of two C(sp3)–H bonds employing visible
light as an economical and environmentally benign source of en-
ergy. Photoredox catalysis is used for the oxidation of a diarylme-
thane to the corresponding cation, which is then trapped by an
enamine intermediate generated in situ from an aldehyde reactant
and a secondary amine organocatalyst. Notably, this mild method
is an ideal synthetic approach from the green chemistry point of
view. It does not require preinstallation of functional groups,
thereby constituting an atom economical, efficient transformation,
and allows the formation of a C–C bond with simultaneous instal-
lation of one or two new stereocenters in a highly enantio- and di-
astereoselective manner. Mechanistic studies by experimental and
computational methods aid to clarify the origin of the observed en-
antioselectivity.
Keywords: asymmetric catalysis, photoredox, coupling, mecha-
nism, DFT, organocatalysis
The direct functionalization of inert C–H bonds has emerged in
recent years as a powerful tool in synthetic organic chemistry.[1,2]
The cross-dehydrogenative coupling (CDC) reaction of the C–H
bond α to a nitrogen, oxygen or a carbonyl group represents one of
the most successful examples of mild and selective C–C bond for-
mations from C–H bonds.[3,4] Compared with non-asymmetric
CDC reactions, only limited examples of enantioselective protocols
for the C–C coupling via C(sp3)–H activation have been reported
so far.[5] Such a combination of dehydrogenative cross-coupling
with asymmetric catalysis not only provides a fast increase of the
structural complexity of a molecule, but also allows to install sim-
ultaneously one or multiple stereocenters.
In the past several years, due to its prominent energy-saving and
environmentally benign features, visible-light photoredox catalysis
has witnessed rapid development and attracted a great deal of
interest in both academia and industry.[6,7] The synergetic combina-
tion of photoredox with other modes of catalytic activation has
emerged as a powerful approach to discover novel reactivities and
improve reaction conditions.[8] However, application of photoredox
catalysis to asymmetric CDC reactions remains a formidable
challenge, and few examples have been described in literature so
far (Figure 1).[5d,9] Rovis and co-workers reported the combination
of NHC-catalysis and visible light photocatalysis for the function-
alization of tetrahydroisoquinolines (Figure 1a).[9a] Meggers group
developed an enantioselective α-alkylation of ketones using a chiral
at metal Rh-complex, which serves both as photoredox catalyst and
chiral Lewis acid in this transformation (Figure 1b).[5d] Despite the
Figure 1. Asymmetric visible-light driven CDC.
We commenced our study by investigating the asymmetric CDC
between xanthene 1a and pentanal 2a under visible-light photore-
dox conditions in presence of the Jørgensen’s catalyst cat.1 (Figure
2). The high-throughput experimentation (Figure 2, see SI for more
details) allowed us to rapidly screen reaction conditions. We used
a 96-well-plate reactor engineered to allow each reaction to be ir-
radiated independently by a single light-emitting diode (LED) to
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evaluate important reaction parameters. Screening of solvents (see
to the -carbon of the enamine intermediate) was obtained as a ra-
cemic mixture.[12] Non-conformationally restricted, electron-rich
diarylmethanes (1l,m) unfortunately did not give the desired prod-
ucts, probably due to a lower stability of the corresponding radical
(vide infra).
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SI for details) and photocatalysts (Figure 2a) allowed us to identify
DCE and Ru(bpy)3Cl2 as an optimal solvent and photocatalyst, cor-
respondingly. We did not observe any reasonable correlation be-
tween the reactivity and oxidation/reduction potentials of tested
photocatalysts. The Ru(bpy)3 complex seems to have both poten-
tials matching the corresponding electrochemical properties of re-
agents/intermediates (vide infra). Due to a better solubility,
Ru(bpy)3(PF6)2 gave slightly better conversion when the reaction
was performed on a catalytic scale (0.2 mmol). Screening of differ-
ent oxidants showed that the presence of a weak C-Br bond is cru-
cial for the reactivity: among different bromoalkanes that were
tested BrCCl3 gave the highest conversion to the product. In con-
trast, other oxidants (O2, CCl4) showed no conversion to the desired
product (Figure 2b).
Table 1. Optimization of reaction conditions and control ex-
periments.
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Reactions performed on 0.2 mmol scale. [a] Conversion was de-
termined by GC analysis. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis using a chiral stationary phase. [d] Re-
sults for cat.2-cat.6 with no variation from standard conditions.
n.d.=not determined.
Figure 2. HTE screening of reaction conditions (see details in SI).
Control experiments (Table 1, entries 3-6) showed that light,
photocatalyst, base and oxidant are all crucial for achieving an ap-
preciable conversion to the product. Notably, base is required in
order to scavenge HBr - a stoichiometric product of the reaction. In
support of this hypothesis, in the absence of any base mostly self-
condensation products of aldehyde 2a along with 12% of the de-
sired product were observed in the reaction crude (Figure 2d, see
SI for details). Other mild phosphate bases (e.g. NaH2PO4,
Na2HPO4) also gave a reasonable conversion, whereas stronger car-
bonate bases (such as K2CO3, Cs2CO3) were ineffective in the stud-
ied reaction (Figure 2c). During the screening of organocatalysts
(Table 1, bottom) we found that MacMillan’s catalysts cat.2 and
cat.3 are catalytically active in the studied reaction, however infe-
rior enantioselectivities were observed. Comparison of different
prolinol derivatives cat.4-cat.6 highlights an importance of both
TMS protecting group and bis(trifluoromethyl)phenyl substituent
for reactivity and enantioselectivity. The loading of cat.1 can be
lowered to 10 mol% without affecting the reaction yield and enan-
tioselectivity (Table 1, entry 2). Finally, when the reaction was per-
formed in the presence of a radical scavenger (Table 1, entry 7),
much lower conversion to product was achieved, thus indicating a
radical nature of the process (vide infra).
The scope of the enantioselective CDC of xanthene with various
aldehydes was then extensively investigated under the optimized
reaction conditions (Figure 3). Aliphatic aldehydes delivered prod-
ucts in good yields and excellent enantioselectivities (3a-d). The
more sterically hindered isobutyraldehyde (2e) gave product 3e in
57% yield and 99.5:0.5 er. Thioxanthene (1b) was well tolerated in
the CDC reaction (3f). Substituted phenylpropanals as well as ben-
zyloxy-substituted aldehydes were compatible with the catalytic
system (3g-k). Surprisingly, product 3k with a benzyloxy substitu-
ent directly attached to the α-carbon of the aldehyde reactant (i.e.,
Figure 3. Scope of aldehydes and diarylmethanes in the asymmet-
ric photoredox CDC. Reactions performed on 0.2 mmol scale. [a]
With 2 mol% of Ru(bpy)3Cl2. [b] With 20 mol% of cat.1.
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omers in moderate yields and high enantiomeric purities. The reac-
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tion tolerates different functional groups, such as methoxy, phe-
nolic hydroxyl, diethylamino, bromo, fluoro. This could open up
possibilities for the orthogonal functionalization of products by
cross-coupling (5m,n) or etherification (5h).
Interestingly, we found that switching from the Jørgensen’s cat-
alyst cat.1 to MacMillan’s catalyst cat.2 allowed to switch the dia-
stereoselectivity in favor of a different diastereomer, where the
configuration of the -carbon had been inverted (Figure 4b).[14]
Several substrate combinations were tested with cat.2, affording
moderate to good yields of the corresponding products (up to 74%
combined yield of diastereomers). Due to the lower diastereoselec-
tivity achieved with this catalyst, the yields of individual diastere-
omers were relatively moderate. Enantioselectivities with cat.2
reached the modest level of 76:24 er (for 6e), and further screening
of imidazolinones did not significantly improve this result (e.g.,
79:21 er for 6e with cat.3, see SI for more details). In general, in
the studied transformation the Jørgensen’s catalyst cat.1 is more
selective in terms of enantio- and diastereoselectivity, compared
with imidazolinones cat.2 and cat.3. In the case of 1-substituted
xanthenes 4e-o it leads to a stronger catalyst control of diastereose-
lectivity by cat.1, whereas the reaction in presence of cat.2 is sub-
strate controlled. The absolute configuration of product 5e was de-
termined by single-crystal X-ray diffraction of its ferrocene deriv-
ative.[15] The second diastereomer (6e) was crystallized as a race-
mate, which allowed us to determine its relative configuration (Fig-
ure 5).[15]
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Figure 5. X-ray structure of ferrocene derivative of 5e (left) and
(rac)-6e (right).
The proposed mechanism for the studied transformation is shown
in Figure 6. It consists of two separate catalytic cycles: photoredox
and organocatalytic. In the photoredox cycle, bromotrichloro-
methane (E1/2 = -0.18 V vs SCE)[16] is first reduced by the excited
state of the Ru(II) complex (E1/2 = -0.81 V vs SCE)[17] to the CCl3
radical (oxidative quenching), which then abstracts a hydrogen
atom from xanthene 1a to generate the xanthyl radical INT1.[19,20]
Suppression of the catalytic reaction in the presence of a radical
scavenger (vide supra) gave the first evidence for the radical nature
of the process. Secondly, an experimentally measured kinetic iso-
tope effect (KIE) of 4.0 indicates that C-H bond cleavage occurs
during the rate-limiting step. This was additionally confirmed by
DFT study of the reaction mechanism (see SI for more details).[21,22]
Calculations show that the hydrogen abstraction step by the CCl3
radical through transition state TS1 is rate-limiting with an activa-
tion barrier ΔG‡ = 8.3 kcal/mol (Figure 6). Moreover, the KIE pre-
dicted by computations (4.3) is in a perfect accordance with the ex-
perimental value of 4.0.
Figure 4. Scope of substituted xanthenes in the asymmetric photo-
redox CDC. Reactions performed on 0.2 mmol scale. [a] Carried
out with 10 mol% cat.1. [b] Diastereomeric ratio determined by
NMR analysis of the crude reaction mixture, given as 5/6 ratio.
Next, different substituted xanthenes were subjected to the pho-
toredox CDC with pentanal (Figure 4a).[13] 2-, 3- and 4-substituted
xanthenes delivered the corresponding products in good yields and
high enantioselectivities (up to 97.5:2.5 er), but eventually as 1:1
mixtures of diastereomers (5a-d). To our delight, the reaction with
1-methyl-substituted xanthenes gave much higher diastereoselec-
tivities (up to 10:1) and in many cases single diastereomers could
be easily isolated (5e-h,m-o). Products derived from benzo-fused
xanthenes (5i,j,n) were obtained in good yields and excellent dia-
stereo- and enantioselectivities. On the other side, 1-methoxyxan-
thenes gave the corresponding products with lower diastereoselec-
tivities (5k,l) allowing, however, the isolation of both diastere-
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Figure 7. Possible pathways of the C-C bond forming step.
Figure 6. Mechanistic proposal and DFT results. The reduction po-
tentials for BrCCl3,[16] Ru complexes[17] and INT2[18] (vs SCE)
In conclusion, we have developed a unique catalytic asymmetric
cross-dehydrogenative coupling of xanthenes and thioxanthenes
with aldehydes using visible light as a sustainable source of energy.
The reaction features high enantioselectivities, good yields and
wide functional group tolerance. The method was extended to the
coupling of non-symmetrical xanthenes, which give CDC products
with high diastereoselectivities, thus allowing isolation of single
diastereomers in good yields and with high enantiomeric purities.
Mechanistic studies by experimental and computational methods
have shown that the reaction proceeds via the rate-limiting hydro-
gen abstraction followed by single-electron transfer and selectivity-
determining attack of cation on enamine. Ongoing studies focus on
the further extension of substrate scope in terms of variation of di-
arylmethane partner and application of this methodology to the syn-
thesis of complex molecules.
were taken from literature.
Stern-Volmer plot measurements show significant quenching of
the excited Ru(bpy)32+ by BrCCl3 (quenching rate kq =1.5 × 108 M-
1 s-1) which is in agreement with the proposed mechanism (Figure
6).[23,24] At this point we cannot exclude a radical chain mechanism
where radical INT1 (E1/2 = 0.12 V vs SCE) would directly reduce
BrCCl3 (E1/2 = -0.18 V vs SCE) to a CCl3 radical (Figure 6).[25] In
this case photocatalyst is only required in the first cycle to start a
chain. The CCl3 radical is then regenerated in a chain propagation
step (ΔGrxn = +6.9 kcal/mol).[26]
In the computational study of the C-C bond forming step we con-
sidered different possibilities, such as attack of radical INT1 onto
enamine INT3 (Pathway A in Figure 7, ΔG‡ = 20.6 kcal/mol) or
oxidation of enamine INT3 to the corresponding radical-cation
(E1/2 = 0.49 V vs SCE)[27] followed by the attack of INT1 (Pathway
B in Figure 7, ΔG‡ = 30.9 kcal/mol). However, the most energeti-
cally favorable pathway was found to be an oxidation of xanthyl
radical INT1 to cation INT2 (E1/2 = 0.12 V vs SCE)[18] by the
Ru(III) complex (E1/2 = 1.29 V vs SCE),[17] followed by the classi-
cal attack of so-generated cation on enamine INT3 via transition
state TS2 (Pathway C in Figure 7, ΔG‡ = 4.3 kcal/mol). The latter
step is the selectivity-determining, deciding which enantiomer of
INT4 and, correspondingly, of product 3b, is formed. Computed
energy difference between diastereomeric transition states (R)-TS2
and (S)-TS2 (ΔΔG‡ = 1.7 kcal/mol) is in a perfect agreement with
the experimental data (ΔΔG‡ = 2.0 kcal/mol).
AUTHOR INFORMATION
Corresponding Author
*mapericas@iciq.es.
Notes
The authors declare no competing financial interests.
ASSOCIATED CONTENT
Supporting Information
We also considered an alternative pathway via the reductive
quenching of excited Ru(II) species (E1/2 = 0.77 V vs SCE)[17] by
enamine INT3 (E1/2 = 0.49 V vs SCE).[27] This redox step is there-
fore energetically favorable (see SI for details). The next step, at-
tack of the corresponding radical-cation by radical INT1, has how-
ever a high activation barrier (Pathway B in Figure 7, ΔG‡ = 30.9
kcal/mol). This pathway is thus less favorable than the oxidative
quenching pathway.
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental and computational details (PDF)
ACKNOWLEDGMENT
Financial support from Marie Skłodowska-Curie action (fellowship
to E. L., 291787-ICIQ-IPMP), ICIQ International PhD Fellowship
Programme (fellowship to M. M.), MINECO (grant CTQ2015-
69136-R (MINECO/FEDER)) and ICIQ Foundation is gratefully
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catalyst cat.2 was employed (Figure 4). This side-differentiation change
could be caused by the increased size of the substituents at the xanthene
partner.
acknowledged. We also thank MINECO for support through the
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Severo Ochoa Excellence Accreditation 2014–2018 (SEV-2013-
0319) and the CELLEX Foundation for funding the CELLEX-ICIQ
high throughput experimentation (HTE) platform. We also thank
the ICIQ X-ray diffraction unit for the X-ray structures and Dr.
Xisco Caldentey for the assistance with the HTE experiments. Dr.
Julio Lloret-Fillol is acknowledged for the design of LED set-up
and providing access to this set-up for the initial experiments.
[15]
CCDC 1511524 and 1511523 for ferrocene derivative of 5e and
(rac)-6e, respectively, contain the supplementary crystallographic data for
this article. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre (CCDC) at www.ccdc.cam.ac.uk/data_re-
quest/cif.
[16]
Murayama, E.; Kohda, A.; Sato, T. J. Chem. Soc., Perkin Trans.
1980, 1, 947–949.
[17]
[18]
Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159–244.
Zhu, X.-Q.; Dai, Z.; Yu, A.; Wu, S.; Cheng, J.-P. J. Phys. Chem.
8
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S.; Fagnoni, M. Chem. Rev. 2016, 116, 9850–9913.
1a (2.3 × 108 M-1 s-1) was observed. It is unlikely to be caused by direct
oxidation of 1a to the corresponding radical cation due to the high value of
the corresponding potential: E1/2 = 1.55 V vs SCE (see ref 25).
[7]
For reviews on C–H bond functionalization reactions by photo-
[25]
The quantum yield measurements would be helpful to clarify
redox catalysis, see: a) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687–
7697; b) Xie, J.; Jin, H.; Zhu, C. Tetrahedron Letters 2014, 55, 36–48.
[8]
J. 2014, 20, 3874–3886; b) Angnes, R. A.; Li, Z.; Correia, C. R. D.; Ham-
mond, G. B. Org. Biomol. Chem. 2015, 13, 9152–9167; c) Skubi, K. L.;
Blum, T. R.; Yoon; T. P. Chem. Rev. 2016, 116, 10035–10074.
this scenario, but they were not possible due to the heterogeneity of the re-
action mixture.
[26]
INT1 onto enamine INT3, followed by the reduction of BrCCl3 by the
formed intermediate, is also feasible. However, according to further discus-
sion this pathway would have a higher activation barrier (20.6 kcal/mol,
Pathway A on Figure 7).
a) Hopkinson, M. N.; Sahoo, B.; Li, J.-L.; Glorius, F. Chem. Eur.
Alternative radical chain pathway via the addition of radical
[9]
a) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134,
8094–8097; b) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-
H. Angew. Chem. Int. Ed. 2017, 56, 3694–3698; c) Kumar, G.; Verma, S.;
Ansari, A.; Khan, N. H.; Kureshy, R. I. Catal. Commun. 2017, 99, 94–99.
[27]
Reduction potential from DFT calculations, see SI for details.
[10]
a) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 10875–10877; b) for a recent review on asymmetric catal-
ysis by visible-light activation, see: Meggers, E. Chem. Commun. 2015, 51,
3290–3301.
[11]
a) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.; Cozzi,
P. G. Chem. Commun. 2009, 5919–5921; b) Ho, X. H.; Mho, S. I.; Kang,
H.; Jang, H. Y. Eur. J. Org. Chem. 2010, 4436–4441; c) Zhang, B.; Xiang,
S.-K.; Zhang, L. H.; Cui, Y.; Jiao, N. Org. Lett. 2011, 13, 5212–5215; d)
Huang, F.; Xu, L.; Xiao, J. Chin. J. Chem. 2012, 30, 2721–2725.
[12]
We think the highly electron-rich nature of the enamine
intermediate could be responsible for this behavior by triggering a non-
enantioselective pathway with participation of the derived radical-cation.
[13]
ringhaus, T.; Nitsch, J.; Klussmann, M. Org. Biomol. Chem. 2011, 9, 1744
– 1748.
[14]
Substituted xanthenes were prepared according to: Böb, E.; Hill-
Although catalysts cat.1, cat.2 and cat.3 gave the same config-
uration of the α-carbon atom in the product 3a (Table 1), an opposite con-
figuration of the α-carbon atom in products 5 and 6 was observed when
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