Tandem Photoredox and Copper-Catalyzed Decarboxylative C(sp3)-N Coupling of Anilines and Imines Using an Organic Photocatalyst

Article abstract of DOI:10.1021/acs.orglett.0c01769

An organic photoredox catalyst, 4CzIPN, was used in combination with a copper catalyst, CuCl, to effect decarboxylative C(sp3)-N coupling. The coupling worked with both anilines and imines as nitrogen sources and could be used to prepare a variety of alkyl amines from readily available alkyl carboxylic acids.

Full text of DOI:10.1021/acs.orglett.0c01769

pubs.acs.org/OrgLett
Letter
Tandem Photoredox and Copper-Catalyzed Decarboxylative C(sp3)−
N Coupling of Anilines and Imines Using an Organic Photocatalyst
̀
Guido Barzano, Runze Mao, Marion Garreau, Jerome Waser, and Xile Hu*
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ABSTRACT: An organic photoredox catalyst, 4CzIPN, was used in combination with a copper catalyst, CuCl, to effect
decarboxylative C(sp3)−N coupling. The coupling worked with both anilines and imines as nitrogen sources and could be used to
prepare a variety of alkyl amines from readily available alkyl carboxylic acids.
drophenazine 1d, was used (10 mol %), together with 20
mol % of CuBr and 5 equiv of triethylamine (Table 1, entry 1),
the reaction occurred (0.1 M acetonitrile, at room temperature,
under the irradiation of blue LEDs, overnight) to give 1c in a
yield of 28%. Decreasing the loading of photocatalyst to 1%
gave a similar yield (Table 1, entry 2). Replacing CuBr with
CuCl increased the yield to 34% (Table 1, entry 3). Decreasing
the loading of CuCl to 5 mol % decreases the yield to 18%
(Table 1, entry 4). Different photocatalysts were then screened
(Table S6, Supporting Information). While Eosin Y (1e) (1
mol %) gave no yield, 2,4,5,6-tetra(9H-carbazol-9-yl)-
isophthalonitrile (4CzIPN)19−26(1f) gave a yield of 56%.
Decarboxylative activation of NHPI esters using 1f was
previously reported.27,28 This catalyst can be easily synthesized
from inexpensive precursors and requires no chromatographic
purification. Several organic and inorganic bases were screened
as bases, but only triethylamine and N,N-diisopropylethyl-
amine (DIPEA) were effective (Table 1, entries 1−5, 9, and
10). Finally, the optimized conditions were: 1 mol % of 1f, 20
mol % of CuCl, 1 equiv of triethylamine, in 0.1 M of
lkyl amines are an important class of organic molecules
1−4
Awith wide applications in materials and medicines.
C(sp3)−N coupling is potentially an efficient method to
streamline the synthesis of alkyl amines, complementing
traditional methods such as reductive amination,5−7 direct N-
alkylation,8,9 the Curtius rearrangement,10 and the Mitsunobu
reaction.11 However, C(sp3)−N coupling remains challenging
due to difficulty in C(sp3)−N reductive elimination as well as
side reactions such as β-H elimination. We and others recently
developed photoredox catalysis to effect decarboxylative
C(sp3)−N coupling (Figure 1A,B).12−18 This approach
employs readily available alkyl carboxylic acids as starting
reagents, activating them via either N-hydroxyphthalimide
(NHPI) esters (Figure 1A) or hyperiodide intermediates
(Figure 1B) and resulting in wide substrate scope. However,
the photocatalysts were all based on precious metals such as
Ru and Ir. Herein, we report a method for decarboxylative
C(sp3)−N coupling using an organic photoredox catalyst in
tandem with a Cu coupling catalyst (Figure 1C). The organic
photocatalyst enabled the coupling of both aniline and imines,
an improvement over precious photocatalysts which worked
for only one type of N coupling partner.13,15
A representative C(sp3)−N coupling of heptanoic acid
NHPI ester 1a with aniline 1b was chosen as the test reaction
for optimization. Conditions previously applied for the
analogous coupling using Ru(bpy)3(PF6)2 as photocatalyst
were first applied.13 When the commercially available organo-
photocatalyst, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihy-
Received: May 25, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01769
© XXXX American Chemical Society
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a
Table 1. Optimization for Decarboxylative Amination
entry
PC
Cu cat.
base
yield
1
2
3
4
5
6
7
8
9
1d 10%
1d 1%
1d 5%
1d 5%
4CzIPN 1%
Eosin Y 1%
4CzIPN 1%
4CzIPN 1%
4CzIPN 1%
4CzIPN 1%
4CzIPN 1% (no light)
/
CuBr 20%
CuBr 20%
CuCl 20%
CuCl 5%
CuCl 20%
CuCl 20%
CuCl 20%
CuCl 20%
CuCl 20%
CuCl 20%
CuCl 20%
CuCl 20%
Et3N 5 equiv
Et3N 5 equiv
Et3N 5 equiv
Et3N 5 equiv
Et3N 5 equiv
Et3N 5 equiv
lutidine 5 equiv
DIPEA 5 equiv
DIPEA 5 equiv
Et3N 1 equiv
Et3N 1 equiv
Et3N 1 equiv
28%
29%
34%
18%
56%
n.d.
n.d.
n.d.
20%
66%
n.d.
10
11
12
n.d.
a
General conditions: NHPI ester (0.5 mmol), aniline (0.25 mmol),
MeCN (2.5 mL), under N2; yields calculated via GC with an internal
standard. DIPEA = diisopropylamine; n.d. = not detected.
Figure 1. Photoredox-based decarboxylative C(sp3)−N coupling: (a)
via NHPI esters and (b) via hyperiodide intermediates. (c) This work,
using an organic photocatalyst.
Benzophenone imine and its derivatives are useful ammonia
equivalents, which allow rapid and selective synthesis of
masked primary amines.23 We previously reported that the
conditions for the decarboxylative coupling of NHPI esters
with anilines were not efficient for the analogous coupling of
NHPI esters with imines, which provided access to alkylated
acetonitrile at room temperature for 12 h under the irradiation
of blue LEDs. The yield of 1c under these conditions was 66%
(Table 1, entry 10). Control experiments showed that no
coupling occurred when there was no light or no photocatalyst
(Table 1, entries 11 and 12).
primary amines upon hydrolysis of coupling products.15
A
change of photocatalyst from Ru(bpy)3(PF6)2 to Ir-[(dtbbpy)-
(ppy)2]PF6 was necessary for the latter coupling. To our
delight, we found that the same organic photocatalyst 1f
catalyzed the coupling of NHPI esters with both anilines and
imines. For the latter coupling, further optimization of
conditions was necessary (Table S3, Supporting Information).
We were able to use benzophenone imine (3a) as the imine
partner. In the previous protocol using an Ir photocatalyst, 3a
was a poor coupling partner, and 3,3′-bis(trifluoromethyl)-
benzophenone imine had to be used. 3a is a better imine
partner than 3,3′-bis(trifluoromethyl)benzophenone imine as
it is less costly and even commercially available. The optimized
conditions for the coupling with 1c were: 1 mol % of 4CzIPN
(1f), 20 mol % of CuCl, 1 equiv of Cs2CO3, in 0.1 M DMA at
room temperature overnight under blue LED light.
These optimized conditions in Table 1 were applied to
explore the scope of the coupling (Figure 2). The coupling
worked well with different types of anilines (1c, 2a−2f). Ortho-
(2a−2c), meta- (2e), and para-substitutions (2f) in the
anilines were tolerated. High yields (>80%) were obtained
with electron-rich anilines (2a, 2b, and 2d). Yields dropped
when electron-poor anilines were used (2c, 2e, and 2f).
Coupling with electron-poor heterocycles, such as amino-
pyridine and aminoquinolines, was unsuccesful. Both primary
(1c, 2g−2i, and 2n) and secondary (2j−2m) alkyl carboxylic
acid derivatives could be used as coupling partners. The
coupling of tertiary alkyl carboxylic acid derivatives, as well as
alkyl amines, was unsuccessful. Coupling was also unsuccessful
if one of the partners bears a nonprotected protic group (e.g.,
free alcohols and amines). The coupling had high functional
group tolerance, as aryl-Cl (2f), ester (2e), nitrile (2c),
NHBoc (2g), and alkyl-Br (2h) groups were compatible.
Moreover, the coupling of NHPI esters derived from a natural
fatty acid (2n) and a indometacin (2o) gave good yields,
demonstrating the utility of the method for late-stage
functionalization. Note that the yields using 4CzIPN as the
photocatalyst were often higher than using Ru(bpy)3(PF6)2 as
the photocatalyst (e.g., 2m, 2n, and 2o).13
The conditions for the coupling of imines worked with
primary, secondary, and tertiary alkyl NHPI esters (3b−3l,
Figure 3), although the coupling of some tertiary substrates
had modest yields (3j and 3k). Coupling of NHPI esters
derived from a complex natural product (3m), a fatty acid
(3n), and a drug (3o) was also successful. Hydrolysis of the
coupling product 3o gave the corresponding primary amine
derivative with negligible loss of yield (3p). Overall, the
coupling was compatible with many functional groups,
including ketones (3m), esters (3b), amides (3o, 3p), halogen
B
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Figure 3. Scope of decarboxylative C(sp3)−N coupling of imines.
General optimized conditions: NHPI ester (0.5 mmol), benzophe-
none imine (0.25 mmol), 4CzIPN (1 mol %), CuCl (20 mol %),
DMA (2.5 mL), Cs2CO3 (0.5 mmol), under N2, blue LEDs,
overnight. 3o was deprotected with 1 M HCl in methanol for 1 h
to obtain 3p.
Figure 2. Scope of decarboxylative C(sp3)−N coupling of anilines.
Isolated yields were reported.1Yields using a Ru photocatalyst as
previously reported.13
of Cu:TEA, varying the ratios of the two components resulted
in only small and nonlinear changes of the quenching rates
(Figure S3). This result suggested the formation of Cu:TEA
species, which is a poor quencher, showing a distinct
quenching effect compared to Ir-based photocatalyst.29,30
Together, these results suggested that due to binding to
aniline or TEA or both there was no free CuCl available as a
quencher in the solution. Both aniline and TEA (in a free or
Cu-coordinated form) could engage in reductive quenching of
the excited state of 4CzIPN. The coupling was successful only
in the presence of TEA or DIPEA but not with other bases,
suggesting that TEA served more than a simple base. The
quantum yield of the coupling was estimated to be 5.4% (SI).
This low quantum yield would be consistent with the scenario
that the dominant reductive quenching of the photocatalyst in
the reaction was by aniline, but this quenching was
nonproductive probably because it was reversible. The
productive quenching was via the oxidation of TEA.
groups (3e, 3o), olefins (3n), ethers (3o), protected amines
(3d), and acetals (3i). A 1 mmol scale synthesis of 3e was
achived in 51% yield.
Fluorescence quenching experiments were conducted to
probe the reaction mechanism. Aniline, CuCl, and TEA, but
not the NHPI ester (1a), could quench the fluorescence of
4CzIPN (Figure 4). Because CuCl might bind to TEA, aniline,
and 1a, fluorescence quenching was monitored for a binary
mixture of CuCl with another reaction component (Figures
S2−S4, Supporting Information). The quenching was nearly
identical with CuCl alone and with a 1:5 mixture of CuCl:1a
(Figure S2, Supporting Information), further excluding the
quenching of the excited photocatalyst by the NHPI ester or its
potential Cu complex, which is different from the Ru-based
photocatalyst.13 The mixtures of Cu:aniline were less efficient
than the sum of the two components alone to quench the
fluorescence of 4CzIPN (Figure S2). This result suggested the
formation of Cu:aniline species that have distinct quenching
properties from their individual components. For the mixtures
Based on the data and considerations above, we propose the
following mechanism (Figure 5). Light excitation of 4CzIPN
formed an excited 4CzIPN*, which was reductively quenched
C
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product and regenerates a CuI species (D) that can now bind
aniline again.
The above mechanism is different from that of the analogous
coupling using Ru(bpy)3(PF6)2 as the photocatalyst. The
difference might originate from the redox potentials of the
excited state of the photocatalysts. 4CzIPN* (E1/2 4CzIPN*/
4CzIPN− = +1.35 V vs SCE)19,20,23 is a more potent electron
acceptor (oxidant) than Ru(bpy)3(PF6)2* (E1/2 *RuII/RuI =
+0.77 V vs SCE).31 Thus, unlike Ru(bpy)3(PF6)2*, 4CzIPN*
can oxidize triethylamine, leading to a reductive quenching
process. This reactivity differs from that of Ru-based
photoredox catalysis, which involved an oxidative quenching
pathway.13
In summary, we have developed tandem photoredox and Cu
catalysis for decarboxylative C(sp3)−N coupling of anilines
and imines using an inexpensive and easy to make organic
photocatalyst.23 The method can be applied for the synthesis
of a broad range of alkylated primary and secondary amines.
The organic photocatalyst not only broadens the scope of the
coupling compared to previously reported Ru or Ir photo-
catalysts but also operates via a different mechanism. This
work further demonstrates the potential of organic photoredox
catalysts.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01769.
Figure 4. Stern−Volmer plots of fluorescence quenching of 4CzIPN
by aniline, NHPI ester (1a), TEA, or CuCl.
Experimental procedures and characterization data
(PDF)
by TEA to form 4CzIPN− and a TEA radical cation. Reduction
of an NHPI ester by 4CzIPN− regenerates the photocatalyst
4CzIPN and yields an NHPI ester radical anion. The latter
quickly releases CO2, a phthalimide anion, and an alkyl radical.
Hydrogen atom transfer between a CuI−aniline species (A)
with the TEA radical cation (see elaborations in SI) yields a
protonated TEA cation and a CuII−anilido complex (B). The
latter traps the alkyl radical to give a CuIII−anilido species (C),
which after C−N reductive elimination delivers the coupling
AUTHOR INFORMATION
■
Corresponding Author
Xile Hu − Laboratory of Inorganic Synthesis and Catalysis,
Institute of Chemical Sciences and Engineering, Ecole
́
́
Polytechnique Federale de Lausanne (EPFL), ISIC-LSCI,
Lausanne 1015, Switzerland; orcid.org/0000-0001-8335-
1196; Email: xile.hu@epfl.ch
Figure 5. Proposed mechanism for decarboxylative C−N coupling with anilines
D
https://dx.doi.org/10.1021/acs.orglett.0c01769
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Authors
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Letter
(13) Mao, R.; Frey, A.; Balon, J.; Hu, X. Decarboxylative C(sp3)−N
cross-coupling via synergetic photoredox and copper catalysis. Nat.
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(14) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Decarboxylative
sp(3) C-N coupling via dual copper and photoredox catalysis. Nature
2018, 559, 83−88.
(15) Mao, R.; Balon, J.; Hu, X. Cross Coupling of Alkyl Redox-
Active Esters with Benzophenone Imines via Tandem Photoredox and
Copper Catalysis. Angew. Chem., Int. Ed. 2018, 57, 9501−9504.
(16) Sakakibara, Y.; Ito, E.; Fukushima, T.; Murakami, K.; Itami, K.
Late-Stage Functionalization of Arylacetic Acids by Photoredox-
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̀
Guido Barzano − Laboratory of Inorganic Synthesis and
Catalysis, Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Federale de Lausanne (EPFL), ISIC-LSCI,
Lausanne 1015, Switzerland
Runze Mao − Laboratory of Inorganic Synthesis and Catalysis,
Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Federale de Lausanne (EPFL), ISIC-LSCI,
Lausanne 1015, Switzerland; orcid.org/0000-0003-4678-
7251
Marion Garreau − Laboratory of Catalysis and Organic
Synthesis, Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Federale de Lausanne (EPFL), ISIC-LSCI,
Lausanne 1015, Switzerland
Jerome Waser − Laboratory of Catalysis and Organic Synthesis,
Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Federale de Lausanne (EPFL), ISIC-LSCI,
Lausanne 1015, Switzerland; orcid.org/0000-0002-4570-
914X
́
́
́
́
́
́
́
́
(19) Le Vaillant, F.; Garreau, M.; Nicolai, S.; Gryn’ova, G.;
Corminboeuf, C.; Waser, J. Fine-tuned organic photoredox catalysts
for fragmentation-alkynylation cascades of cyclic oxime ethers. Chem.
Sci. 2018, 9, 5883−5889.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01769
(20) Shang, T. Y.; Lu, L. H.; Cao, Z.; Liu, Y.; He, W. M.; Yu, B.
Recent advances of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
(4CzIPN) in photocatalytic transformations. Chem. Commun. 2019,
55, 5408−5419.
Notes
The authors declare no competing financial interest.
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hexanes by (3 + 2) annulation of cyclopropenes with amino-
cyclopropanes. Chem. Sci. 2019, 10, 10716−10722.
ACKNOWLEDGMENTS
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This work is supported by the Swiss National Science
Foundation.
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