Cross-Coupling of Alkyl Redox-Active Esters with Benzophenone Imines: Tandem Photoredox and Copper Catalysis

Article abstract of DOI:10.1002/anie.201804873

Alkyl amines are an important class of organic compounds in medicinal and materials chemistry. Until now very have been very few methods for the synthesis of alkyl amines by metal-catalyzed cross-coupling of alkyl electrophiles with nitrogen nucleophiles. Described here is an approach to employ tandem photoredox and copper catalysis to enable the cross-coupling of alkyl N-hydroxyphthalimide esters, readily derived from alkyl carboxylic acids, with benzophenone-derived imines. Hydrolysis of the coupling products furnish alkylated primary amines. Primary, secondary, and tertiary alkyl groups can be transferred, and the coupling tolerates a diverse set of functional groups. The method allows rapid functionalization of natural products and drugs, and can be used to expedite syntheses of pharmaceuticals from readily available chemical feedstocks.

Full text of DOI:10.1002/anie.201804873

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Accepted Article
Title: Cross Coupling of Alkyl Redox-Active Esters with Benzophenone
Imines via Tandem Photoredox and Copper Catalysis
Authors: Runze Mao, Jonathan Balon, and Xile Hu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804873
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10.1002/anie.201804873
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COMMUNICATION
Cross Coupling of Alkyl Redox-Active Esters with Benzophenone
Imines via Tandem Photoredox and Copper Catalysis
Runze Mao, Jonathan Balon, and Xile Hu*
Abstract: Alkyl amines are an important class of organic compounds
in medicinal and materials chemistry. Until now very few methods
exist to synthesize alkyl amines by metal-catalyzed cross coupling of
alkyl electrophiles with nitrogen nucleophiles. Described here is an
approach to employ tandem photoredox and copper catalysis to
enable the cross coupling of alkyl N-hydroxyphthalimide esters,
readily derived from alkyl carboxylic acids, with benzophenone imines.
Hydrolysis of the coupling products furnish alkylated primary amines.
Primary, secondary, and tertiary alkyl groups can be transferred, and
the coupling tolerates a diverse set of functional groups. The method
allows rapid functionalization of natural products and drugs, and can
be used for expedite syntheses of pharmaceuticals from readily
available chemical feedstock.
Alkyl amines are prevalent in synthetic intermediates and bio-
active molecules.[1-2] Although certain alkyl amines can be
conveniently prepared by direct substitution of alkyl halides with
nitrogen nucleophiles,[3] the substitution is difficult or even
impossible for bulky secondary and tertiary alkyl halides.
Moreover, elimination and overalkylation are common pitfalls of
substitution. Transition metal catalyzed C(sp3)-N cross coupling
has the potential to overcome the shortcomings of direct
substitution. However, this coupling method is only at its infancy.[4-
12] -H elimination from metal alkyl intermediates and difficulty in
C(sp3)-N reductive elimination are two perceived problems.
The groups of Baran[13] and others[14] have reported
remarkable applications of alkyl redox-active esters in C-C cross
coupling reactions. These esters can be easily prepared from
Figure 1. (A) A previous method for the intramolecular C-N coupling of alkyl
NHPI esters (B) A previous method for the cross coupling of alkyl bromides with
benzophenone imines (C) Reaction scheme for the present C-N coupling
alkyl carboxylic acids, which are readily available, stable, and
non-toxic. Due to the challenge in C(sp3)-N cross coupling
method. (D) Design of tandem photoredox and Cu catalysis for the present C-
N coupling method.
described above, alkyl redox active esters have not been widely
12, 15]
used for C-N coupling.[7,
Fu, Peters, and co-workers[7]
developed
photoindued,
Cu-catalyzed
intramolecular
decarboxylative C-N coupling of primary and secondary alkyl N-
hydroxyphthalimide (NHPI) esters, a prototypical class of redox-
active esters, to give alkyl phthalimides (Fig. 1A). However, only
primary and secondary alkyl NHPI esters could be coupled. We
reasoned that the inability to couple tertiary alkyl NHPI esters in
this method might be due to steric hindrance or difficulty in
reductive elimination.
[*]
R. Mao, J. Balon, Prof. Dr. X.L. Hu*
Laboratory of Inorganic Synthesis and Catalysis, Institute of
Chemical Sciences and Engineering, École Polytechnique Fédérale
de Lausanne (EPFL), ISIC-LSCI
BCH 3305, Lausanne 1015, Switzerland
E-mail: xile.hu@epfl.ch
Website: http://lsci.epfl.ch
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Table 1. Summary of the effects of reaction parameters and conditions on the
reaction efficiency
a clear advantage over reductive amination and substitution (not
suitable for tertiary alkyl groups). Broad scope, highly functional
group tolerance, and applications in medicinal chemistry have
been demonstrated.
We envisioned the following tandem photoredox and copper
catalysis[19-20] for the decarboxylative coupling of alkyl NHPI esters
with benzophenone imines (Figure 1D). Initially, the coordination
of the benzophenone imines with a low-valent copper catalyst (I)
followed by deprotonation would form the copper(I)-amido
species (II). Concurrently, excitation of a photocatalyst (PC)
would generate a photoexcited complex (PC*), which could
reduce the NHPI ester through a single-electron transfer (SET),
affording an alkyl radical upon fragmentation. Subsequent
capture of the alkyl radical by II would yield intermediate (III).
Oxidation of III by the oxidized photocatalyst (PC+) forms a high-
valent metal alkyl amido complex IV and regenerates the PC. IV
is expected to undergo reductive elimination to give the desired
coupling product and regenerate a low-valent Cu species (I),
closing the copper catalytic cycle. In this design, the photoredox
catalysis has two important roles: generation of an alkyl radical
from an alkyl NHPI ester and one-electron oxidation of a Cu alkyl
amido complex. The former is necessary because metal amido
species has not been shown to activate alkyl NHPI ester under
thermal conditions. The latter is intended to facilitate the difficult
C(sp3)-N reductive elimination.
We recently applied a similar design for the decarboxylative
coupling of alkyl NHPI esters with anilines.[12] Using the optimized
conditions in that study, however, the coupling of cyclohexyl NHPI
ester 1a with benzophenone imine 2a was inefficient (Table 1,
entry 1). Optimization was conducted to search for the best
conditions for this coupling (Table 1; SI, Table S1). After various
ligands were screened, it was found that ligand-less conditions
gave even slighly higher yields (Table 1, entry 2; SI, Table S1,
entries 1-10). Among various copper salts, Cu(MeCN)4PF6 gave
the best yield (SI, Table S1, entries 7-10). Cs2CO3 was the best
base (Table 1, entries 2-6; SI, Table S1, entries 11-17), probably
due to coordination the NHPI ester with Cs2CO3 as proposed in a
previous study.[21] Dimethylacetamide (DMA) was the best solvent
(Table 1, entries 3-4; SI, Table S1, entries 12, 18-20). By
changing the photocatalyt from Ru(bpy)3(PF6)2 (A) to an Ir(III)
Entry
1[b]
2[b]
3[c]
4
Imine
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
PC
A
Copper catalyst
CuBr/L1
Yield (%)[a]
30
A
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu (100 mol%)
CuCl2
32
A
19
A
39
5[d]
6[e]
7
A
trace
trace
40
A
B
8
C
49
9
C
24
10
11
12
13
14
15
16[f]
C
28
C
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
none
33
C
29
C
70
none
C
trace
trace
trace
C
Cu(MeCN)4PF6
[a] Corrected GC yield using n-dodecane as an internal standard. [b] Same
condition as the optimized reaction condition in reference 12. Reaction was
carried out with 1a (0.2 mmol), 2a (2 equiv.), Ru(bpy)3(PF6)2 (1 mol%), CuBr (20
mol%), L1 (7.5 mol%), Et3N (5 equiv.) and MeCN (2.0 mL). [c] MeCN (0.1 M).
[d] K2CO3 (2 equiv.) as the base. [e] KOtBu (2 equiv.) as the base. [f] No light.
complex such as
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(B)
or
Ir[(dtbbpy)(ppy)2]PF6 (C), the yield was improved (Table 1, entries
4, 7-8; Table S1, entries 21-23). An optimized yield of 49% was
obtained using 1a (0.2 mmol), benzophenone imine (2a, 2 equiv.),
Ir[(dtbbpy)(ppy)2]PF6 (1 mol%), Cu(MeCN)4PF6 (20 mol%),
Cs2CO3 (2 equiv.), and DMA (0.1 M) under blue LED irradiation
for 20 h at room temperature (Table 1, entry 8). Interestingly,
when the Cu(I) complex Cu(MeCN)4PF6 (20 mol%) was replaced
by either a Cu metal (100 mol%) or a Cu(II) salt CuCl2 (20 mol%),
the coupling product was also obtained, but with lower yields
(Table 1, entries 9-10). The Cu metal might be oxidized by the
excited Ir photocatalyst to Cu(I), generating the Ir(II) form of the
photocatalyst which upon reducing the NHPI ester regenerates
the photocatalyst. Likewise, CuCl2 might be reduced by the
excited Ir photocatalyst to Cu(I), while the resulting Ir(IV) species
might be reduced to the Ir(III) photocatalyst by the solvent. In
these cases, a catalytic cycle similar to Fig. 1D is operating.
Alternatively when CuCl2 is used as catalyst, the catalytic might
occur via an alternative pathway where Cu(II) imine species
PC=photocatalyst; A=Ru(bpy)3(PF6)2; B=Ir[dF(CF3)ppy]2(dtbbpy)PF6;
=Ir[(dtbbpy)(ppy)2]PF6; DMA=N,N-dimethylacetamide.
C
These issues might be solved using a benzophenone imine
nucleophile with a sp2-hybridized nitrogen, which is sterically
more accessible and more prone to reductive elimination.[16] The
benzophenone imine group in the products can be easily
17-18]
hydrolyzed or transaminated to give primary amines[10,
Furthermore, Hartwig and co-workers[10] showed that
benzophenone imines could be coupled to secondary and tertiary
alkyl bromides to give protected amines (Fig. 1B). However,
coupling to primary alkyl bromides was not reported.
Here we report the successful development of a method that
indeed allows the intermolecular coupling of alkyl NHPI esters
with benzophenone imines (Fig. 1C). This method works with
primary, secondary and tertiary alkyl electrophiles, which provides
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mol%), and Cs2CO3 (2 equiv.) in DMA (0.1 M), irradiated at room temperature
for 20 h, isolated yield. [b] General conditions for primary NHPI ester: NHPI ester
(2 equiv.), 2d (1 equiv.), Ir[(dtbbpy)(ppy)2]PF6 (1 mol%), Cu(MeCN)4PF6 (20
mol%) and diisopropylamine (2 equiv.) in MeCN (0.1 M), irradiated at room
temperature for 16 h, isolated yield. [c] 2a as the nucleophile. [d] Following acidic
work-up was conducted.
captures the alkyl radical from the NHPI ester to give the key
Cu(III) intermediate,[15] which upon reductive elimination gives the
C-N coupling product (Fig. S1, SI).
Different substituted benzophenone imines were then
explored as the imine partners (Table 1, entries 8, 11-13). The
coupling of the electron-deficient imine 2d (Table 1, entry 13)
gave a higher yield (70%) than that of electron-rich imines 2b and
2c as well as the parent imine 2a (Table 1, entries 8, 11-12). An
added advantage of using 2d is that the products are less
sensitive to silica gel chromatography. Thus, 2d was chosen as
the preferred nitrogen nucleophile. Photocatalyst, copper catalyst
and light are all essential for the coupling. Without any one of the
three elements, no coupling was obtained (Table 1, entries 14-
16).
The optimal reaction conditions in Table 1 (entry 4) could be
applied to the coupling of a wide range of secondary alkyl NHPI
esters (Table 2). Cyclic alkyl groups including small and large
rings (3ad-3c), indane group (3d) and heterocyclic alkyl group
(3e-3f), as well as acyclic secondary alkyl groups (3g-3h) were all
successfully coupled. Tertiary alkyl electrophiles are challenging
substrates in cross-coupling reactions due to their bulky nature.
To our delight, tertiary alkyl NHPI esters are viable substrates as
well (Table 2). Protected amines substituted by acyclic (4a-4b),
cyclic (4c) alkyl groups as well as those containing relatively
complex skeletons such as adamantane (4d-4e) and a bridged
bicyclic structure (4f) could be obtained in synthetically useful
yields.
Table 2. Scope of the cross coupling of alkyl NHPI esters with substituted
benzophenone imines
Figure 2. Synthesis of amine drugs using the present coupling method.
The coupling of primary alkyl NHPI esters was also possible,
but required a slight modification of reaction conditions (SI, Table
S2). The optimized conditions employed the same reaction
stroichiometry, photocatalyst, and Cu catalyst as in the coupling
of secondary alkyl NHPI esters, but the base was changed to
diisopropylamine (2 equiv) and the solvent was changed to
acetonitrile (MeCN). The modified conditions were successfully
applied to the coupling of various primary alkyl NHPI esters (5a-
5i, Table 2) in moderate to excellent yields. Functional groups
such as aryl, ester and bromo groups were tolerated (5d-5f). A
polyfluorinated alkly ester could also be coupled (5g), providing a
convenient route to a polyfluorinated alkyl amine, which can be
difficult to access otherwise. Coupling of the esters derived from
6-heptenoic acid and cyclopropylacetic acid, which served as
radical-clock probes, gave the 5-exo-trig cyclized and ring-
opening products 5h and 5i, respectively. This result indicates the
intermediacy of alkyl radicals. This decarboxylative amination
method also enabled the synthesis of protected primary amines
substituted by a complex alkyl group, derived from natural
resources and known drugs (Table 2). For example, NHPI esters
from fatty acids such as elaidic acid, oleic acid, and linoleic acid
could be used to give the corresponding coupling products in
good yields (6a-6c), without isomerization or oxidation of the
[a] General conditions for secondary and tertiary NHPI ester: NHPI ester (1
equiv.), 2d (2 equiv.), Ir[(dtbbpy)(ppy)2]PF6 (1 mol%), Cu(MeCN)4PF6 (20
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[5]
[6]
[7]
[8]
[9]
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olefin group. Drugs and natural products such as dehydrocholic
acid (6d), chlorambucil (6e), abietic acid (6f) and gemfibrozil (6g)
were easily transformed into their protected amine derivatives,
demonstrating the potential of the method in post-synthetic drug
and natural product modification. The cases of 5f, 6d and 6e
highlight the orthogonal functional group compatibility of the
present method compared to direct alkylation and reductive
amination: 5f has a bromo group and 6e has two chloro groups
which are incompatible with direct alkylation; 6d has three keto
groups which are incompatible with reductive amination. It is
important to note that multiple stereocenters are conserved in 6d
and 6f.
To further demonstrate the synthetic utility of the present
coupling method, it was applied for the synthesis of two drugs:
amphetamine and tranylcypromine. As shown in Figure 2, both
cases were successful, and following acidic deprotection of the
imine group, amphetamine•HCl and tranylcypromine•HCl were
obtained in 60% (7a) and 41% (7b, d.r. > 20:1) overall yields,
respectively.
In summary, tandem photoredox and Cu catalysis has been
developed to enable the cross coupling of alkyl NHPI esters with
benzophenone imines. The method allows the rapid
transformation of readily available alkyl carboxylic acids into
alkylated primary amines, which are important compounds in
medicinal and materials chemistry. The work significantly
expands the scope of C(sp3)-N coupling. Analogous tandem
photoredox and Cu catalysis may find further applications in C-C
and C-heteroatom coupling reactions.
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This work is supported by the NoNoMeCat Marie Skłodowska-
Curie training network funded by the European Union under the
Horizon 2020 Program (675020-MSCA-ITN-2015-ETN).
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Keywords: photoredox · decarboxylation · C-N coupling ·
copper catalysis · alkylation
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COMMUNICATION
COMMUNICATION
A tandem photoredox and
Cu catalysis has been
developed to enable the
cross coupling of alkyl NHPI
esters with benzophenone
imine derivatives.
R. Mao, J. Balon, X. Hu*
Page No. – Page No.
Cross Coupling of Alkyl
Redox-Active Esters with
Benzophenone Imines via
Tandem Photoredox and
Copper Catalysis
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