Visible-Light Photoredox-Catalyzed Giese Reaction: Decarboxylative Addition of Amino Acid Derived α-Amino Radicals to Electron-Deficient Olefins

Article abstract of DOI:10.1002/chem.201602257

A tin- and halide-free, visible-light photoredox-catalyzed Giese reaction was developed. Primary and secondary α-amino radicals were generated readily from amino acids in the presence of catalytic amounts of an iridium photocatalyst. The reactivity of the α-amino radicals has been evaluated for the functionalization of a variety of activated olefins.

Full text of DOI:10.1002/chem.201602257

DOI: 10.1002/chem.201602257
Communication
&
Photoredox Catalysis
Visible-Light Photoredox-Catalyzed Giese Reaction:
Decarboxylative Addition of Amino Acid Derived a-Amino
Radicals to Electron-Deficient Olefins
+
[a]
+ [a]
[a, b]
Anthony Millet , Quentin Lefebvre , and Magnus Rueping*
after oxidation of the carboxylic acid, decarboxylation occurs
to provide the carbon-centered radical. This radical adds onto
the olefin and the resulting intermediate can be reduced and
protonated, thus regenerating the catalyst. UV-light irradiation
in the presence of sensitizers was reported to efficiently pro-
Abstract: A tin- and halide-free, visible-light photoredox-
catalyzed Giese reaction was developed. Primary and sec-
ondary a-amino radicals were generated readily from
amino acids in the presence of catalytic amounts of an iri-
dium photocatalyst. The reactivity of the a-amino radicals
has been evaluated for the functionalization of a variety
of activated olefins.
[5,6]
mote such Giese-type reactions,
however it was only very
recently that this general type of reaction was successfully per-
formed using visible light in combination with organic dyes or
[7]
metal-based photocatalysts.
With these considerations in mind, we became interested in
developing a method for the generation of a-amino radicals
for secondary amines in an easy and efficient manner and
apply them as nucleophiles in Giese-type transformations. If
successful, these reactions would allow access to a wide range
of valuable compounds including natural product derivatives.
For this purpose, we turned our attention to glycine deriva-
tives as precursors for a-amino radicals, as these have relatively
low oxidation potentials (N-phenylglycine: EOx =0.42 V
Since its discovery in the 1980s, the reductive addition of radi-
cals to electron-deficient olefins, also known as the Giese reac-
tion, has found tremendous applications in the synthesis of
[
1]
key structures and total synthesis. Although the original con-
ditions require the use of stoichiometric amounts of trialkyl tin
reagents, the overwhelming interest in this reaction led to the
rapid development of more practical and safer additives. First,
the use of catalytic amounts of tin reagents combined with
borohydride, silane, or thiol additives was reported, and later
the potential of silanes and organoboranes alone to promote
[8]
vs.SCE). In this context, we predicted that the classical and
III
easy to access Ir photocatalyst Ir(ppy) (dtbbpy)PF (1a) should
2
6
be able to furnish our desired radical intermediate, as, despite
[
2]
Red
III
II
and propagate radical reactions was demonstrated. Reactions
making use of indium, samarium, chromium, nickel, and zinc
its simplicity, it is a relatively good oxidant (E
Ir */Ir =
1/2
[9]
0.66 V vs. SCE in acetonitrile).
Following our interest in oxidative and radical photoredox
[
3]
salts as additives were also developed. However, a drawback
is the need for iodine- or bromine-containing starting materi-
als, which are converted into radicals by direct reduction or by
halide abstraction. After addition, the resulting radical is either
reduced and protonated, or abstracts directly a hydrogen
atom to give the hydrofunctionalized product. Thus, this reac-
tion manifold is not redox-neutral and generates stoichiometric
amounts of halogen-containing wastes. As a sustainable alter-
native to the reduction of halogen-containing derivatives, the
oxidation of aliphatic carboxylic acids has attracted growing at-
[10,11]
catalysis,
we report here the successful validation of this
challenging task using a visible-light photocatalyst for the re-
ductive radical addition of primary and secondary a-amino rad-
icals to various olefins. To evaluate this transformation, we first
turned our attention to the reaction of N-phenylglycine (2a)
with 2-cyclohexen-1-one (3a) as a model substrate using Ir(p-
py) (dtbbpy)PF (1a) as photocatalyst.
2
6
Upon evaluating different reaction conditions, we found
that when equimolar amounts of 2a and 3a were irradiated
with blue LEDs in methanol (0.3m) in the presence of a catalytic
amount of lithium carbonate (20 mol%) and 1 mol% of photo-
catalyst, the desired product 4a was obtained in 84% yield
[
4]
tention in the past years. In this context, a catalytic variant of
the Giese reaction is possible, as the process is redox-neutral:
(
Table 1, entry 1). The reaction occurred in an efficient manner
+
+
[
a] Dr. A. Millet, Dr. Q. Lefebvre, Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
and with a complete selectivity for the 3-position of 3a. Exami-
nation of different reaction parameters showed no impact on
the reactivity in the case of dilution (0.1m, entry 2), but the
yield dropped to only 56% at a concentration of 1m (entry 3).
The catalyst loading was also evaluated, however when using
E-mail: magnus.rueping@rwth-aachen.de
[
b] Prof. Dr. M. Rueping
KAUST Catalysis Center (KCC), King Abdullah University of Science and Tech-
nology (KAUST)
Thuwal, 23955-6900 (Saudi Arabia)
0
.5 mol% of 1a, the reaction did not reach completion and
+
the product was obtained with a yield of 55% only (entry 4).
Appling white light resulted in a yield of 64% for the desired
product (entry 5). We also noticed the crucial role of Li CO , as
[
] Both authors contributed equally to this work.
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201602257.
2
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[
a]
Table 1. Evaluation of the reaction parameters.
[
b]
Entry
Modification from standard conditions
Yield [%]
1
2
3
4
5
6
7
8
9
none
0.1 m
1 m
84
83
56
55
64
26
0
0.5 mol% of photocatalyst
11 W White light bulb
without Li
in the dark
without photocatalyst
under air atmosphere
2 3
CO
0
0
[
a] Reactions performed using N-phenylglycine 2a (0.3 mmol, 1 equiv), 2-
cyclohexen-1-one 3a (0.3 mmol, 1 equiv), Li CO (20 mol%), Ir(p-
py) (dtbbpy)PF 1a (1 mol%) in degassed MeOH (1 mL) under argon and
2
3
2
6
blue LEDs (11 W rubber strip) for 14 h. [b] Yield after purification.
only 26% yield was obtained in its absence (entry 6). Finally,
we confirmed that no reactivity was observed in the dark, in
the absence of photocatalyst, or under an air atmosphere (en-
tries 7–9). Additionally, using N-methylaniline as substrate gave
no conversion, confirming the importance of the decarboxyla-
tion event for the generation of the a-amino radical.
Scheme 1. Evaluation of N-aryl amino acids. Reaction conditions: N-aryl
amino acids 2b–m (0.3 mmol, 1 equiv), 2-cyclohexen-1-one 3a (0.3 mmol,
1 equiv), Li CO (20 mol%), Ir(ppy) (dtbbpy)PF 1a (1 mol%) in degassed
2 3 2 6
MeOH (1 mL) under argon and blue LEDs (11 W rubber strip) for 14 h, yields
after purification. [a] The reaction was performed with 2 equiv of amino acid
for 18 h. [b] Reaction was performed for 18 h.
With the optimal conditions in hand, we started to explore
the scope and limitations of the reaction with regard to amino
acid partners (Scheme 1). Pleasingly, a very good reactivity was
observed for para-halogenated anilines (2b–d) and no dehalo-
genation was thereby noticed (4b–d). Highly electron-with-
drawing groups were also tolerated but led to a moderate re-
activity (4e, 4 f). Interestingly, poor reactivity was observed
with electron-donating groups in the para position, but the
products could be obtained in good yields when these groups
were placed in the ortho positions (4g, 4h). In addition, we ap-
plied this reaction to natural amino acids with success (see the
Supporting Information). N-phenylalanine led to the desired
product in very high yields (4i), whereas more bulky amino
acids gave moderate to good yields (4j, 4k). We also observed
a good functional group tolerance with the presence of a free
OH group for the serine-derived substrate (4l), or the methyl-
thiolated residual chain of the methionine-derived substrate
of natural products, which was relatively efficient for isophor-
one (4o) and very good for (R)-(À)-carvone (4p), although the
product was obtained as a mixture of diastereomers. We also
looked at other cyclic acceptors with five-membered rings. We
observed a limited reactivity of 2-cyclopenten-1-one, whereas
the presence of a methyl group in the 2-position restored
good yields (4r), as it supposedly disfavored the unselective
polymerization and cycloaddition pathways.
Furanone also underwent the transformation in moderate
yield (4s). Regarding the use of acyclic substrates, although
these initially reacted poorly, addition of two equivalents of
water provided good yields in most of the cases. Using this
strategy, we observed moderate to good reactivity of N-phe-
nylglycine 2a with mono-substituted olefins such as acrylates
(3h–j), acrylonitrile (3k) or N,N-dimethylacrylamide (3l). The re-
action with 1,1-diphenylethylene led to a good reactivity after
24 h (74% yield, 5 f), whereas only 58% yield was obtained
under the standard conditions. Substrates derived from maleic
and fumaric acids participated successfully in the reaction
when two equivalents of water were added. Finally, we
showed that other amino acid-derived substrates exhibit simi-
(
4m).
Next, our attention focused on establishing the reactivity
pattern with respect to the olefin partner (Scheme 2). First, we
were interested in evaluating the reactivity for the formation
of a quaternary center and we successfully obtained the de-
sired product 4n of the addition of a-amino radical onto 3-
methyl-2-cyclohexenone, although with a moderate yield of
50%. In addition, we looked at the possibility of derivatization
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Scheme 3. Evaluation of the reactivity of a-amino radicals derived from N-
heterocyclic amino acids.
Scheme 2. Evaluation of radical acceptors. Reaction conditions: N-phenylgly-
cine 2a (0.3 mmol, 1 equiv), olefins 3b–l (0.3 mmol, 1 equiv), Li CO
20 mol%), Ir(ppy) (dtbbpy)PF 1a (1 mol%) in degassed MeOH (1 mL) under
argon and blue LEDs (11 W rubber strip) for 14 h, yields after purification.
a] 24 h reaction. [b] With 2 equiv H O.
2
3
(
2
6
[
2
lar reactivity to the one observed with N-phenylglycine 2a, as
the addition of N-phenylalanine 2i to ethyl acrylate proceeded
in comparable yield (5i).
Scheme 4. Synthesis of valuable structural motifs.
Encouraged by these results, we next turned our attention
towards the generation of a-amino radicals of unsaturated het-
erocycles to further expand the scope of our transformation
We could access the desired product 7 using two different
sets of conditions. The first one involved a saponification reac-
tion with sodium hydroxide (2 equiv), followed by a peptide-
type coupling using HBTU (N,N,N’,N’-tetramethyl-O-(1H-benzo-
triazol-1-yl)uranium hexafluorophosphate, 1 equiv) in the pres-
ence of diisopropylethylamine (DIPEA, 3 equiv) in dichlorome-
thane for an overall yield of 57%. Using a complementary ap-
proach, we could also directly access the lactam 7 in 75%
yield by refluxing the starting material in 1,4-dioxane in the
presence of trifluoroacetic acid (5 equiv). We also realized the
three-step synthesis of 3-phenyl-3-azabicyclo[3.3.1]nonane (8)
from 4a (Scheme 4b). A two-step Wittig homologation of the
ketone to the aldehyde was performed by stirring the starting
material in THF in the presence of (methoxymethyl)triphenyl-
phosphonium chloride (2 equiv) and potassium tert-butoxide
(3 equiv), followed by hydrolysis of the enol ether with 10%
hydrochloric acid. The crude aldehyde was then directly sub-
mitted to the reductive amination step using sodium triacetox-
yborohydride (1.5 equiv) to give the desired bicyclic product 8
in 27% yield over three steps after purification. Although this
(Scheme 3). However, the alanine-derived pyrrole 6a did not
give the desired radical intermediate using our previous condi-
tions. We rationalized that Ir(ppy) (dtbbpy)PF (1a) might not
2
6
be oxidizing enough for this substrate, and we thus decided to
use the more oxidizing catalyst Ir[dF(CF )ppy] (dtbbpy)PF (1b;
3
2
6
Red
III
II
[11]
see Table 1) (E1/2 Ir */Ir = +1.21 V vs: SCE in acetonitrile).
To our delight, we could achieve the generation of the radical
followed by addition to 2-cyclohexen-1-one in good yield (4t),
or to methyl acrylate in moderate yield (5j), forming a product
which is an intermediate for the synthesis of monomorine,
[
12]
a Pharaoh’s ant pheromone. Thus, our methodology might
be applied to the synthesis of various analogues of this natural
product using inexpensive natural amino acids as starting ma-
terials instead of harder to access g-lactones. We also could
extend this reaction to indole 6b, which underwent the reac-
tion with 2-cyclohexen-1-one (3a) in relatively good yield (4u).
Finally, we were interested in taking advantage of our struc-
tures for the synthesis of valuable structural motifs. First, we in-
vestigated the synthesis of g-lactam 7 from 5b (Scheme 4a).
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13]
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In conclusion, we have successfully developed a tin-free and
halide-free Giese reaction by efficiently generating primary and
secondary a-amino radicals starting from readily accessible
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[
Acknowledgements
The research leading to these results has received funding
from the European Research Council under the European
Union’s Seventh Framework Programme (FP/2007–2013)/ERC
Grant Agreement no. 617044 (SunCatChem).
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8
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Received: May 12, 2016
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Photoredox Catalysis
A. Millet, Q. Lefebvre, M. Rueping*
& – &&
&
Easy CO upling! A tin- and halide-free,
of catalytic amounts of an iridium pho-
tocatalyst and catalytic amounts of
base. These radicals added readily onto
2
Visible-Light Photoredox-Catalyzed
Giese Reaction: Decarboxylative
Addition of Amino Acid Derived a-
Amino Radicals to Electron-Deficient
Olefins
visible-light photoredox-catalyzed Giese
reaction was developed. Primary and
secondary a-amino radicals were gener-
ated from amino acids in the presence
activated olefins, giving CO as sole by-
2
product.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!