α-Arylation/Heteroarylation of Chiral α-Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross-Coupling Catalysis

Article abstract of DOI:10.1002/anie.201506147

Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross-coupling dual catalysis strategy has been developed. New C(sp³)-C(sp²) bonds are forged starting from abundant and inexpensive natural amino acids.

Full text of DOI:10.1002/anie.201506147

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International Edition: DOI: 10.1002/anie.201506147
German Edition: DOI: 10.1002/ange.201506147
Cross-Coupling
a-Arylation/Heteroarylation of Chiral a-Aminomethyltrifluoro-
borates by Synergistic Iridium Photoredox/Nickel Cross-Coupling
Catalysis
Mirna El Khatib, Ricardo Augusto Massarico Serafim, and Gary A. Molander*
Abstract: Direct access to complex, enantiopure benzylamine
architectures using a synergistic iridium photoredox/nickel
cross-coupling dual catalysis strategy has been developed. New
Our group has established an interest in the development
of complementary aminomethylating[7,14–18] and related[19,20]
cross-coupling procedures that take advantage of the vast
number of commercially available aryl halides by using air-
and moisture-stable N-trifluoroboratomethyl derivatives in
cross-coupling reactions. Based on this strategy, a preparation
of enantiopure aminomethylarenes was sought. However, all
efforts in our group to utilize N-trifluoroboratomethyl salts
derived from naturally occurring amino acids to cross-couple
with aryl halides failed under traditional palladium-catalyzed
Suzuki–Miyaura conditions. This failure can be attributed to
the slow rate of transmetalation of the alkylboron species and
the high temperatures and basic conditions required, an
inherent problem related to the two-electron nature of the
process.[21,22]
3
2
À
C(sp ) C(sp ) bonds are forged starting from abundant and
inexpensive natural amino acids.
T
he impetus to discover novel chemical transformations for
the construction of biologically active compounds is of
continuing interest in the pharmaceutical and agrochemical
industries.[1–3] Among nitrogen-containing molecules, amino-
methylated arenes are privileged substructures that are found
in many bioactive materials exhibiting activity against a wide
array of diseases.[4–7]
Despite their importance, access to enantioenriched
benzylic amines is not general, and traditional routes to
aminomethylated arenes, including reductive amination,[8]
CN reduction,[9,10] or N-alkylation methods (Figure 1)[11–13]
A recent focus of research in our laboratory has been the
exploration of cross-coupling through C(sp3)-centered radi-
cals formed by a single-electron oxidation/transmetalation of
organotrifluoroborate precursors, a process that allows access
3
2
[22–26]
À
to C(sp ) C(sp ) cross-coupling products.
Organotri-
fluoroborate derivatives are excellent radical precursors
because of their high stability, low toxicity, and functional-
group tolerability. In the current context, efforts were thus
directed toward the generation of a-amino radicals starting
from chiral N-trifluoroboratomethyl salts. These versatile a-
amino radicals[6,27–35] were envisioned to allow the assembly of
enantioenriched building blocks of potential value.[6,28]
The intermediacy of a-amino radicals to elaborate aryl-
and heteroaryl substructures has recently been demonstrated
in photoredox catalysis[6,25,28,36] from both unfunctionalized
amines (toward the preparation of JAK2 inhibitor
LY2784544),[6] and those with the TMS[35,37,38] and CO2H[2,39]
activating groups (Scheme 1). Herein, the first report of
complementary, photoredox-generated, enantiopure a-amino
radicals from chiral N-trifluoroboratomethyl amino acids and
their subsequent a-arylation/heteroarylation is described,
thus exploiting iridium photoredox/nickel cross-coupling
dual catalysis to generate complex enantiopure benzylic
amines (Scheme 1). This process represents an efficient and
general transformation that has not previously been accom-
plished, and importantly, both the carboxylate functional
group and the stereogenic centers of the amino-acid starting
materials remain intact in the cross-coupling. An overarching
goal of this work was to establish the precedent that amino
acids[8,40,41] with an N-trifluoroboratomethyl moiety can be
efficiently oxidized to generate versatile and unique, enan-
tiopure a-amino radicals under photoredox conditions.
The process envisioned for a-arylation/heteroarylation
of N-trifluoroboratomethyl amino acids (Scheme 2) was
Figure 1. Synthetic approaches toward benzylic amines. Boc=tert-
butoxycarbonyl, Cbz=benzyloxycarbonyl.
may not be readily applicable. Additionally, these approaches
suffer from limitations because of their intolerability toward
reducible functional groups or the limited commercial avail-
ability of benzylic halides, benzylic amines, aryl nitriles, and
aryl aldehydes (compared to aryl halides).[14–16]
[*] Dr. M. El Khatib, Dr. R. A. M. Serafim, Prof. G. A. Molander
Department of Chemistry, University of Pennsylvania
Roy and Diana Vagelos Laboratories
231 S. 34th St., Philadelphia, PA 19104-6323 (USA)
E-mail: gmolandr@sas.upenn.edu
Dr. R. A. M. Serafim
Department of Pharmacy, Faculty of Pharmaceutical Sciences
University of S¼o Paulo—FCF/USP (Brazil)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506147.
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synchronized, whereby the generated NiI species 11 is
reduced to 8 at the same time the iridium photocatalyst is
reoxidized by a SET process. The entire process was expected
to occur without a strong exogenous base or high temper-
ature.[23,25,39,42–44]
The requisite Boc-protected N-trifluoroboratomethyl
amino acids 1 were prepared starting from inexpensive and
naturally abundant amino acids (Table 1).[15–18] N-Alkylation
of the Boc-protected amino acids 13 with iodomethylpina-
colboronate in the presence of KHMDS afforded the
corresponding pinacol esters 14. Addition of KHF2 generated
the desired N-trifluoroboratomethyl amino acids 1 required
to test the mechanistic hypotheses.
An investigation of the cross-coupling process was
examined by exposing Boc-N-CH2BF3K-Gly-OMe (1a) to
p-bromobenzonitrile (3a) under reaction conditions previ-
ously successful for benzylic trifluoroborates (Table 2).[23]
Although the result was promising, showing that the proposed
mechanism was feasible, the observed reaction efficacy was
very poor, with a yield of 5% of the desired product. A deeper
investigation of the reaction conditions was undertaken, and
a variety of solvents, nickel catalysts, ligands, and bases were
screened (comprehensive results and all screenings employed
are shown in Table S1 of the Supporting Information). Based
on the initial screenings, the first study using Ni(NO3)2·6H2O
and the ligand L1 in a variety of solvents (entries 1, 2, and 5–
7) was deemed ineffective, with EtOAc giving the highest
yield of 10%. The role of the ligand was recognized to be
critical, and thus an evaluation of a variety of structurally and
electronically different ligands (L1–L4; entries 2, and 6–10;
data for L5–L11 are in the Supporting Information) was
performed. The bioxazole ligand L4 (entry 10) was deter-
mined to provide the optimal yield in this ligand screen. An
examination of various substituted bioxazole ligands (see
Table S1 in the Supporting Information) did not improve the
yield of the reaction. 2,6-Lutidine afforded the best results
among the bases tested, while the use of pyridine, dicyclo-
Scheme 1. Photoredox-generated a-amino radicals utilized in a-aryla-
tion/heteroarylation cross-coupling.
Scheme 2. Proposed mechanism toward enantioenriched
aminomethylarenes.
founded on established evidence that visible-light irradiation
(26 W compact fluorescent lamp, CFL) of [Ir(dFCF3ppy)2-
(bpy)]PF6 [dFCF3ppy = 2-(2,4-difluorophenyl)-5-trifluorome-
thylpyridine, depicted as 5 in Scheme 2], generates the
excited state [Ir]* species 6, a strong oxidant (E1/2 [Ir*III/II] =
+ 1.21 vs. SCE in MeCN)[22,32,34,35,38,41–43] which was antici-
pated to undergo single-electron transfer (SET) oxidation of
N-trifluoroboratomethyl amino acids (1; e.g., Boc-N-
CH2BF3K-l-Val-OMe, E1/2red =+ 1.01 V vs. SCE in MeCN),
thus forming the desired reactive C(sp3)-centered a-amino
radicals 2. Based on the developed rationale,[34] the process
was expected to be an autoregulated release because the
radical does not accumulate, but rather is captured by the
second catalytic cycle mediated by the nickel species. The
predominant pathway was expected[26] to involve capture of
the a-amino radical by the Ni0 species 8 to generate NiI
species 9, which would then undergo oxidative addition[26]
with the aryl/heteroaryl bromide 3 to afford the NiIII
intermediate 10. The low energy of activation expected in
the formation of 10[26] would facilitate the cross-coupling, thus
Table 1: Preparation of N-methyltrifluoroborate-derived amino-acid
starting materials.[a]
Entry
Amino acid
Yield [%]
14
1
1
2
3
4
5
6
7
Boc-Gly-OMe
49
68
61
55
65
92
94
94
85
91
93
95
Boc-l-Ala-OMe
Boc-d-Ala-OMe
Boc-l-Phe-OMe
Boc-l-Tyr(OMe)-OMe
Boc-l-Val-OMe
Boc-l-Ile-OMe
[b]
–
[b]
–
[a] Reagents and conditions: 1) ICH2Bpin (1.0 equiv), KHMDS
(0.9 equiv), THF (0.35m), À788C to RT, 5 h; 2) KHF2 (5.0 equiv, 4.5m),
K2CO3 (1.0 equiv), MeCN (0.3m), 08C to RT, 1–3 h. [b] The intermediate
14 was directly converted into 1 without isolation and characterization.
KHMDS=potassium hexamethyldisilazide, THF=tetrahydrofuran.
À
overcoming the slow C C bond-formation step that would
otherwise be necessary in such systems to afford the desired
chiral benzylic amine 4. The dual catalytic cycles need to be
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Table 2: Optimization of reaction conditions with Boc-N-trifluoro-
boratomethyl glycine methyl ester and p-bromobenzonitrile.
Entry
Ligand (mol%)
Solvent
Catalyst
Yield [%][a]
1
2
3
4
5
6
7
8
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L2 (5)
L3 (5)
L4 (5)
L4 (10)
L4 (15)
THF
Ni(NO3)2·6H2O
Ni(NO3)2·6H2O
[Ni(cod)2]
n.r.
10
2
EtOAc
EtOAc
EtOAc
iPrOAc
MeCN
acetone
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
NiCl2·dme
n.r.
n.r.
n.r
n.r.
20
12
45
65
62
Ni(NO3)2·6H2O
Ni(NO3)2·6H2O
Ni(NO3)2·6H2O
Ni(NO3)2·6H2O
Ni(NO3)2·6H2O
Ni(NO3)2·6H2O
Ni(NO3)3·6H2O
Ni(NO3)2·6H2O
9
10
11[b]
12
[a] Yields are based on isolated 4a. [b] 1a (1 equiv) and 3a (1 equiv) were
used for the optimized reaction conditions. cod=1,5-cyclooctadiene,
dme=1,2-dimethoxyethane, n.r.=no reaction.
hexylamine, Cs2CO3, or a combination of bases was deemed
ineffective. An assessment of Ir/Ni/L4 loadings (entries 10–12
and see the Supporting Information) revealed that a ratio of
2:5:10 mol% provided the best yield (65%) of the isolated
product for this reaction, thus affording 4a as a mixture of
rotamers as confirmed by NMR analysis. Finally, the required
participation of the iridium and nickel complexes, L4, base,
light, and inert conditions (argon atmosphere) were verified
by control experiments (see Table S1). An important obser-
vation was that the starting aryl bromide is not fully consumed
in the reaction. The conversion is not improved by the
addition of a second batch of catalyst after 12 hours, thus
suggesting that trifluoroborate decomposition rather than
catalyst decomposition is responsible for this phenomenon.
As a test of the mechanistic hypothesis, the quantum yield
of the reaction was measured (see the Supporting Informa-
tion). Although the heterogeneity of the reactions and
resulting light scattering introduced uncertainty into these
measurements, the photochemical quantum yield (F) (lex =
406 nm) was measured to be F = 0.45, thus indicating that
chain-radical mechanisms do not appear to be the major
reaction pathway.
Scheme 3. Substrate scope with respect to the Boc-protected amino-
glycine methylarenes.
well as piperazin-1-yl-pyrimidine (4k; performed on
a 1.5 mmol scale) cores. In general, the use of para and
meta substituents afforded the desired products. However,
ortho substituents inhibited the reaction.
Modification of the amino-acid component, incorporating
chiral alkyl side chains (l-Ala, d-Ala, l-Val, and l-Ile), was
then examined with various aryl- and heteroaryl bromides
(Scheme 4) and proved successful, thus affording interesting
enantiopure benzylic amines in good to excellent yields.
Remarkably and most notable is the use of complex aryl- and
heteroaryl bromides, including motifs such as caffeine (4o),
the SF5 functional group (4v), thienyl sulfonamides (4l),
ketones (4m and 4m’), and 4-oxadiazolylphenyl (4n, 4w and
4z). Moreover, the products 4r and 4u demonstrate the
possibility of orthogonal cross-coupling, because the Bpin and
boronic acid moieties are not affected under the reaction
conditions. Also notable is the fact that in those cases where
the stereochemical integrity of the process was rigorously
tested (4m/4m’, 4o/4o’, 4q/4q’, 4y, and 4z), no epimerization
of the stereogenic center could be detected, thus validating
further the ambient conditions required to obtain such
complex, chiral benzylic amines.
Under the reaction conditions developed, the scope of
aryl- and heteroaryl bromides was first examined using 1a
(Scheme 3). The mild reaction conditions readily accommo-
dated a range of electron-withdrawing and electron-donating
functional groups, including nitrile, amide, ester, aldehyde,
phenol, ketone, sulfonamide, and trifluoromethyl groups.
Complex architectures were tolerated, thus affording prod-
ucts containing coumarin (4 f) and benzothiophene (4h), as
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Scheme 5. Substrate scope with respect to the chiral aromatic Boc-
protected aminomethylarenes.
reported methods in providing access to novel, enantiopure
amino-acid derivatives through a process which begins with
stable, storable reagents, and transpires at room temperature
under exceedingly mild reaction conditions.
Acknowledgments
We thank the National Institute of General Medical Sciences
(R01-GM113878) for financial support. Johnson-Matthey and
Sigma Aldrich are acknowledged for donation of chemicals
toward the preparation of the photocatalyst. We thank Dr.
Yohei Yamashita (University of Pennsylvania) for providing
the p-Bpin-aryl bromide, Dr. Mark Nelson (Echelon Inc.) for
encouragement, and Dr. Davit Jishkariani (University of
Pennsylvania) for helpful discussions. Dr. Simon Berritt
(University of Pennsylvania) is acknowledged for his help
with the SFC measurements. Professors Eric J. Schelter and
Sergei Vinogradov and Haolin Yin are thanked for their help
in the quantum yield measurements. Drs. Patrick Carroll and
Rakesh Kohli (University of Pennsylvania) are thanked for
the X-ray crystallography measurements and acquisition of
HRMS spectra, respectively. R.M.A.S. thanks CAPES (Coor-
denażo de AperfeiÅoamento Pessoal de Nível Superior:
012849/2013-08) for a postdoctoral fellowship.
Scheme 4. Substrate scope with respect to the enantiopure aliphatic
Boc-protected aminomethylarenes.
Finally, the use of aromatic side chains on the amino-acid
moiety was studied (Scheme 5). From these, enantioenriched
benzylic amines were afforded, using l-Tyr and l-Phe amino
acids containing the ketone (4aa), nitrile (4ab and 4ae),
pyrimidine (4ac), and biphenyl (4ad) components, in good to
excellent yields. Importantly, these target structures possess
both aminomethylated arenes as well as phenethylamines
within their cores, both units of which are important in many
pharmacologically active materials.
Keywords: amino acids · cross-coupling · heterocycles · nickel ·
photochemistry
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