Catalytic Strategy for Regioselective Arylethylamine Synthesis

Article abstract of DOI:10.1021/jacs.9b01077

A mild, modular, and practical catalytic system for the synthesis of the highly privileged phenethylamine pharmacophore is reported. Using a unique combination of organic catalysts to promote the transfer of electrons and hydrogen atoms, this system performs direct hydroarylation of vinyl amine derivatives with a wide range of aryl halides (including aryl chlorides). This general and highly chemoselective protocol delivers a broad range of arylethylamine products with complete regiocontrol. The utility of this process is highlighted by its scalability and the modular synthesis of an array of bioactive small molecules.

Full text of DOI:10.1021/jacs.9b01077

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Article
A Catalytic Strategy for Regioselective Arylethylamine Synthesis
Allyson J Boyington, Ciaran P Seath, Avery M Zearfoss, Zihao Xu, and Nathan T. Jui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01077 • Publication Date (Web): 13 Feb 2019
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A Catalytic Strategy for Regioselective Arylethylamine Synthesis
Allyson J. Boyington, Ciaran P. Seath, Avery M. Zearfoss, Zihao Xu, and Nathan T. Jui*
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Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, Georgia, 30322, USA.
Supporting Information Placeholder
The Arylethylamine Scaffold: A Highly-Privileged Pharmacophore
ABSTRACT: A mild, modular, and practical catalytic sys-
tem for synthesis of the highly privileged phenethylamine
pharmacophore is reported. Using a unique combination
of organic catalysts to promote the transfer of electrons
and hydrogen atoms, this system performs direct hy-
droarylation of vinyl amine derivatives with a wide range
of aryl halides (including aryl chlorides). This general and
highly chemoselective protocol delivers a broad range of
arylethylamine products with complete regiocontrol. The
utility of this process is highlighted by its scalability and
the modular synthesis of an array of bioactive small mol-
ecules.
HO
HO
HO
N
NMe2
N
NH2
HO
O
H
NH2
NH
dopamine
Pristiq
Zejula
Anti-Markovnikov Styrene Hydroamination (Grubbs, Knowles, Nicewicz)
R1
R1
R3
H
catalyst
N
R3
R2
N
conditions
R2
H
styrenes
amine derivatives
arylethylamines
This Work: Arylethylamine Construction via Radical Enamide Hydroarylation
The arylethylamine scaffold is a key pharmacophore in
endogenous neurotransmitters, natural products and
pharmaceuticals that accomplish a wide range of important
functions (a small sampling of which are provided in Figure 1).
While this molecular scaffold can be produced through a range
of classical technologies (e.g. amino acid decarboxylation or
reductive amination) that utilize functionalized precursors, the
ability to access this structural array with modular flexibility
remains limited. Specifically, catalytic methods for direct
arylethylamine synthesis from readily available synthons where
alteration of the aryl unit, ethyl skeleton, and nitrogen atom
would be particularly powerful if they utilized readily available
starting materials. Toward this aim, significant progress has
been made in intermolecular anti-Markovnikov styrene
hydroamination using N,N-dialkylamines,1–4 N-arylamines,5
and sulfonamides.6,7 As a complement to these technologies, we
became interested in developing a process for hydroarylation of
vinylamine derivatives, where flexible substitution of nitrogen
would be possible. The utility of this method would be partially
driven by its ability to deliver the desired products with
complete anti-Markovnikov selectivity and good functional
group compatibility, while employing widely available
precursors. We envisioned that a mechanism for reductive
activation of aryl halides to the corresponding radicals and
intermolecular addition could be utilized to accomplish these
goals.
R1
R1
R2
H
Boc
N
5% CySH, 5% PTH
HCO2Na, light
Boc
R3
N
X
R2
R3
flexible N-substitution
mild conditions
complete regiocontrol
•
•
Figure 1. Modular Catalytic Strategies for Arylethylamine
Synthesis
pyridyl radicals (accessed via pyridyl halide reduction) undergo
chemoselective intermolecular coupling with either electron-
defficient22,23 or electron-rich olefins,24,25 and Weaver has
reported
a number of processes involving azolyl or
perfluoroaryl radicals.16 However, because aryl halide
reduction potentials are very negative and the resulting aryl
radicals undergo rapid reduction through hydrogen atom
transfer (HAT), general translation of these findings to aryl
systems has yet to materialize.
From the outset, we recognized two elements that would be
critical to the success of the proposed transformation: a
powerful catalytic reductant (capable of aryl halide activation)
and a catalytic hydrogen atom source (such that the rate of aryl
radical addition to vinylamines would be competitive with
reduction pathways involving HAT). Accordingly, we reasoned
that the highly-reducing N-phenylphenothiazine (PTH) and
cyclohexanethiols (CySH) could operate in concert through
transferring electrons and hydrogen atoms, respectively, as
illustrated in Figure 2. Specifically, iodobenzene (E1/20 = –1.51
to –2.20 V vs. SCE)12 activation via single electron transfer
(SET) from photoexcited PTH (E1/2* = –2.10 V vs. SCE)14
would give rise to the corresponding radical anion. Rapid
Aryl radicals are highly reactive intermediates that readily
engage a range of unsaturated systems.8,9 As an alternative to
arenediazonium salt-based approaches, single electron
reduction of aryl halides using photoredox catalysts10,11 is a
powerful method for aryl radical formation from stable starting
materials.12–19 Building on previous results by Stephenson,12
Konig,20,21 and Read de Alaniz and Hawker, we have shown that
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Single Electron Transfer (SET) catalyst
Hydrogen Atom Transfer (HAT) catalyst
O
CO2 + Na+
1
2
3
4
NaO
H
S
S
H
PTH
=
=
CySH
N
PTH+•
Ph
SET
HAT
CyS•
5
6
7
SET
catalytic cycle
HAT
catalytic cycle
H
O
8
9
N
OtBu
I
H
PTH
CySH
SET
HAT
iodobenzene
N-Boc-phenethylamine 1
10
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hv
PTH*
O
O
•
I–
+
OtBu
N
H
N
OtBu
H
tert-butyl vinylcarbonate
iodide
phenyl radical
nucleophilic radical
Figure 2. Proposed Dual-Catalytic Mechanism for Intermolecular Radical Hydroarylation.
mesolytic fragmentation would expel iodide, thereby delivering
the neutral phenyl radical. Regioselective intermolecular
addition to the vinylcarbamate substrate would deliver the
nucleophilic a-carbamoyl radical, which would undergo
polarity-matched HAT from the electrophilic thiol catalyst.26
This event would concurrently furnish the desired product 1 and
the thiyl species CyS•. Finally, regeneration of both catalysts
(via HAT and SET events) would liberate the innocuous
byproducts CO2 and NaI.
In practice, we found that iodobenzene effectively reacts with
tert-butylvinylcarbamate (2.5 equivalents) in the presence of 5
mol% of each catalyst and 3 equivalents of sodium formate
under irradiation with blue light in 5% H2O/DMSO, affording
the desired adduct as a single regioisomer (82% isolated yield)
Control experiments indicated that all of the reaction
components are required for effective conversion of the starting
materials. This mechanistic proposal is supported by Stern-
Volmer experiments, and an experiment with alternating light-
dark periods (optimization and mechanistic experiments are
given in the SI). To more accurately interrogate the potential
contributions of short radical chains to the observed results,27
we measured the quantum yield of this process. While Φ = 0.29
is most consistent with a photosensitized mechanism, radical
chains may contribute to product formation.
Further evaluation revealed that the aryl iodide scope of this
transformation is broad. As shown in Table 1, iodobenzene and
derivatives that contained chloride or triflate substituents
reacted smoothly with complete retention of the electrophilic
cross coupling handles (1–3, 70–88% yield). Electron-poor
arenes were excellent substrates here, and the para-
trifluoromethyl and -carboxymethyl groups were not affected (4
and 5, 85% and 73% yield, respectively). Electron-releasing
substituents (methoxy, carbamate, hydroxy) were tolerated,
although yields of the desired products were slightly lower (6–
9, 60–72%). These results are in line with the assertion that the
aryl radical SOMO lies within the plane of the arene, such that
the presence of electron-donating or -withdrawing substituents
does not significantly impact reactivity.28 We also found that
substitution is tolerated at various positions around the aryl ring
and, as expected, acidic elements did not negatively impact
reaction efficiency.
Also demonstrated in Table 1 is the ability of this mechanistic
blueprint to tolerate substitution of the olefinic partner on
nitrogen (11) and at the b-position (12). Hydroarylation of a
cyclic encarbamate, derived from cyclohexanone through vinyl
triflate formation and subsequent C–N coupling with tert-
butylcarbamate, occurred in moderate yield 42%, delivering 13
as a mixture of diastereomers (1:1 dr). Further, this strategy is
useful for synthesis of complex saturated nitrogen heterocycles,
through transformation of endocyclic enecarbamate substrates.
Specifically, the 3-arylpiperidine (14) framework was
accessible under this paradigm, albeit in diminished yield
(42%). This is noteworthy because this particular motif has
proven challenging to access directly, where 3-arylpyridine
reduction or a lactam a-arylation and reduction sequence were
utilized in the development of Zejula.29,30 Likewise, a
dihydropyridine derivative underwent hydroarylation to afford
3-phenylpyrrolidine 15 in 53% yield.
Given our experience with the complications associated with
intermolecular heteroaryl radical coupling, we were pleased to
find that halogenated heteroaromatics were good substrates
under these conditions. Intermolecular coupling of 3-
iodopyridine with the same vinylamine derivatives afforded
pyridylethylamines 16–20 in comparable yields (43–90%
yield). Moreover, these conditions generally activate a range of
other halogenated pyridines, where regiospecific radical
formation enables alkylation of the 2-, 3-, or 4-position in 66–
91% yield. As demonstrated before, iodide cleavage occurs
with excellent fidelity, even in the presence of chloride
substituents. Pyridylethylamines 26–28 were produced in good
yield without overreduction products, thus retaining the ability
to perform subsequent cross-coupling or nucleophilic aromatic
substitution (SNAr) reactions. In addition, products 26 and 28
further illustrate the ability of this system to tolerate ortho-
substitution. Incorporation of other nitrogen-containing
heterocyclic units was seamless, where reduction of
halogenated pyrimidine (24 and 25), quinoline (29), or pyrazine
(30) substrates resulted in acceptable amounts of alkylated
products.
The outlined dual catalytic process employs inexpensive
organic compounds as catalysts and reagents. Moreover, it is
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Table 1. Photocatalytic Radical Hydroarylation of Vinyl Amine Derivatives: Substrate Scopea
4
5
6
7
8
9
R1
R1
5 mol% PTH
O
H
R2
R4
byproducts:
5 mol% CySH
N
R4
H
ONa
N
I
R3
5% H2O/DMSO
R2
R3
CO2
+
NaI
blue LEDs, 23 °C
aryl iodide
olefin (2.5 equiv)
formate (3 equiv)
aryl ethylamine product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aryl iodide scope
Cl
TfO
F3C
MeO2C
H
H
H
H
H
Boc
Boc
Boc
Boc
Boc
Boc
N
N
N
H
N
N
H
H
H
H
1: 82% yield
2: 70% yield
3: 88% yield
4: 85% yield
5: 73% yield
MeO
H
MeO
H
H
H
H
Boc
Boc
Boc
N
Boc
N
H
HO
N
H
N
H
N
H
H
NHBoc
OMe
6: 61% yield
7: 61% yield
8: 72% yield
9: 60% yield
10: 74% yield
olefin scope
Cl
Cl
Cl
Cl
Cl
H
H
NHBoc
H
H
H
Boc
Boc
N
Boc
N
N
Boc
N
H
Me
Me
11: 62% yield
12: 60% yield
13: 42% yield (1:1 dr)
14: 42% yieldb
15: 53% yieldc
H
H
NHBoc
H
H
H
N
N
N
Boc
N
Boc
N
Boc
N
N
N
N
Boc
H
Me
Me
16: 70% yield
17: 66% yield
18: 43% yield (1:1 dr)
19: 47% yield
20: 67% yieldc,d
heteroaryl iodide/bromide scope
N
N
H
H
H
N
H
H
Boc
N
Boc
Boc
Boc
N
Boc
N
N
N
H
N
N
H
N
N
H
H
H
22: 69% yielde
23: 89% yielde
24: 70% yielde
25: 64% yielde
21: 91% yield
Cl
Cl
H
Cl
Me
N
H
N
H
H
H
N
Boc
N
Boc
Boc
N
Boc
Boc
N
H
N
N
N
H
N
N
H
H
H
Cl
26: 66% yield
27: 78% yield
28: 75% yield
29: 72% yieldb
30: 68% yield
aReaction conditions: Iodoarene (1.0 mmol), olefin (2.5 mmol), PTH (5 mol%), CySH (5 mol%), sodium formate (3.0 mmol),
5% (v/v) H2O/DMSO (10.0 mL), blue light, 16 h; isolated yields given. bReaction was conducted on 0.5 mmol scale (1-chloro-
4-iodobenzene). N-1-Naphthylphenothiazine (5 mol%) was used in place of PTH. dOlefin (1.0 mmol) was used as limiting
c
reagent with 5.0 mmol 3-iodopyridine. eCorresponding heteroaryl bromide was used as aryl substrate.
highly tolerant of important functional groups and completely
selective for the linear hydroarylation regioisomers. However,
we recognize that the requirement for aryl iodide substrates as
radical precursors is suboptimal because they are relatively
expensive in comparison to the corresponding aryl bromides or
chlorides. While these substrate classes are cheaper and more
accessible, they are more difficult to reduce (with aryl chloride
reduction potentials being the most negative throughout this
series). However, as demonstrated earlier by Read de Alaniz
and Hawker,14 reductive activation of these classes can be
performed using PTH. Indeed, activated chlorobenzene
derivatives couple readily with the benchmark vinyl carbamate
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the aryl radical intermediates that are produced here:
Scheme 1. Hydroarylation Reactions of Aryl Chlo-
rides and Basis for Intermolecular Reactivitya
1
2
3
4
5
6
7
8
intermolecular addition to olefins (desired) and reduction by
HAT from the electrophilic thiol (undesired). The relative rates
of these pathways can be conveniently manipulated by varying
thiol loading, and yields of the desired product were highest
using aliphatic thiol catalysts (see SI for details). Increasing
thiol loading was accompanied by a clear increase in arene
reduction through HAT. Optimal conditions (with 5 mol%
CySH, Ph–I as radical precursor) delivered hydroarylation
product 1 in 78% yield. In contrast, when of a full equivalent of
thiol (100 mol%) was utilized, the selectivity was completely
overturned giving benzene (PhH) as the major product (81%
yield). While it is understood that radical anion fragmentation
rates vary with halide substituent, we propose that this system
operates uniformly via neutral aryl radicals, regardless of the
Ar–X substrate class. This hypothesis is supported by thiol
loading experiments across a series of halobenzene substrates
(using methyl-4-iodo, -bromo, and -chlorobenzoate), where the
same thiol-dependent product ratios were observed throughout.
The arylethylamine scaffold is conserved across a wide range
of natural and synthetic neuromodulators. To demonstrate
practical utility, we applied this protocol to the synthesis of the
endogenous neurotransmitter dopamine, as well as the trace
amine associated receptor (TAAR) agonists32 that are shown in
Scheme 2. This system allows for modular substitution of the
aryl unit, affording phenethylamine (35), all three
methylphenethylamine isomers (36–38), and dopamine (39)
through a two-step hydroarylation/boc deprotection sequence
(66–75% yield). In addition, this method allows for flexible
substitution of the nitrogen atom, where tyramine (40), N-
methyltyramine (41), and hordenine (42) were all accessible in
two-steps from tert-butyl (4-iodophenyl) carbonate.
5 mol% PTH
H
5 mol% Cy-SH
R1
R1
NHBoc
Cl
NHBoc
3 equiv HCO2Na
5% H2O/DMSO
blue LEDs, 23 °C
aryl chloride
alkene
hydroarylation product
NC
CO2Me
F3C
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
N
N
31: 86% yield
32: 88% yield
33: 70% yieldb
34: 74% (2.2 g)c
Thiol Concentration Dictates Reaction Outcome
CySH
olefin
H
H
NHBoc
PhH (undesired)
phenyl radical (from Ph–I)
1 (desired)
100
80
60
40
20
0
1
PhH
5 mol%
25 mol%
50 mol% 100 mol%
CySH loadingd
To illustrate the potential of this process in the early-stage
development of medicines or agrochemicals, we reacted 2-
bromopyridine 43 with N-vinylbenzamide 44 to directly afford
aReactions conducted as in Table 1 using the indicated aryl
b
chloride. Reaction performed on 0.5 mmol scale. cReaction
performed on 10 mmol scale. dProduct ratios were determined
using GC with an internal standard.
Scheme 2. Flexible Synthesis of Neuromodulatorsa
R1
R1
under standard conditions. As indicated in Scheme 1, 4-
chlorobenzonitrile and ethyl-2-chlorobenzoate (E1/20 = –2.00 to
–2.10 V vs. SCE)31 were effectively converted to the
corresponding arylethylamines (31 and 32: 86% and 88% yield,
1) hydoarylation
2) deprotection
Boc
N
I
NH2
R2
vinyl carbamate
0
iodoarenes
respectively), but chlorobenzene (E1/2 = –2.79 V vs. SCE)31
trace amines
conversion was slower (28% yield after 16 h) where the mass
balance was largely comprised of unreacted chlorobenzene.
Alkylation of 2,4-dichloropyrimidine occurred exclusively at
the 4-position, giving 33 in 70% yield. The selectivity here
parallels those which were observed in SNAr or Pd-catalyzed
cross coupling processes. Retention of chloride substituents (in
products 16–20, 31–33, and 38) is possible presumably because
installation of the alkyl substituent via hydroarylation would
effectively increase reduction potential, thereby protecting the
product from subsequent activation. Without alteration of the
standard conditions, this catalytic protocol functioned on 10
mmol scale from the chloropyridine, affording 2.15 g of the
trifluoromethylpyridine product 34 (74% yield), further
illustrating the utility of this protocol (Scheme 1). Importantly,
tert-butylvinylcarbamate can be accessed on large scale (100
mmol) in a single pot from inexpensive reagents.
modular substitutiuon of aryl unit
HO
HO
Me
phenethylamine
methylphenethylamines
dopamine
35: 74% yield
36–38: 66–72% yield
39: 75% yield
flexible substitution of amino group
HO
HO
HO
Me
Me
N
H
NH2
N
Me
tyramine
hordenine
N-methyltyramine
40: 69% yield
41: 62% yield
42: 58% yieldb
This design enables remarkably effective intermolecular
reactivity of aryl radial species by employing a combination of
thiol HAT catalyst and stoichiometric formate reductant. As
illustrated in Scheme 1, there are two competing pathways for
aHydroarylation was accomplished as in Table 2, Boc-depro-
a
tection was performed with acid. Hordenine synthesis by
reduction with LiAlH4.
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Scheme 3. Rapid Synthesis of Fluopyram/Analogsa
The Supporting Information is available free of charge on
the ACS Publications website.
1
2
3
4
O
F3C
Cl
Br
Experimental procedures and spectral data (PDF)
O
N
H
H
ONa
N
AUTHOR INFORMATION
F3C
5
6
7
8
9
43 (3 equiv)
44 (1 equiv)
formate (3 equiv)
Corresponding Author
*njui@emory.edu
Notes
F3C
Cl
Fluopyram (Bayer)
fungicide (SDH inhibitor)
patent route: 7-steps LLS
This route:
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The authors declare no competing financial interests.
N
N
2-steps total
H
ACKNOWLEDGMENT
F3C
45
73% overall yield
This project was supported by funds from the National Insti-
tutes of Health (R01 GM129495) and NMR data were col-
lected under support of the National Science Foundation
(CHE-1531620). Z. X. was supported by the U.S. Depart-
ment of Energy, Office of Science, Office of Basic Energy
Sciences, Solar Photochemistry Program under Award Num-
ber (DE-FG02-07ER-15906). The authors would like to
thank Professors R. Brian Dyer, Jennifer Heemstra, and
Tianquan Lian (Emory University) for the generous access
to instrumentation and Henry Zecca (Emory University) for
his assistance in preparing cyclic enecarbamates.
Rapid analog synthesis via hydroarylation
H
Cl
Cl
Cl
F3C
H
N
N
46: 92% yield
47: 86% yield
48: 88% yield
O
O
H
N
H
N
H
CF3
49: 84% yield
50: 82% yield
REFERENCES
aReaction conditions: Haloarene (3.0 mmol), olefin (1.0
mmol), PTH (5 mol%), CySH (5 mol%), sodium formate
(3.0 mmol), 5% (v/v) H2O/DMSO (10.0 mL), blue light, 16
h; isolated yields given.
(1)
(2)
(3)
Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F.
Rhodium-Catalyzed Anti-Markovnikov Hydroamination of
Vinylarenes. J. Am. Chem. Soc. 2003, 125, 5608–5609.
Utsunomiya, M.; Hartwig, J. F. Ruthenium-Catalyzed Anti-
Markovnikov Hydroamination of Vinylarenes. J. Am. Chem. Soc.
2004, 126, 2702–2703.
Basalov, I. V.; Roşca, S. C.; Lyubov, D. M.; Selikhov, A. N.;
Fukin, G. K.; Sarazin, Y.; Carpentier, J. F.; Trifonov, A. A.
Divalent Heteroleptic Ytterbium Complexes - Effective Catalysts
the fungicide Fluopyram (45),33,34 shown in Scheme 3. Optimal
conditions for this transformation involved inverted
stoichiometry (using 3 equiv of radical precursor 43). This
olefinic partner is available in a single step from commercial
materials. This two-step sequence compares favorably to the
patent route of this agrochemical (7-steps). The value of this
modular hydroarylation strategy is further highlighted by the
expedient preparation of Fluopyram analogs 46–50, where
systematic substitution on either side of the scaffold could be
accomplished with excellent fidelity (82–92% yield for the
corresponding hydroarylation processes).
for
Intermolecular
Styrene
Hydrophosphination
and
Hydroamination. Inorg. Chem. 2014, 53, 1654–1661.
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In conclusion, we have developed
a protocol for
intermolecular addition of aryl and heteroaryl radicals to
enecarbamate substrates. This process operates at ambient
temperature, mediated by the concerted action of two different
catalytic species (PTH and CySH) that accomplish transfer of
electrons and hydrogen atoms, respectively. This system
directly affords valuable arylethylamine structures with
complete regiocontrol with excellent functional group
compatibility, and it utilizes stable halogenated arenes as
radical precursors. The highly-reducing character of the organic
photoredox catalyst here allows for effective activation of a
wide range of aryl halides, including electron-deficient aryl
chlorides. We expect that this protocol, founded on the use of a
thiol HAT catalyst in combination with stoichiometric
reductant, will enable a range of mild aryl radical-based
transformations.
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Stephenson, C. R. J. Engaging Unactivated Alkyl, Alkenyl and
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SUPPORTING INFORMATION
Kim, H.; Lee, C. Visible-Light-Induced Photocatalytic Reductive
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