A visible light-mediated, decarboxylative, desulfonylative Smiles rearrangement for general arylethylamine syntheses

Article abstract of DOI:10.1039/d0cc05049k

A decarboxylative, desulfonylative Smiles rearrangement is presented that employs activated-ester/energy transfer catalysis to decarboxylate β-amino acid derived starting materials at room-temperature under visible light irradiation. The radical Smiles rearrangement gives a range of biologically active arylethylamine products highly relevant to the pharmaceutical industry, chemical biology and materials science. The reaction is then applied to the synthesis of a chiral unnatural amino acid, 2-thienylalanine, used in the treatment of phenylketonuria. We also show how the reaction can proceed under metal-free and catalyst-free conditions.

Full text of DOI:10.1039/d0cc05049k

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DOI: 10.1039/D0CC05049K
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A Visible Light-Mediated, Decarboxylative, Desulfonylative Smiles
Rearrangement for General Arylethylamine Syntheses
David M. Whalley,[a,b] Hung A. Duong, *[a] Michael F. Greaney*[b]
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
and our own laboratory have used sulfnamide addition to sp-
Abstract: A decarboxylative, desulfonylative Smiles rearrangement
is presented that employs activated-ester/energy transfer catalysis
to decarboxylate β-amino acid derived starting materials at room-
temperature under visible light irradiation. The radical Smiles
rearrangement gives a range of biologically active arylethylamine
products highly relevant to the pharmaceutical industry, chemical
biology and materials science. The reaction is then applied to the
synthesis of a chiral unnatural amino acid, 2-thienylalanine, used in
the treatment of phenylketonuria. We also show how the reaction
can proceed under metal-free and catalyst-free conditions.
carbons for carbanion aryl transfer.[3b,c]
1. Desulfonylative Smiles
R
R
O
N
N
O
H
S
-SO2
N
O
S
R
O
Ar
Ar
Ar
3
2
1
2. Representative substrate classes - Csp2 and Csp common
Nevado - Acrylamide
conjugate addition
Greaney - Enaminoate
synthesis
Motherwell - Biaryl
synthesis
O
O2
S
O2
S
R
CO2R
SO2NHR
N
N
R
H
X
Introduction
Bu3SnH
X
The desulfonylative Smiles rearrangement is a powerful
arylation method that exploits easy to make sulfonamides, to
forge more challenging Caryl-Csp3 bonds via ipso-substitution
(Scheme 1.1).[1] The reaction often features mild and
operationally simple conditions, creating versatile pathways to
functionalized amino heteroarenes 3 with no requirement for
stoichiometric arylmetals. The best exemplified arylations in
this regime proceed through a 5-membered transition state
with where one or both of the two carbon centres illustrated in
red are sp2 hybridised. [2-5] Representative examples are shown
in Scheme 1.2: Seminal work in this area from Motherwell
established the reaction for Csp2 radicals in biaryl synthesis,[2b]
the Nevado group have developed an acrylamide system
triggered by a wide range of radical conjugate additions,[3i,j,k]
O
X
N
RH
CO2R
N
RH
R
N
H2
Scheme
1 Desulfonylative Smiles rearrangements to access arylethylamine
structures.
Smiles reaction on Csp3-tethered substrates, by contrast, is
far more limited in the literature, and represents a highly
appealing target for method development. The product
arylethylamines 3 are amongst the most privileged scaffolds in
chemistry and biology, found in endogenous signalling
molecules such as melatonin, adrenaline, serotonin and
dopamine, and have been widely exploited in medicines for
central nervous system (CNS) disorders (e.g. antidepressants
agomelatine and venlafaxine, parkinson’s treatment baclofen,
and stimulants such as amphetamine and Ritalin).[6]
a. D. M. Whalley, Dr H. A. Duong
Institute of Chemical and Engineering Sciences (ICES) Agency for Science,
Technology and Research (A*STAR)
A small number of aryl transfer routes to arylethylamines are
known, including some of the earliest reports from Speckamp on the
α-halomethylpiperidinyl system.[2],[7] Zard established the reaction
for xanthates 4, using thermal cleavage with a peroxide initiator to
give the substituted arylethylamines 5 (Scheme 2.1).[8] Recent work
by Stephenson used the visible light SET oxidation of p-
methoxystyrenes to trigger sulfonamide addition, followed by Smiles
8 Biomedical Grove, Neuros, #07-01, 138665 (Singapore)
b. Email: duong_hung@ices.a-star.edu.sg
c. D. M. Whalley, Prof M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: michael.greaney@manchester.ac.uk
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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[3a]
rearrangement to 1,1-diarylethylamines 8.
Our laboratory has incorporate a plethora of aryl species including electron rich and
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DOI: 10.1039/D0CC05049K
effected radical Smiles rearrangement using visible light-mediated poor arene rings as well heterocycles. We hypothesised that the
addition of bromodifluoroacetate to alkenes 9, giving the gem- synergy of these two strategies would provide arylethylamine
difluoro substituted arylethylamines 11.[9] In most cases, the reaction examples largely inaccessible by other reports in the field of Smiles
design generates secondary radicals for desulfonylative Smiles chemistry.
rearrangement, producing branched products. A notable exception
from Reiser and co-workers used decarbonylative Smiles
rearrangement from the tert-butylated benzoylamides 12 to access
Results and Discussion
the parent phenylethylamines 13.[5c] The more demanding amide
We began by preparing a series of β-alanine oxime esters 16 (three
steps, no purification of intermediates required, see Supporting
decarbonylation step necessitated an intramolecular single electron
transfer mechanism, requiring electron rich migrating aryl groups for
Information). Recent work from Glorius has used these moieties in
efficient reaction.
the room-temperature decarboxylation of aliphatic carboxylic acids
via visible light-mediated energy transfer catalysis.[10] This approach
1. Previous work - arylethylamine synthesis
Zard
(xanthate radical)
is attractive as it removes the need for stoichiometric reductants,
commonly necessary for redox-active phthalimide based
strategies.[11] We used thiophenes as the migrating arenes in our
initial optimization studies, owing to their prevalence in
pharmaceuticals[12] and their success in literature aryl transfer
reactions (Table 1).[3a,g,5d] Using [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 as
catalyst, we were delighted to observe successful reaction for various
oxime esters, with the p-fluoro derivative giving the best conversion.
N
N
N
N
Dilauryl peroxide
F3C
F3C

O
O
NHAc
NHAc
S
S O
OEt
S
O
4
5
Br
Br
Stephenson
(photoredox catalysis)
MeO
NHAc
Ir(III) (cat)
O
S O
NHAc
Table 1. Oxime ester optimizationa
MeO
6
7
8,
41%
NHAc
O
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6
(1 mol%)
O
S
O
R
N
S
Greaney
(electron-donor acceptor complex)
S
O
N
Cl
Ac
THF [0.20 M], Blue LEDs,
15 h, r.t.
R'
Cl
16
17
AcN
EtO2C
TMEDA
NHAc
O
S O
BrCF2CH2O2Et
F
F
entry
R
R'
Ph
H
conversionb
10
9
11
, 80%
1
2
3
4
Ph
Ph
41
50
45
63
Reiser
(photoredox catalysis)
O
MeO
Ir(III) (cat)
Cl
CO2NPht
p-ClC6H4
p-FC6H4
p-ClC6H4
p-FC6H4
CO2Me
N
But
Cl
13
N
12
But
, 53%
MeO
a 0.05 mmol scale. b Yields determined using a 1, 3, 5 trimethoxybenzene NMR standard.
2: This work
O
O
O
S
A screen of catalysts, solvents, and concentrations established
the iridium photosensitizer (1 mol%) in a tetrahydrofuran (THF)
solvent [0.08M] under blue LED irradiation, successfully delivered
the arylethylamine product in 56% yield (17a). Notably, we also
found that we could lower the catalytic loading to 0.25 mol% with
only a small reduction in reaction efficiency (see Supporting
Information).
Ar
N
OA
Ar
NHAc
cat
Ac
14
15
-Alanine substrate
(cheap feedstock)
arylethylamine product
(valuable pharmaceutical)
Scheme 2 Extrusion Smiles rearrangements to access arylethylamine structures
We were interested in establishing a general approach to
unsubstituted and substituted arylethylamines under mild, catalytic
conditions. Our reaction design is shown in Scheme 2.2 and
represents the first example of a desulfonylative, decarboxylative
Truce-Smiles rearrangement. The extrusion of CO2 provides
expedient access to the key Csp3 radical species (1 in Scheme 1.1) and
uses readily available amino acid starting materials 14, exploiting
their low cost, high availability and in certain cases, enantiopurity.
On the other hand, the extrusion of SO2 to irreversibly drive the
Truce-Smiles rearrangement has proven to be an efficient means to
We
explored
the
scope
of
the
reaction
for
thiophenylethylamines, initially. Compound 16b, containing the 3-
chlorothiophene substituent, gave a substantially higher yield,
possibly due to prevention of side-reactions through ortho addition
to the thiophene. It was possible to carry out this reaction under
metal free conditions using an organic thioxanthone photosensitizer
(10 mol%), albeit at reduced efficiency. Both the brominated and un-
substituted thiophene rings reacted in moderate yield (17c and 17d),
2 | J. Name., 2012, 00, 1-3
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along with the Boc-protected substrate 17e, establishing an unsubstituted phenyl ring proved to be an ineffective migrating
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orthogonal nitrogen- protecting group pathway. [14]
group, 2-fluorophenylethylamine 17h could be incorporated with
moderate yield by increasing the electrophilicity of the ipso position.
This is further demonstrated in example 17i where both the 2 and 6
positions are blocked, preventing deleterious alkyl radical addition
products. 2-Trifluoromethoxyphenyl 17k also acted as a good
substrate for desulfonylative Smiles chemistry.[15] Additional
examples with 2-substitution included 17l, showing that we could
incorporate anisyl rings in our chemistry, as well as meta substitution
for further functionalisation of the arene system (17m). 1-
Naphthylethylamine, a known tryptamine analogue, could be
synthesized (17n), potentially opening up new synthetic routes to the
antidepressant agomelatine.[16] In accordance with other reports on
radical ipso substitution, the reaction was tolerant of steric
hindrance demonstrated with compound 17o, containing a mesityl
ring.[17]
DOI: 10.1039/D0CC05049K
F
O
R2
Ar
O
R1
H
N
S
O
Ir(III) (1 mol%)
O
N
N
Ac
R1 Ac
Ar
R2
17
THF, 15 h
room temp
16
F
Cl
NHAc
NHAc
NHAc
NHAc
S
S
S
S
Cl
Br
17d
59%
17b
81%
17a
56%
17c
52%
(Metal-free: 41%) b
(47%, 1 mmol scale)
Cl
Cl
Cl
Cl
NHBoc
NHAc
NHAc
NHAc
S
S
S
S
Finally, we were keen to demonstrate the methodology in the
synthesis of a phenylalanine pharmaceutical. β-2-Thienylalanine has
been used to treat infants with phenylketonuria, a genetic disorder
resulting in the accumulation of phenylalanine in the blood, leading
to brain damage if left untreated.[18] Using the oxime ester derived
from cheap and readily available L-methyl aspartate, photocatalytic
Smiles rearrangement gave the protected β-2-thienylalanine 17p in
68% yield and 98% ee. Our approach compliments existing routes to
this class of molecule, which use asymmetric Rh hydrogenation[19] or
enzymatic catalysis with phenylalanine ammonia lyase.[20]
S-17g
17g
85%
17e
60%c
17f
94%
78%d
F
F
F
Cl
F
NHAc
NHAc
NHAc
NHAc
F
F
S
F
F
R-17g
83%d
17h
39%
17i
83%
17j
51%
OMe
Cl
Cl
NHAc
OCF3
NHAc
NHAc
NHAc
Cl
17n
54%
17k
61%
17l
77%
17m
87%
The mechanism for the Smiles arylation likely begins with an
energy transfer (EnT) event between the excited iridium catalyst and
the activated imine I giving II, a diradical species (Scheme 4).
Homolytic N-O bond cleavage can then take place, releasing iminyl
radical III which can be quenched via hydrogen atom abstraction
(HAT),[21] from the solvent’s relatively weak C-H bond (α-CH: BDE =
385 kJmol-1).[22] IV can spontaneously decarboxylate to give a primary
alkyl radical V.[23] This can then undergo a radical desulfonylative-
Smiles rearrangement via ipso substitution, forming a spirocyclic
intermediate VI, releasing SO2 to irreversibly drive the process to
completion. One further HAT event between amidyl radical VII and
the solvent gives the product, VIII. Owing to the inability of similarly
reducing photocatalyst (see Supporting Information) to yield any
product, the absence of a suitable stoichiometric reductant, and the
irreversible reduction potential of -2.0 V (vs. SCE)[10] we can rule out
a photoredox mechanism as a viable pathway for N-O bond cleavage.
Furthermore the reaction can proceed with reasonable efficiency
using the organic photosensitizer thioxanthone (17b scheme 3). In
the dark no conversion is observed but under blue LED irradiation
(catalyst free), a 20% NMR yield of the product is observed.
O
NHAc
OMe
S
NHAc
17p
68%
98% ee
17o
54%
a
b
0.20 mmol scale, Ir(III)
=
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6, 2.5 mL THF. 10 mol%
thioxanthone catalyst, blue LED irradiation. c NMR yield using 1,3,5-trimethoxybenzene
as an internal standard. d No evidence of racemization, isolated as single enantiomers.
Scheme 3. Scope of the decarboxylative, desulfonylative Truce-Smiles
rearrangement.a
Substitution on the ethyl backbone was easily tolerated, with the
α and β-methyl substrates rearranging in excellent yield (17f and
17g). Pleasingly, we were able to show for 17g that reaction occurred
without racemization, with both R and S starting materials delivering
the enantiopure heterocyclic amphetamine-type structures,
biosteres of other biologically active amines.[13]
Moving away from thiophene, the transformation could facilitate
the migration of phenyl rings, creating a collection of biologically
active phenylethylamines 17h – 17o. Fluorinated aryl rings have
gained much attention within the medicinal chemistry community
and we were keen to demonstrate the applicability to our system.
Hydrolysis products of 17h – 17j have all been used in the literature
as components for pharmaceutically relevant compounds as well as
active components in organic semiconductors.[14] Whilst the
In view of this last observation, we were intrigued to see if the
reaction could be carried out catalyst-free by direct excitation of the
oxime moiety using UVA radiation at room temperature (scheme 5).
This would allow for a reagent-free approach to sp3-sp2 C-C bond
formation, at room temperature. We were pleased to find that we
obtained a 41% NMR yield of the final product (cf example 17a,
scheme 3), indicating the viability of this approach. [24]
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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W. Crossley, R. M. Martinez, S. Guevara-ZuluagaV,ieRw. AAr.ticSlehOennlivnie,
Org. Lett. 2016, 18, 2620; g) J. J. Douglas, H. Albright, M. J.
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Ir cat
EnT
Sevrin, K. P. Cole, C. R. J. Stephenson, Angew. Chem. Int. Ed.
2015, 54, 14898. h) O. K. Rasheed, I. R. Hardcastle, J. Raftery,
P. Quayle, Org. Biomol. Chem. 2015, 13, 8048. i) N. Fuentes,
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O
Ar
O
O
Ar
O
Ar
N
S
O
N
Ar
N
S
O
O
N
Blue LEDs
O
Ar
Ac
Ar
Ac
Ar
II
I
N
-
Ar
III
Ac
Ac
O
4
5
For desulfonylative Smiles that proceed through 4-membered
transition states, see: a) M. W. Wilson, S. E. Ault-Justus, J. C.
Hodges, J. R. Rubin, Tetrahedron, 1999, 55, 1647. b) V. Lupi,
M. Penso, F. Foschi, F. Gassa, V. Mihali, and A. Tagliabue,
Chem. Commun. 2009, 5012. c) S. Johnson, E. Kovacs, M. F.
Greaney, Chem. Commun. 2020, 56, 3222.
Recent non-desulfonylative Smiles examples: a) Chang, X.;
Zhang, Q.; Guo, C. Org. Lett. 2019, 21, 4915; b) Li, J.; Liu, Z.;
Wu, S.; Chen, Y. Org. Lett. 2019, 21, 2077; c) Faderl, C.; Budde,
S.; Kachkovskyi, G.; Rackl, D.; Reiser, O. J. Org. Chem. 2018, 83,
12192; d) D. Alpers, K. P. Cole, C. R. J. Stephenson, Angew.
Chem. Int. Ed. 2018, 12167. e) D. L. Leonard, J. W. Ward, J.
Clayden, Nature, 2018, 562, 105. f) Costil, R.; Lefebvre, Q.;
Clayden, J. Angew. Chem. Int. Ed. 2017, 56, 14602; g) Wang,
S.-F.; Cao, X.-P.; Li, Y. Angew. Chem. Int. Ed. 2017, 56, 13809;
h) Costil, R.; Dale, H. J. A.; Fey, N.; Whitcombe, G.; Matlock, J.
V.; Clayden, J. Angew. Chem. Int. Ed. 2017, 56, 12533;
i) Janssen-Mueller, D.; Singha, S.; Lied, F.; Gottschalk, K.;
Glorius, F. Angew. Chem. Int. Ed. 2017, 56, 6276; j) Bhojgude,
S. S.; Roy, T.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2016, 18,
5424.
N
S
N
O
Ar
O
O
O
S
S
-CO2
O
N
O
O
Ar
Ar
Ac
VI
V
IV
-SO2
Ac
Ac
HAT
(from solvent)
N
H
N
Ar
Ar
Scheme 4. Proposed
mechanism
of
the
VII
VIII
decarboxylative, desulfonylative radical Truce-Smiles rearrangement. Ar = 4-F-
phenyl.
F
O
O
O
(365 nm)
Reagent-free
THF, r.t.
N
S
O
N
S
Cl
Ac
S
NHAc
Cl
17a
, 41%
16a
6
7
S. Freeman, J. F. Adler, Eur. J. Med. Chem. 2002, 37, 527.
H. J. Köhler, W. N. Speckamp, J. Chem. Soc., Chem. Commun.
1980, 142; and references therein.
F
Scheme 5. Reagent-free desulfonylative, decarboxylative Truce-Smiles
rearrangement.
8
9
A. Gheorghe, B. Quiclet-Sire, X. Vila, S. Zard, Org. Lett. 2005, 7,
1653.
D. Whalley, H. Duong, M. Greaney, Chem. Eur. J. 2019, 25,
1927.
Conclusions
In conclusion, we have developed
10 T. Patra, S. Mukherjee, J. Ma, F. Strieth-Kalthoff, F.
Glorius, Angew. Chem. Int. Ed. 2019, 58, 10514.
11 T. Patra, D. Maiti, Chem.: Eur. J. 2017, 23, 7382.
12 S. Pathania, R. K. Narang, R. K. Rawal, Eur. J. Med. Chem. 2019,
180, 486.
13 M. M. Goodman, G. W. Kabalka, J. Lee, G. W. Kabalka, R. C.
Marks, Y. Liang, F. F. Knapp, J. Med. Chem. 1992, 35, 280.
14 R. Schmidt, J. H. Oh, Y. Sen Sun, M. Deppisch, A. M. Krause, K.
Radacki, H. Braunschweig, M. Könemann, P. Erk, Z. Bao, et al.,
J. Am. Chem. Soc. 2009, 131, 6215.
15 K. Lee, Z. Lei, C. Morales-Rivera, P. Liu, M. Ngai, Org. Biomol.
Chem. 2016, 14, 5599.
a new decarboxylative,
desulfonylative Truce-Smiles rearrangement enabled by visible light
energy transfer catalysis. The reaction uses starting materials derived
from commercially available β-amino acids, giving extensive control
over the aryl species, ethyl chain substitution and amino protection
for the synthesis of new arylethylamines. The reaction can be carried
out metal-free and catalyst-free and applied to the synthesis of chiral
unnatural amino acids.
16 M. Dukat, C. Smith, K. Herrick-Davis, M. Teitler, R. A. Glennon,
Bioorganic Med. Chem. 2004, 12, 2545.
Conflicts of interest
17 M. L. E. N. Da Mata, W. B. Motherwell, F. Ujjainwalla,
Tetrahedron Lett. 1997, 38, 137.
There are no conflicts to declare.
18 C. Krips, D. R. Lines, J. Paediatr. Child Health 1972, 8, 318.
19 B. Mohar, M. Stephan, Adv. Synth. Catal. 2013, 355, 594.
20 C. Paizs, A. Katona, J. Rétey, Chem.: Eur. J. 2006, 12, 2739-.
21 L. Chen, L. Guo, Z. Ma, Y. Gu, J. Zhang, X. Duan, J. Org.
Chem. 2019, 84, 6475.
22 C. Meyer, S. Hell, A. Misale, A. Trabanco, V.
Gouverneur, Angew. Chem. Int. Ed. 2019, 58, 8829-8833.
23 a) T. Patra, P. Bellotti, F. Strieth-Kalthoff, F. Glorius, Angew.
Chem. Int. Ed. . 2020, 59, 3172. b) V. Soni, S. Lee, J. Kang, Y.
Moon, H. Hwang, Y. You, E. Cho, ACS Catal 2019, 9, 10454.
24 Reiser and co-workers reported an example of acetone-
sensitised, UV-mediated Smiles reaction in their
decarbonylative system, see ref 5c.
Notes and references
1
2
C. Holden, M. F. Greaney, Chem.: Eur. J. 2017, 23, 8992-9008.
Early work: a) R. Loven, W. N. Speckamp, Tetrahedron Lett.
1972, 13, 1567. b) W. B. Motherwell, A. M. K. Pennell, Chem.
Commun. 1991, 877.
3
Recent desulfonylative Smiles reports: a) T. Monos, R.
McAtee, C. Stephenson, Science 2018, 361, 1369. b) P. G. T.
Rabet, S. Boyd, M. F. Greaney, Angew. Chem. Int. Ed. 2017, 56,
4183. c) C. A. Holden, S. M. A. Sohel, M. F. Greaney, Angew.
Chem. Int. Ed. 2016, 55, 2450. d). E. Brachet, L. Marzo, M.
Selkti, B. König, P. Belmont, Chem. Sci 2016, 7, 5002. e) S.
Coulibali, T. Godou, S. Canesi, Org. Lett. 2016, 18, 4348; f) S.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05049K
O
O
O
Ir cat
19 examples, up to 94% yield
S
Ar
Bioactive phenethylamines
Unnatural amino acid example
Room temp, mild conditions
AO
N
Ar
- SO2
- CO2
NHR
R
Arylethylamines
-Amino acid
A decarboxylative, desulfonylative Smiles rearrangement is reported for the synthesis of a wide range of biologically
relevant arylethylamines, including fluorinated phenylethylamines, heterocyclic amphetamines and an unnatural amino
acid. The reaction uses an activated oxime ester/energy transfer mechanism to decarboxylate the β-amino acid derived
starting material at room temperature. We also show how the reaction can proceed under metal-free and catalyst-free
conditions.