A novel Barton decarboxylation produces a 1,4-phenyl radical rearrangement domino reaction

Article abstract of DOI:10.1016/j.tet.2018.05.043

A novel 1,4-Phenyl radical rearrangement (1,4-PhRR) is described in a typical Barton decarboxylation procedure. While carrying out this reaction in presence of a N,N-disubstituted β-amino acid derivative, the decarboxyphenyl rearranged derivative is obtained, as well as in presence of β-N,N-acylamide. On the other hand, secondary amines give the β-lactam derivative without rearrangement, as well as N-Fmoc derivatives give the normal decarboxylation reaction. In regards of amines which are far away from the carboxylic group, such as δ-amino acid derivatives, the reaction occur through a typical Barton decarboxylation without rearrangement. The diversity of the reaction proves synthetic usefulness paving the way to interesting biologically active compounds.

Full text of DOI:10.1016/j.tet.2018.05.043

Accepted Manuscript
A novel Barton decarboxylation produces a 1,4-phenyl radical rearrangement domino
reaction
Alejandro Manchado, Mercedes García, Mateo M. Salgado, David Díez, Narciso M.
Garrido
PII:
S0040-4020(18)30578-7
10.1016/j.tet.2018.05.043
TET 29550
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 April 2018
Revised Date: 14 May 2018
Accepted Date: 15 May 2018
Please cite this article as: Manchado A, García M, Salgado MM, Díez D, Garrido NM, A novel Barton
decarboxylation produces a 1,4-phenyl radical rearrangement domino reaction, Tetrahedron (2018), doi:
10.1016/j.tet.2018.05.043.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A novel Barton decarboxylation produces a 1,4-phenyl radical rearrangement domino reaction.
Alejandro Manchado, Mercedes García, Mateo M. Salgado, David Díez and Narciso M. Garrido.∗
Me
H
Bn
Ph
N
Ph
Barton decarboxylation
Ph
N
Ph
R
N
COOH
R
R
H
R1
amino acid derivatives
R1
R1
-
Ph
N
Me
H Bn
Ph
R
R
N
R1
Phenethylamine derivatives
H
R1
∗
Corresponding author. Tel.: +34-666589065; fax: +34-923-294574; e-mail: nmg@usal.es
1

ACCEPTED MANUSCRIPT
A novel Barton decarboxylation produces a 1,4-phenyl radical rearrangement domino reaction.
Alejandro Manchado, Mercedes García, Mateo M. Salgado, David Díez and Narciso M. Garrido.∗
Dpto. de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los
Caídos 1-5, 37008 Salamanca, Spain.
Dedicated to the memory of Professor Barton.
ABSTRACT
A novel 1,4-Phenyl radical rearrangement (1,4-PhRR) is described in a typical Barton decarboxylation
procedure. While carrying out this reaction in presence of a N,N-disubstituted β-amino acid derivative, the
decarboxyphenyl rearranged derivative is obtained, as well as in presence of β-N,N-acylamide. On the other
hand, secondary amines give the β-lactam derivative without rearrangement, as well as N-Fmoc derivatives
give the normal decarboxylation reaction. In regards of amines which are far away from the carboxylic
group, such as δ-amino acid derivatives, the reaction occur through a typical Barton decarboxylation
without rearrangement. The diversity of the reaction proves synthetic usefulness paving the way to
interesting biologically active compounds.
KEYWORDS
Barton decarboxylation, radical rearrangement, domino reaction, phenethylamine, amphetamine,
ethamphetamine, adrenaline, ephedrine.
∗
Corresponding author. Tel.: +34-666589065; fax: +34-923-294574; e-mail: nmg@usal.es
2

ACCEPTED MANUSCRIPT
1. Introduction
D.H.R. Barton has provided us with useful tools for organic synthesis, specially dealing with radical
1
reaction since the discovery in 1960 of γ-functionalization using nitrite esters, the radical
2
deoxygenation known as Barton-McCombie reaction, and the noteworthy decarboxylation reaction
3
described first in collaboration with W.B. Motherwell and D. Crich and then studied
4
mechanistically with S.Z. Zard et al. this reaction has been used several times by our group,
especially with thiohydroxamic acids and it is the basic of this communication.
We have demonstrated two domino reactions by using chiral lithium amide with functionalized α,β-
unsaturated esters: first when lithium (α-methylbenzyl)benzylamide (R)- or (S)-1 is used to initiate
the asymmetric conjugate addition cyclisation of nona-2,7-diendioate (scheme 1) to generate chiral
5
cyclohexane derivatives I, and applied it to the synthesis of (1R,5R,9R)-2-azabicyclo[3.3.1]nonane-
5
d
9
-carboxylic acid (morphanic acid), with a morphan scaffold, which was used in the synthesis of a
5
e
new class of opioid receptor ligands. Importantly, the chemoselective hydrolysis of the acetic ester
5c,6
and further Barton decarboxylation pave the way to a formal synthesis of pumiliotoxin C. Second,
a novel domino reaction: stereoselective Ireland-Claisen rearrangement and asymmetric Michael
7
addition. A protocol starting from Baylis-Hillman adducts II (Scheme 1) using chiral lithium amide
(R)-1 to afford δ-aminoacids III, that can be transformed to piperidones IV and further to piperidines
V. When benzaldehyde was used as starting material in Baylis-Hillman reaction we have proved the
application of the methodology toward the enantioselective synthesis of (+)-L-733,060 and (+)-CP-
7
b
9
9,994. When cinnamaldehyde was used as starting material in Baylis-Hillman reaction, we have
7
c
proved the application toward the synthesis of piperidinedicarboxylic acids (PDA) and actually our
8
studies toward the synthesis of anabasine required the use of the Barton decarboxylation reaction.
3

ACCEPTED MANUSCRIPT
COOMe
COOMe
Me
Me
Ph
N
Ph
Barton
R=H
N
COOMe
COOMe
COOMe
Me
COOR
Ph
N
Li
I, R=Me
H
Ph
N
Ph
COOR2
OAc
2: R =Ph; R =Me
1
2
Ph
N
R1
Ph
Li
1
2 t
3
: R =Ph; R = Bu
COOR2
N
1
2 t
R1
4: R =pyridinꢀ3ꢀyl; R = Bu
H H
-)-pumiliotoxin C
(
R)-1
(
COOH
II
III
R3
R1
R3
1
3
5
7
6
8
: R =Ph; R =COOMe
a
1
3
: R =Ph; R =COOH
N
1
3
t
: R =pyridinꢀ2ꢀyl; R =COO Bu
R1
N
H
b
N
O
1
3
H
H
: R =pyridinꢀ2ꢀyl; R =COOH
N
Anabasine
IV
V
Scheme 1: Domino reactions: 1) With diendioate derivatives. 2) With Baylis-Hillman derivatives.
Obtention of compounds 4, 7 and 8. Reagents and conditions: a) LiOH. b) TFA.
Phenethylamine-based drugs are a well-known family of compounds with highly and important
9
bioactivity. Small molecules such as adrenaline, noradrenaline, ephedrine or amphetamine and its
derivatives have this kind of skeleton and they are used to treat neurologic disorders and mental
10
issues, as they are neuronal central system stimulants. Herein, we report the synthesis of
phenethylamine derivatives bases on the discovery of a new domino reactions initiated in Barton
decarboxylation from β-aminoacid derivatives followed by a 1,4-phenyl radical rearrangement (1,4-
PhRR), which is a powerful tool in the synthesis of variety of these derivatives such as
1
0
ethamphetamine , which is under study.
Results and discussion
As it has been reviewed recently by Davies et al., a great number of β-amino acids are accessible by
1
1
asymmetric aza-Michael addition of chiral lithium amide to α,β-unsaturated esters, alkaline
hydrolysis provides the corresponding N,N-dibenzyldisubstituted amino acids in which we can
anticipate a constrained environment for the incoming radical (VI) when performing Barton
decarboxylation (scheme 2). The homobenzylic rearrangements indicated in the scheme 2 are
1
2
known, and usually take place when, in addition to regenerating the aromatic structure, a low
4

ACCEPTED MANUSCRIPT
energy VII radical is obtained, or as when one of the R groups is an electron donor heteroatom, as it
is indicated in the rearrangement of the radical epoxy described in scheme 2.
Ph
Ph
Barton
a
decarboxylation
Ph
N
Ph
R1
N
COOR2
COOH
N
R1
R1
.
1
1
2
12: R =Ph;
9
: R =Ph; R =Me
1
VI
1
2
13: R =fur-2-yl
1
0: R =fur-2-yl; R =Me
1
1
2
14: R =Me
1
1: R =Me; R =Me
.
.
.
R
CH
R
2
R
R
R
VII
R
O
R
R
O
. VIII
.
Scheme 2: Radical obtention proposal and known rearrangement. Reagents and conditions: a) LiOH.
The
β
-amino acids 12-14 were achieved by the aforementioned methodology and 2-4 by domino
7
reaction to produce γ-aminoacid, in this way we get to 7 and 8 (scheme 1). The rest of compounds
that were treated under the mentioned reaction conditions were obtained as described below.
First of all, it is required a β-amino carboxyl derivative instead of δ-, for which the following
reactions are carried out:
Scheme 3: Interchange of carboxy functionality. Reagents and conditions: a: Me SiCHN 2.0 M,
3
2
C H /MeOH; b: TFA.
6
6
5

ACCEPTED MANUSCRIPT
The treatment of 3 and 4 with Me SiCHN leads to the diesters 15 and 16 with 100% and 70% yields
3
2
respectively. The hydrolysis products 17 and 18 are obtained in 100% and 71% yield after treating
the diesters with TFA.
With a variety of
β-amino acids and α-alkyl-β-amino acids in hand the reactivity of Barton
decarboxylation via thiohydroxamate esters was undertaken and the results are shown in scheme 4.
Reactivity of β-amino acid derivatives.
Reactivity of α-alkyl-β-amino acid and δ-amino acid derivatives.
Scheme 4: Reactivity of amino acids. Reagents and conditions: a: 1) 2,2’-dithiodipyridine-1,1’-
di-N-oxide, PPh , DCM. 2) tBuSH, hν.
3
6

ACCEPTED MANUSCRIPT
The decarboxylation of 18 could produce a derivative that by hydrogenolysis would give the
piperidone precursor of anabasine. However, when testing the decarboxylation on 18, the expected
reaction product is not obtained, but the rearranged compound 23 is obtained.
The spectroscopic data of 23 shows the existence of an ethyl group at
δ
ppm: 0.82 (3H, t, J = 6.9 Hz,
(ppm): 3.35 (1H, ddd,
NCH CH ) and 2.55-2.64 (2H, m, NCH CH ) and two unpaired methines at
δ
2
3
2
3
J = 11.3, 11.2 and 3.0 Hz, H-4) and 3.90 (1H, d, J = 11.0 Hz, H-5). In order to ascertain the structural
complexity two-dimensional normal heteronuclear (HMQC) and long-range correlation (HMBC)
experiments corroborate the structure of 23 and allow the assignment of all its spectroscopic data.
The conectivities of Cipso of phenyl on C-4 with H-5 and H-4 that fix its position and those of CH2
(
of ethyl) with CH Ph and with H-5 stand out.
2
Thus, a radical benzylic rearrangement is described in which a 1,4 migration of phenyl occurs and
which is unprecedented in the literature.
In our case, the proposed reaction mechanism is the one indicated in scheme 5, in which the radical,
which initially formed IX, evolves due to the proximity of the aromatic ring, in analogy with the
homobenzylic rearrangement described, giving the radical with the spiranic carbon X that evolves
immediately to produce the low energy intermediate XI due to the existence of nitrogen as an
electron donor, which in the presence of the hydrogen donor (tBuSH) generates the final product of
reaction.
7

ACCEPTED MANUSCRIPT
Scheme 5: Proposed mechanism for 1,4-phenyl radical rearrangement.
Given the unexpected result, the reaction was carried out several times, always obtaining the same
result. The loss of stereoselectivity found in C-4 could be due to inversion of radical configuration
from IXa to IXb, shown in scheme 5. Similar retention of configuration is account by Walborsky et
13
al. in cycloprpyl radical system by Barton decarboxylation reaction with a level of retention till
1
4
8
4% using tert-butylthiol as the hydrogen donating reagent, and by Buckmelter et al. by
enantioselective decarboxylation in tetrahydropyran core with different hydrogen atom donors (tert-
butylthiol included).
Phenyl derivative 17 behave in the same way but with better selectivity (12:1),
β
-amino acids 12 and
13 produce 1,4-PhRR derivatives 19 and 20 with 41% and 43% yields respectively. But, when the
carboxyl is
δ to the amine group, the radical is far away from the phenyl group and the
decarboxylation compound 24 is obtained, as well as when methyl derivative 14 is treated under
same conditions yielding 21, probably by a less steric demanding environment or probably the
reaction needs more time under radical mediation, as could be by using a slower hydrogen atom
15
donor such as n-Bu SnH, 1,4-cyclohadiene, Ph SiH or Et SiH. Computational and kinetic studies
3
3
3
are underway to control this reactivity.
8

ACCEPTED MANUSCRIPT
In order to amplify the scope of the reaction we get some new
β-amino acid such as 27, 29 and 33 as
shown in scheme 6, and the cyclic -amino acids 7 and 8 in scheme 1.
β
Scheme 6: Reagent and conditions: a: Me SiCHN , C H /MeOH. b: CAN, MeCN/H O. c: TFA.
3
2
6
6
2
d: BH , THF. e: Ac O, pyr. f: H , Pd/C, AcOH. g: NaHCO /Fmoc-OSu, Acetone/H O. h: TFA. i:
3
2
2
3
2
LiOH, MeOH/THF/H O.
2
In scheme 7 it is shown the results of performing Barton decarboxylation with these compounds.
9

ACCEPTED MANUSCRIPT
O
Ph
Ph
Ph
NH
N
a
COOMe
e.e. 95%. Yield: 66%
Ph
Ph
Ph
COOMe
COOH
7
34
2
N
O
N
O
a
e.e. 95%. Yield: 39%
Ph
COOH
Ph
3
5
29
Fmoc
Fmoc
HN
Ph
HN
Ph
a
OAc
OAc
e.e. 95%. Yield: 52%
36
33
COOH
HOOC
Ph
a
Ph
N
H
O
N
H
O
e.e. 95%. Yield: 79%
7
37
HOOC
N
a*
X
N
O
N
H
O
H
N
8
*
A complex mixture is obtained
a: 1) 2,2'-dithiodipyridine-1,1'-di-N-oxide, PPh , DCM. 2) tBuSH, hv
3
Scheme 7: Reactivity of modified amines, and piperidone carboxylic acids. Reagents and
conditions: a: 1) 2,2’-dithiodipyridine-1,1’-di-N-oxide, PPh , DCM. 2) tBuSH, hν.
3
N-α-methylbenzyl and N-acetyl amide 29 gives way to compound 35 through the 1,4-PhRR, in
which decarboxylation was established by MS and the structure by two-dimensional NMR
1
1
1
13
experiments ( H/ H and H/ C, SI) showing the existence of rotamers. On the other hand, N-α-
methylbenzyl secondary amine under the same condition provides -lactam 34, as a conveniet
β
method for activation of carboxyl group toward cyclic amide formation, HNFmoc derivative 33
provides decarboxylation showing an alternative way to obtained anabasine and his phenyl
homologue. N-debenzylation of 19 and 20 will provide aromatic homologues of ethamphetamine.
From these results it could be assess that tertiary β-amine or β-amide acids with an aromatic β-
substituent under Barton decarboxylation will provide the 1,4-PhRR described. It is probably that π-
1
0

ACCEPTED MANUSCRIPT
stacking interaction within IXa in scheme 5 favors the appropriate configuration for the
rearrangement. With β-alkyl substituent only decarboxylation has been observed and further studies
are needed to retard the donation of the hydrogen atom. Other compounds devoid of the proximity of
dibenzylamine give rise to usual decarboxylation.
Further work is overtaken in our laboratory to obtain the pharmacological active compound as well
as to perform SAR studies.
Conclusions
D.H.R. Barton has provided us with tools for diversity in this way by using his typical procedure for
decarboxylation. We can achieve it properly in compounds such as 4, 7, 14 and 33 to provide 24, 21,
37 and 36 respectively. Nevertheless, when we treat in this condition secondary derivative 27, we
obtain β-lactam 34 by carboxyl activation, and, interestingly, when β-amino acid 10 and 11 or α-
alkyl-β-amino acids 17 and 18 were treated under the same condition we got 20, 21, 22 and 23
respectively via an unknown 1,4-phenyl radical rearrangement that we described for the first time.
This gives way to provide in one pot procedure a domino process by radical decarboxylation
followed by 1,4-phenyl radical rearrangement to provide from β-amino acids derivatives
phenethylamines, interesting class of pharmaceutical derivatives from which ethamphetamine and
related compounds is a future objective.
Experimental
All chemical reagents were purchased from Sigma-Aldrich or Acros. High-purity reaction solvents
®
were purified accordingly to literature. All reactions were carried out in borosilicate Pyrex type
glassware and under inert conditions, using Ar as inert gas. Reaction monitoring was followed by
TLC, type Merck 60 F254, which visualization was achieved with UV light and ninhydrin or
potassium permanganate as appropriate stains. Flash chromatography was carried out on Kieselgel
40 (Merck, 0.040-0.063) silica. Yields and characterization data belong to chromatography purified
compounds. Deuterated solvents were purchased from Carlo Erba. Optical rotations were measured
20
on a Perkin Elmer 241 polarimeter in 1 dm cells ([α]D ). Infrared spectra were recorded on a
1
Shimadzu IRAffinity-1 (IR). NMR experiments were recorded on a Varian 200 VX ( H NMR/200
13
1
MHz, C NMR/50 MHz) and on a Bruker DRX 400 ( H NMR/400 MHz). 2D HMBC, HMQC or
representative compounds were also recorded to assign protons and carbons on new structures. 2D
1
1
1
1
COSY H- H homonuclear correlations have been determined by H- H COSY experiment with
1
13
double function filler and gradients on a Bruker DRX 400. 2D HSQC H- C heteronuclear
1
1

ACCEPTED MANUSCRIPT
1
13
correlations have been determined by H- C HSQC experiment with single quantum filler and
gradients, also on a Bruker DRX 400. Chemical shifts are reported in ppm (parts per million)
relative to referenced values. High-resolution mass spectrometry (HRMS) analyses were performed
on an Applied Biosystems QSTAR XL (ESI, electrospray ionization) and in a VG-TS 250 (EI,
electronic impact), at 70 eV (m/z).
1
1
7c
7a
The compounds 12, 13, 14, , 7 and 17, 18 were prepared according to the cited references.
General Barton decarboxylation procedure
The suitable substrate is dissolved in DCM. In a dark room, as the Barton reagent is photosensitive, 1
equivalent of 2,2’-dithiodipyridine-1,1’-di-N-oxide (Barton reagent) is added, as same as 1
equivalent of triphenylphosphine. In constant agitation, the reaction is carried out in darkness
conditions.
Once the reaction finished, 3 equivalents of tert-butylthiol are added and the mixture is irradiated
with two 220 W lights.
After an hour, all the solvent is evaporated and the reaction product is chromatographed.
(S)-N-benzyl-N-ethyl-1,2-diphenylethan-1-amine (19)
Following the general Barton decarboxylation procedure, the reaction was carried out with 70 mg of
(0.20 mmol), 52 mg of triphenylphosphine (0.20 mmol) and 50 mg of 2,2’-dithiodipyridine-1,1’-
9
di-N-oxide (0.20 mmol). After stirring the reaction for 3 hours, 0.07 mL of tert-butylthiol (0.60
mmol) were added and after irradiation the mixture for 1 hour the product were isolated with
hex:EtAcO 99:1. In the end, 20 mg were obtained. Yield: 31%.
2
6
1
[
α]D = -5.4 (c 0.53, CHCl ) NMR H δ (ppm) (200 MHz, CDCl ): 1.05 (3H, t, J= 7.10 Hz,
3
3
NCH CH ), 2.2-2.4 (1H, dq, J= 13.0 and 6.95 Hz, NCH HCH ), 2.65-2.83 (1H, dq, J= 13.0 and 6.95
2
3
A
3
Hz, NCHH CH ), 2.93-3.07 (1H, m, PhCH H), 3.22-3.35 (1H, AB, J = 14.33, NCH HPh), 3.3-
B
3
A
AB
A
3.38 (1H, m, PhCHH ), 3.75-3.85 (1H, d, J = 14.33, NCHH Ph), 4.00 (1H, t, J= 7.42, PhCH),
B AB B
1
3
7
.02-7.51 (15H, m, ArH). NMR C δ (ppm) (50 MHz, CDCl ): 29.72 (CH , NCH CH ), 38.30
3
3
2
3
(
CH , NCH CH ), 43.13 (CH , C-2), 53.94 (CH , NCH Ph), 64.99 (CH, C-1), 127-129.4 (Cx15, Ar),
2 2 3 2 2 2
139.95-142.5 (Cx3, Cipso).
(S)-N-benzyl-N-ethyl-1-(furan-2-yl)-2-phenylethan-1-amine (20)
1
2

ACCEPTED MANUSCRIPT
The general procedure was followed and the next reagent amounts were added: 88 mg of 10 (0.25
mmol), 66 mg of triphenylphosphine (0.25 mmol) and 63 mg of 2,2’-dithiodipyridine-1,1’-di-N-
oxide (0.25 mmol). The reaction was stirred for 4 hours and then 0.085 mL of tert-butylthiol (0.75
mmol) were added and, after 1 hour, the product mixture was chromatographed. In the end, 9 mg of
20 were obtained after eluting with hex:EtAcO 99:1. Yield: 33% .
2
6
1
[
α]D = -44.7 (c 0.30, CHCl ). NMR H δ (ppm) (200 MHz, CDCl ): 0.99 (3H, t, J = 7.1 Hz,
3
3
NCH CH ), 2.28 (1H, dq, J= 13.5 and 6.8 Hz, NCH HCH ), 2.84 (1H, dq, J= 13.5 and 6.8 Hz,
2
3
A
3
NCHH CH ), 3.14 (2H, d, J= 7.6 Hz, CH , C-2), 3.29 (1H, d, J= 14.3 Hz, NCH HPh), 3.89 (1H, d,
B
3
2
A
J= 14.3 Hz, NCHH Ph), 4.02 (1H, t, J= 7.6 Hz, CH, C-1), 6.35 – 6.05 (3H, m, CH, Fur), 7.66 – 6.89
B
1
3
(
10H, m, ArH). NMR C δ (ppm) (50 MHz, CDCl ): 13.61 (CH , NCH CH ), 37.57 (CH ,
3 3 2 3 2
NCH CH ), 44.07 (CH , C-2), 54.59 (CH , NCH Ph), 58.49 (CH, C-1), 106.28-109.67 (CH, Fur),
2
3
2
2
2
-1
1
25.84-130.05 (CHx10, Ph), 139.67-141.43 (Cx3, Cipso). IR νmax (cm ): 2964, 2926, 2852, 737, 698.
N-benzyl-N-ethylpropan-2-amine (21)
The next quantities were added following the general procedure: 22 mg of 11 (0.07 mmol), 20 mg of
triphenylphosphine (0.07 mmol) and 19 mg of 2,2’-dithiodipyridine-1,1’-di-N-oxide (0.07 mmol).
After 4 hours, 0.025 mL of tert-butylthiol were added and after 1 hour, the product mixture was
chromatographed. In the end, 5 mg of 21 was obtained with hex:EtAcO 99:1. Yield: 26%.
1
NMR H δ (ppm) (200 MHz, CDCl ): 0.91 (6H, d, J= 6.6 Hz, CH(CH ) ), 1.05 (3H, d, J= 6.6 Hz,
3
3 2
NCHCH ), 3.00 (1H, quint, J= 6.6 Hz, CH(CH ) ), 3.70 (2H, AB, J = 15.4 Hz, NCH Ph), 3.91 (1H,
3
3 2
AB
2
q, J= 6.6 Hz, NCHCH ), 7.91 – 7.00 (10H, m, ArH).
3
Methyl (4S,5R)-5-(benzyl(ethyl)amino)-4,5-diphenylpentanoate (22)
Following Barton decarboxylation procedure, the next quantities were added: 91 mg of 17 (0.20
mmol), 63 mg of triphenylphosphine (0.23 mmol) and 60 mg of 2,2’-dithiodipyridine-1,1’-di-N-
oxide (0.20 mmol). After 4 hours of reaction, 0.070 mL of tert-butylthiol (0.60 mmol) were added
and the mixture was irradiated for 90 minutes. After eluting the product mixture with hex:EtAcO
99:1, 29 mg of 22 were obtained. Yield: 37%.
2
6
1
[
α]D = +33.2 (c 1.44, CHCl ). NMR H δ (ppm) (400 MHz, CDCl ): 0.81 (3H, t, J= 6.9 Hz,
3
3
NCH CH ), 1.54-1.62 (1H, m, H-3 ), 1.67-1.74 (2H, m, H-2), 1.98-2.04 (2H, m, NCH CH ), 2.53-
2
3
B
2
3
2
3
7
.58 (1H, m, H-3 ), 2.92 (1H, AB, J = 14 Hz, NCH HPh), 3.34 (1H, dt, J= 11.0 and 3.6 Hz, H-4),
A AB A
.51 (3H, s, COOCH ), 3.75 (1H, AB, J = 14.0 Hz, NCHH Ph), 3.88 (1H, d, J= 11.1 Hz, H-5),
3
AB
B
1
3
.00-7.46 (15H, m, ArH). NMR C δ (ppm) (50 MHz, CDCl ): 13.3 (CH3, NCH CH ), 29.6 (CH ,
3
2
3
2
1
3

ACCEPTED MANUSCRIPT
C-3), 32.4 (CH , C-2), 42.9 (CH , NCH CH ), 47.2 (CH, C-4), 51.5 (CH , COOCH ), 53.6 (CH ,
2
2
2
3
3
3
2
NCH Ph), 67.9 (CH, C-5), 126.4-129.3 (CHx15, Ar), 137.2 (C, Cipso), 140.5 (C, Cipso, CHPh), 142.7
2
-1
(
C, Cipso, CH Ph), 174.1 (C, COOCH ). IR ν (cm ): 3394, 3059, 3026, 2922, 2804, 1736, 1488,
2 3 max
+
1
452, 1365, 1156, 1073, 753, 700. H.R.M.S., FAB, calcd for C H O N [M+H] : 402.2427, found:
27 32 2
402,2423.
Methyl (4S,5R)-5-(benzyl(ethyl)amino)-4-phenyl-5-(pyridin-3-yl)pentanoate (23)
Following the Barton decarboxylation procedure, the reaction was carried out with these reagent
quantities: 100 mg of 18 (0.22 mmol), 69 mg of triphenylphosphine (0.26 mmol) and 67 mg of 2,2’-
dithiodipyridine-1,1’-di-N-oxide (0.26 mmol). After 3 hours, 0.074 mL of tert-butylthiol (0.66
mmol) were added and the reaction mixture irradiated for 50 minutes. After the reaction product was
chromatographed, 34 mg of 23 were obtained when eluting with hex:EtAcO 9:1. Yield: 39%.
2
6
1
[
α]D = +11.3 (c 1.21, CHCl ). NMR H δ (ppm) (400 MHz, CDCl ): 0.82 (3H, t, J= 6.9 Hz,
3
3
NCH CH ), 1.48-1.57 (1H, m, H-3 ), 1.59-1.68 (1H, m, H-3 ), 1.99-2.02 (2H, m, H-2), 2.55-2.64
2
3
B
A
(
2H, m, NCH CH ), 2.87 (1H, AB, J = 14.0 Hz, NCH HPh), 3.35 (1H, ddd, J= 11.3, 11.2 and 3.0
2 3 AB A
Hz, H-4), 3.52 (3H, s, COOCH ), 3.74 (1H, AB, J = 14.0 Hz, NCHH Ph), 3.90 (1H, d, J=11.0 Hz,
3
AB
B
H-5), 7.06-7.31 (10H, m, ArH), 7.56 (1H, d, J= 8.4 Hz, H-5-pyr), 8.46 (1H, d, J= 3.4 Hz, H-4-pyr),
1
3
8
.54 (2H, s, J= 3.4 Hz, H-2-pyr and H-6-pyr). NMR C δ (ppm) (50 MHz, CDCl ): 13.2 (CH ,
3 3
NCH CH ), 29.3 (CH , C-3), 32.0 (CH , C-2), 42.8 (CH , NCH CH ), 46.5 (CH, C-4), 51.7 (CH ,
2
3
2
2
2
2
3
3
COOCH ), 53.6 (CH , NCH Ph), 65.7 (CH, C-5), 126-128.9 (CHx10, Ar), 136.3 (C, C-3-pyr), 139.7
3
2
2
-1
(
C, Cipso, CH Ph), 141.9 (C, C , CHPh), 173.9 (C, COOCH ). IR ν
(cm ): 3060, 3027, 2930,
2
ipso
3
max
2
847, 2800, 1736, 1452, 1425, 1365, 1211, 1166, 1026, 700. H.R.M.S., FAB, calcd for C H O N
26 31 2 2
+
[
M+H] : 402.2427, found: 102, 2423
Tert-butyl (S)-2-((S)-(benzyl((R)-1-phenylethyl)amino)(pyridin-3-yl)methyl)butanoate (24)
After following the general procedure and adding 50 mg of 4 (0.10 mmol), 31 mg of
triphenylphosphine (0.10 mmol) and 30 mg of 2,2’-dithiodipyridine-1,1’-di-N-oxide (0.11 mmol),
the reaction was stirred for 5 hours and, then, 0.034 ml of tert-butylthiol (0.30 mmol) were added.
After irradiating the mixture for 50 minutes, the reaction crude was chromatographed and the desired
product isolated with hex:EtAcO 8:2. In the end, 20 mg of 24 were obtained. Yield: 35%.
2
6
1
[
α]D = +37.9 (c 1.33, CHCl ). NMR H δ (ppm) (400 MHz, CDCl ): 0.81 (3H, t, J= 7.5 Hz,
3
3
CH CH ), 0.98 (3H, d, J=6.8 Hz, NCHCH ), 1.01 (9H, s, C(CH ) ), 2.10-2.16 (2H, m, CH CH ),
2
3
3
3 3
2
3
2
.86 (1H, dt, J= 11.6 and 3.6 Hz, H-2), 3.58 (1H, AB, J = 13.8 Hz, NCH HPh), 3.87 (1H, d, J=
AB A
1
4

ACCEPTED MANUSCRIPT
1
1.6 Hz, H-3), 4.00 (1H, AB, J = 13.8 Hz, NHH Ph), 4.13 (1H, q, J= 6.8 Hz, NCHCH ), 7.23-7.37
AB
B
3
(10H, m, ArH), 7.56 (1H, d, J= 8.4 Hz, H-5-pyr), 8.46 (1H, d, J= 3.4 Hz, H-4-pyr), 8.54 (2H, s, J=
1
3
3
.4 Hz, H-2-pyr and H-6-pyr). NMR C δ (ppm) (50 MHz, CDCl ): 11.9 (CH , CH CH ), 15.0
3 3 2 3
(
CH , C(α)Me), 24.0 (CH , CH CH ), 27.7 (CH x3, C(CH ) ), 50.8 (CH , NNCH Ph), 51.7 (CH, C-
3 2 2 3 3 3 3 2 2
2
), 56.1 (CH, C(α)), 60.9 (CH, C-3), 80.5 (C, C(CH ) ), 123.3 (CH, C-5-pyr), 127.2-129.2 (CHx10,
3 3
Ar), 136.8 (C, C-3-pyr), 137.2 (CH, C-4-pyr), 139.8 (C, C , CH2Ph), 177.0 (C, Cipso, CHPh), 148.3
ipso
t
-1
(
CH, C-6-pyr), 150.4 (CH, C-2-pyr), 173.5 (C, COO Bu). IR ν (cm ): 3031, 2971, 2933, 2875,
max
+
1
724, 1446, 1370, 1261, 1158, 1073, 936, 700. H.R.M.S., FAB, calcd for C H O N [M+H] :
29
37
2
2
445.2855, found: 445,2883.
Methyl 3-((3S,4S)-2-oxo-4-phenyl-1-((S)-1-phenylethyl)azetidin-3-yl)propanoate (34)
The following reagent amounts were added using the general Barton decarboxylation procedure: 20
mg of 27 (0.06 mmol), 19 mg of triphenylphosphine (0.06 mmol) and 17 mg of 2,2’-
dithiodipyridine-1,1’-di-N-oxide (0.06 mmol). After 5 hours of reaction, 0.020 mL of tert-butylthiol
(0.18 mmol) were added and after 1 hour of irradiation, the product mixture was chromatographed
and the desired product was eluted with hex:EtAcO 8:2. Yield: 66%.
2
6
1
[
α]D = +103.3 (c 0.96, CHCl ). NMR H δ (ppm) (400 MHz, CDCl ): 1.36-1.41 (1H, m, H-1’ ),
3 3 B
1
.43 (3H, d, J= 7.2 Hz, NCHCH ), 1.74-1.82(1H, m, H-1’ ), 2.13-2.20 (2H, m, H-2’), 3.31 (1H, q,
3 A
J= 5.6 Hz, H-3), 3.57 (3H, s, COOCH ), 4.52 (1H, d, J= 5.6 Hz, H-4), 4.98 (1H, q, J= 7.2 Hz,
3
1
3
NCHCH ). 7.23-7.34 (10H, m, ArH). NMR C δ (ppm) (50 MHz, CDCl ): 19.6 (CH , C(α)Me),
3
3
3
2
1.1 (CH , C-1’), 31.4 (CH , C-2’), 51.8 (CH , COOCH ), 52.8 (CH, C-4), 53.6 (CH, C-3), 58.0
2 2 3 3
(CH, C(α)), 127.5-129.9 (CHx10, Ar), 136.8 (C, Cipso, CHPh), 140.4 (C, Cipso, CHPh), 170.6 (C,
-1
COOCH ), 173.4 (C, C-2). IR νmax (cm ): 3031, 2951, 1743, 1495, 1455, 1376, 1200, 1026, 700.
3
+
H.R.M.S., FAB, calcd for C H O N [M+H] : 338.1751, found: 338.1730.
2
1
24
3
(S)-N-(1,2-diphenylethyl)-N-ethylacetamide (35)
Following the general Barton decarboxylation procedure, the next quantities were added: 25 mg of
9 (0.08 mmol), 21 mg of triphenylphosphine (0.08 mmol) and 20 mg of 2,2’-dithiodipyridine-1,1’-
2
di-N-oxide (0.08 mmol). After 3 hours, 0.030 mL of tert-butylthiol (0.24 mmol) were added and
after 50 minutes of irradiation, the product mixture was chromatographed and 5 mg of the desired
1
product was isolated with a elution of hex:EtAcO 8:2. A rotamer mixture H RMN spectra was
found. Yield: 39%.
1
5

ACCEPTED MANUSCRIPT
1
NMR H δ (ppm) (400 MHz, CDCl ): Rotamer A: 0.76-0.82 (3H, m, CH CH N), 1.76 (3H, s,
3
3
2
CH CO), 3.10-3.18 (1H, AB, J =6.8 Hz, CH CH H N), 3.30-3.34 (2H, m, PhCHCH Ph), 3.49-
3
AB
3
A
B
2
3
.54 (1H, AB, J =6.7 Hz, CH CH H N), 5.10-5.14 (1H, m, PhCH), 7.2-7.4 (10H, m, ArH).
AB 3 A B
Rotamer B: 0.75-0.81 (3H, m, CH CH N), 1.9 (3H, s, CH CO), 3.17-3.23 (2H, m, CH CH N), 3.35-
3
2
3
3
2
3
.37 (2H, d, J=7.9 Hz PhCHCH Ph), 6.1-6.14 (1H, t, J=7.9 Hz, PhCHCH Ph), 7.2-7.4 (10H, m,
2
2
1
3
ArH) NMR C δ (ppm) (50 MHz, CDCl ): Rotamer A: 13.7 (CH , CH CH N), 22.6 (CH , CH CO),
3
3
3
2
3
3
3
6.7 (CH , CH CH N), 37.3 (CH , PhCHCH Ph), 57.2 (CH, NCHPh), 126.3-129.2 (CH, Ar), 138.3
2 3 2 2 2
(
Cx2, C ), 170.7 (C, CO). Rotamer B: 13.7 (CH3, CH CH N), 22.6 (CH , CH CO), 37.2 (CH ,
ipso 3 2 3 3 2
CH CH N), 39.8 (CH , PhCHCH Ph), 63.2 (CH, NCHPh), 126.3-129.2 (CH, Ar), 139.9 (Cx2, C ),
3
2
2
2
ipso
+
1
70.7 (C, CO). H.R.M.S., FAB, calcd for C H ON [M+H] : 268.1696, found: 268.1704.
18 22
(R)-5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-phenylpentyl acetate (36)
Barton decarboxylation procedure was followed and 14 mg of 33 (0.04 mmol), 11 mg of
triphenylphosphine (0.04 mmol) and 10 mg of 2,2’-dithiodipyridine-1,1’-di-N-oxide (0.04 mmol)
were added and the reaction was carried out for 3 hours. Then, 0.012 mL of tert-butylthiol were
added and the reaction was irradiated for 1 hour. The desired product was isolated after a
chromatography by eluting with hex:EtAcO 9:1 and 8 mg were obtained. Yield 52%.
2
6
13
[
α]D = +18.8 (c 0.58, CHCl ). NMR C δ (ppm) (50 MHz, CDCl ): 22.8 (CH , OCOCH ), 21.2
3 3 3 3
(
CH , C-3), 28.5 (CH , C-2), 36.3 (CH , C-4)47.5 (CH, Fmoc), 55.5 (CH, C-5), 64.3 (CH , C-1),
2 2 2 2
6
6.7 (CH , CH Fmoc), 120.2-129.0 (CHx13, Ar), 139.8 (C, Cipso), 141.5 (Cx2, CipsoFmoc), 144.1 (Cx2,
2 2
-1
CipsoFmoc), 156.0 (C, NHCO), 171.4 (C, OCOCH ). IR ν (cm ): 3336, 3063, 3031, 2948, 2862,
3
max
1734, 1533, 1450, 1367, 1243, 1089, 1030, 759, 741.
(R)-6-phenylpiperidin-2-one (37)
General Barton procedure was carried out with 29 mg of 7 (0.13 mmol), 41 mg of
triphenylphosphine (0.16 mmol) and 39 mg of 2,2’-dithiodipyridine-1,1’-di-N-oxide (0.15 mmol).
After 90 minutes 0.044 mL of tert-butylthiol were added and the solution was irradiated for 1 hour.
After chromatographed, 18 mg of 37 were obtained while eluting with hex:EtAcO 1:1. Yield: 79%.
2
6
1
[
α]D = +34.2 (c 0.68, CHCl ). NMR H δ (ppm) (400 MHz, CDCl ): 1.68 (1H, m), 1.80 (1H, m),
3
3
1.90 (1H, m), 2.11 (1H, m), 2.43-2.54 (2H, m, H-5), 4.55 (1H, m, H-6), 5.97 (1H, s, NH), 7.25-7.37
1
3
(
5H, m, ArH). NMR C δ (ppm) (50 MHz, CDCl ): 19.9 (CH , C-4), 31.5 (CH , C-5), 32.3 (CH ,
3 2 2 2
-1
C-3), 58.0 (CH, C-6), 126.3-129.1 (CHx5, Ar), 142.7 (C, C ), 172.7 (C, C-2). IR ν (cm ): 3228,
ipso
max
1
6

ACCEPTED MANUSCRIPT
+
2
926, 2854, 1654, 1457, 1406, 1340, 1302, 700. H.R.M.S., FAB, calcd for C H ON [M+H] :
11 14
176.1075, found: 176.1058.
(R)-6-(pyridin-3-yl)piperidin-2-one
Following the general Barton decarboxylation procedure, the reaction was carried out with 40 mg of
(0.18 mmol), 57 mg of triphenylphosphine (0.22 mmol) and 54 mg of 2,2’-dithiodipyridine-1,1’-
8
di-N-oxide (0.22 mmol). After 22 hours, 0.06 mL of tert-butylthiol (0.54 mmol) were added and the
mixture was irradiated with two 220 W lights for 90 minutes. The solvent was removed and, after the
mixture was chromatographed, no desired product was isolated.
Acknowledgments
The authors are grateful for financial support from MINECO CTQ2015-68175-R, FEDER Junta de
Castilla y León (UIC21) and Junta de Castilla y León, (SA162A12-1). The authors also thank Dr. A.
M. Lithgow for work on the NMR spectra and Dr. César Raposo for the Mass spectra and X-ray
diffraction service of the NUCLEUS platform of the University of Salamanca. C.T.N. thanks Junta
de Castilla y León for a FPI predoctoral fellowship.
Supplementary Material
Supplementary material that may be helpful in the review.
References and notes
1
2
2
. D. H. R. Barton, J. M. Beaton, L. E. Geller, and M. M. Pechet, J. Am. Chem. Soc. 1960, 82, 2640-
641.
. a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
b) McCombie, S. W.; Motherwell, W. B.; Tozer, M. Org. React. 2011, 77, 161.
. a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939-941.
3
b) Barton, D. H. R.; Crich, D.; Motherwell, W. B., Tetrahedron Lett., 1983, 24, 4979.
c) Barton, D. H. R.; Crich, D.; Motherwell, W. B., Tetrahedron Lett., 1985, 41, 3901.
d) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901-3924.
4. a) Barton, D. H. R.; Bridon, D.; Zard, S. Z.; Fernandaz-Picot, I., Tetrahedron. 1987, 43, 2733.
b) Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675-684.
5
. a) Urones, J. G.; Garrido, N. M.; Dıez, D.; Dominguez, S. H.; Davies, S. G. Tetrahedron: Asymmetry 1999,
́
10, 1637-1641.
1
7

ACCEPTED MANUSCRIPT
b) Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price, P. D.; Smith, A. D. Org.
Biomol. Chem. 2005, 3, 1284-1301.
c) Garrido, N. M.; Díez, D.; Domínguez, S.H.; García, M.; Sánchez, M.R.; Davies, S.G.; Tetrahedron:
Asymmetry 2006, 17, 2183-2186.
d) Garrido, N. M.; Rubia, A. G.; Nieto, C.; Díez, D. Synlett 2010, 2010, 587-590.
e) Nieto, C. T.; Gonzalez-Nunez, V.; Rodríguez, R. E.; Diez, D.; Garrido, N. M. European Journal of
Medicinal Chemistry 2015, 101, 150-162.
6
1
7
2
. Daly, J.W.; Takuma, T.; Habermahl, G.; Karle, I.L.; Witkop, B. Liebigs Ann. Chem. 1969, 729,
98.
. a) Garrido, N.M.; García, M.; Díez, D.; Sánchez, M.R.; Sanz, F.; Urones, J. G. Organic Letters
008, 10, 1687-1690.
b) Garrido, N. M.; García, M.; Sánchez, M. R.; Díez, D.; Urones, J. G. Synlett 2010, 3, 387-390.
c) Garrido, N. M.; García, M.; Sánchez, M. R.; Díez, D.; Sanz F.; Urones, J. G. Tetrahedron:
Asymmetry 2011, 22, 872-880.
8. a) Mann, J.; Davidson, R. S.; Hobbs, J. B.; Banthorpe, D. V.; Harborne, J. B. “Natural Products:
Their Chemistry and Biological significance” Longman, U. K. 1996.
b) Leete, E.; Mueller, M. E. J. Am. Chem. Soc. 1982, 104, 6440-6444.
c) Kumar, S. P.; Nagaiah, K.; Chorghade, M. S. Tetrahedron Lett. 2006, 47, 7149-7151.
9
1
4
1
. Bentley, K. W, Natural product reports, 2006, 23, 444-463.
0. Sulzer, D., Sonders, M. S., Poulsen, N. W., & Galli, A, Progress in neurobiology, 2005, 75, 406-
33.
1. a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833-2891;
b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2012, 23,
111-1153.
c) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2017, 28,
1
1
1
842-1868.
2. a) Motherwell, W. B.; Crich, D. “Free Radical Chain Reactions in Organic Synthesis” Best
Synthetic Methods, AP. 1992.
b) Jarvis, B. B.; Yount, J. B. J. Org. Chem. 1970, 35, 2081.
c) Tada, M.; Akinaga, S.; Okabe, M. Bull. Chem. Soc. Jpn. 1982, 55, 3939-3940.
13. Gawronska, K. Gawronski, J. Walborsky, H. M. J. Org. Chem. 1991, 56, 6, 2193-2197.
14. Buckmelter, A. J. Kim, A. I. Rychnovsky, S. D. J. Am. Chem. Soc. 2000, 122, 9386-9390.
15. Newcomb, M. Park, S. U. J. Am. Chem. Soc. 1986, 108, 4132-4134.
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