Evidence of single electron transfer from the enolate anion of an: N, N ′-dialkyldiketopiperazine additive in BHAS coupling reactions

Article abstract of DOI:10.1039/c7ob02209c

A designed N,N′-dialkyldiketopiperazine (DKP) provides evidence for the role of DKP additives as initiators that act by electron transfer in base-induced homolytic aromatic substitution reactions, involving coupling of haloarenes to arenes.

Full text of DOI:10.1039/c7ob02209c

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COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Evidence of single electron transfer from the enolate anion of an
N,N’-dialkyldiketopiperazine additive in BHAS coupling reactions
a
a
a
Katie J. Emery, Tell Tuttle* and John A. Murphy*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Abstract. A designed N,N’-dialkyldiketopiperazine (DKP) provides evidence for the role of DKP additives as initiators that
act by electron transfer in base-induced homolytic aromatic substitution reactions, involving coupling of haloarenes to
arenes.
www.rsc.org/
A)
I
Introduction
1
2
−
I
There has been an explosion of interest in transition metal-
free reactions, used to achieve aryl-aryl bond formations
+ e
e
6
3
1
-15
between a haloarene and an arene.
believed to follow the base-promoted homolytic aromatic
The mechanism is
−
1
6
K
substitution pathway (BHAS) (Scheme 1A). The initiation step
involves a single electron transfer (SET) to the haloarene to
t
HO Bu
t
H
KO Bu
form the aryl radical
of arene, e.g. benzene 3, to form the inter-ring bond in
Radical undergoes a deprotonation to yield radical anion
which is electron-rich and donates an electron to the starting
material to form the product and propagate the radical
2, and this aryl radical attacks a molecule
5
4
4.
4
5,
B)
Pr
N
Pr
N
Pr
O
O
N
O
1
6
t
O Bu
− e
(to 1)
chain. Although it is accepted that the initiation step is a SET
process, the species responsible for this initial electron
donation to 1 has been debated. Recent findings point to the
O
N
Pr
7
HOBu
t
O
N
Pr
8
O
N
Pr
9
formation of an organic electron donor that is created by the
t
17-19
reaction between KO Bu and an organic additive.
the most successful additives is the N,N’-dipropyldiketo-
piperazine (DKP) additive , which was very effective in
promoting C-C bond formation both in transition metal-free
One of
The HOMO of 8:
Electron density resides
on the C=C double-bond
The spin density of 9:
The spin density of the radical 9
principally resides on the α−carbon
7
1
8,20,21
aryl-aryl couplings and in SRN1 reactions.
proposed that the DKP additive , in the presence of KO Bu,
forms an electron-rich enolate anion , which donates an
electron to the haloarene in the initiation step of the BHAS
reaction pathway and, in doing so, forms the captodatively
It has been
t
7
8
1
1
8
stabilised radical
to look for evidence that the enolate anion of DKP
an electron to the haloarene, such as , to form the
, under the transition metal-free reaction
9
(Scheme 1B). The aim of this project was
8
donates
1
captodative radical
conditions.
The first step in achieving this goal was to design and prepare
9
Scheme 1A) The base-promoted homolytic aromatic substitution
16
mechanism. B) The proposed electron donor 8 formed in situ from DKP 7.
an analogue of the DKP additive, 7, that is capable of trapping
a captodatively stabilised radical like
reporting that SET can take place from DKP additives under the
conditions of the coupling reactions. Radicals analogous to
9, and therefore
9
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A)
1. KHMDS
tBu
O
tBu
2.
O
O
Pr
O
Pr
N
OH
SPh
O
N
O
Pr
N
1) PBr , 0 0CꢀRT,
Pr
N
3
Br
10
78 0CꢀRT,
overnight, THF
K2CO3
O
O
1.25 h, Et2O
N
O
0 0CꢀRT,
2) PhSH, NaH
0 0CꢀRT,
−
N
O
Pr
Pr
N
O
N
O
5 h, MeOH
Pr
Pr
overnight, THF
7
11 53%
12 73%
13 88%
B)
SPh
O
H atom
abstraction
PrN
N
O
Pr
2
5
SPh
O
SPh
SPh
SPh
Pr
Pr
N
Pr
N
t
O
N
O Bu
O
− e
O
− SPh
O
PrN
PrN
t
HO Bu
N
SPh
N
N
O
N
O
N
O
O
Pr
O
Pr
18
Pr
Pr
Pr
13
14
15
16
17
Pr
N
Pr
N
Pr
SPh
O
SPh
O
SPh
O
N
SPh
SPh
PhS SPh
t
t
HO Bu
O Bu
18
24
N
O
N
O
N
O
23
Pr
2
Pr
27
Pr
8
26
SPh
SPh
Pr
Pr
N
Pr
N
Pr
N
O
N
SPh − SPh
O
O
O
−e
SPh
18
N
O
N
Pr
20
O
N
O
N
O
Pr
Pr
Pr
21
19
22
Scheme 2.A) Synthesis of the additive 13 from 7. B) The mechanism of cyclisation of 15 and 20, both of which arise through SET from an enolate anion of
DKP additive 13.
can be trapped intramolecularly by an appropriate tether on and conversion of the resulting alcohol (73%) into the bromide
2
3-25
the DKP scaffold.
For example, Jahn et al. synthesised was followed by displacement by the thiolate to yield 13 (88%
diketopiperazines that contained alkene “tethers” attached to over two steps).
the DKP scaffold. They prepared TEMPO-derivatives as The initial investigations were to determine whether its
precursors to radicals analogous to
derivatives liberated the radicals which successfully cyclised capable of donating an electron, and, if so, what products
onto the alkene within the tether to form bridged would be observed from the radicals formed, 15 and 20
9. Homolysis of these derived enolate anions, 14 and/or 19, (Scheme 2B) were
,
diketopiperazine products. Based on this information, allylic through cyclisation onto the cis-alkene within the tether,
sulfide 13 was identified as our candidate probe. Its synthesis under the conditions of the BHAS coupling reaction. The
is shown in Scheme 2A. Deprotonation of
7 and allylation with cyclised radicals could progress as shown in Scheme 2B;
bromide 10 afforded 11 (53%). Hydrolysis of the pivalate ester
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Looking firstly at radical 20, the equilibria between On the other hand, cyclisation of 15 affords radical 16, for
cyclopropylcarbinyl radical 21 and captodative radicals 20 and which three types of termination could occur: (i) loss of
is likely to lie heavily in favour of the captodative radicals, phenylthiyl radical 18 would afford alkene 17; (ii) hydrogen
notably the more stable (E)-isomer 27] due not only to their atom abstraction, likely from another molecule of 13, would
27
[
stabilisation, but also to the added strain present in the convert 16 to 25; (iii) reversal of the ring-closure would afford
cyclopropane in 21. This means that radical 21 is unlikely to 15 or, more likely, its (E)-isomer 28. Detection of the (E)-
proceed to vinylcyclopropane 22. The most likely outcome is isomer of 13 at the end of the reaction could therefore
that radical 27 is converted to closed-shell diketopiperazine 26 support a pathway involving reversible radical cyclisation.
by hydrogen atom abstraction (e.g. from another molecule of Radical cyclisation to give bridged products is possible, but we
1
3
).
were curious to compare the energy landscape for anionic
cyclisation from the enolate with the radical pathway, and so
computational analysis of the two possibilities was performed
(Scheme 3). In silico, the anionic cyclisation of enolate 14
formed 17 in a concerted mechanism. However, the cyclisation
via the radical pathway shows that the intermediate 16 is the
most stable species in the reaction pathway. The equilibrium
for the thiyl radical elimination from 16 was computationally
Ionic cyclisation
SPh
SPh
O
+
SPh
O
PrN
Pr
O
PrN
N
N
N
O
Pr
N
O
Pr
O
Pr
modelled and the C-S fragmentation to form 17 and 18 was
ǂ
G = 6.6 kcal/mol and
14
29
17
30
calculated to be endergonic:
ꢀ
1.9 kcal/mol. This agrees with previously reported equilibria
ꢀ
G
rxn
=
Radical cyclisation
SPh
2
5
SPh
for elimination of thiyl radicals in the formation of alkenes.
O
+
From 16, hydrogen atom abstraction leads to 25, so 25 is a
PrN
SPh
O
N
PrN
signature product from a radical cyclisation process.
O
Pr
N
O
Pr
Pr
O
SPh
N
16
17
18
Table 1. The synthesis of allylic thioether 34 and its reactions with
t
KO Bu, in the presence of various additives
N
O
Pr
H atom
abstraction
O
15
PrN
N
O
Pr
25
Ionic cyclisation
20
29
10
18.4
t
a.
0
Entry
Additive (eq.)
--
KO Bu (eq.)
24 (%)
14
b.
1
2
1
2
0
-
10
20
b.
-30.7
DKP 7 (1)
6
35 (1)
-
b.
3
(pinacolone)
2
4
-30
17 + 30
Reaction coordinate
a.
b.
Isolated yield. Yield calculated using 1,3,5-trimethoxybenzene as the
1
internal standard in H-NMR of the crude mixture. (spectra were
compared with an authentic and pure samples).
Radical cyclisation
We were also keen to probe anionic chemistry experimentally
to investigate the effect of basic conditions on an allylic
thioether. The substrate 34, which is analogous to the tether
on the additive 12, was synthesised and reacted under the
different reaction conditions to determine (i) whether diphenyl
disulfide is formed (in the absence of radical conditions, it was
expected not to form) and (ii) to check whether isomerisation
of the (Z)-alkene occurred under the basic conditions (Table 1).
9
.9
15
-5.9
17 + 18
.9
6.6
1
16
Reaction coordinate
Scheme 3. Ionic (black line) vs. radical cyclisation (blue line) and
cleavage of the C-S bond, in benzene as solvent
t
When the substrate 34 was reacted in the presence of KO Bu,
.
no diphenyl disulfide 24 was observed in the crude reaction
mixture (Table 1, entry 1; note that no 34 was recovered).
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However, when either the DKP additive
7
(Table 1, entry 2) or
t
pinacolone 35, Bu(C=O)Me (Table 1, entry 3) was used in the
t
presence of KO Bu, diphenyl disulfide 24 was formed (6% and
4% respectively). In these cases, both DKP 7 and pinacolone 35
are transformed into their respective enolate anions under the
basic conditions of the reaction; and pinacolone enolate has
previously been shown to act as an electron donor to
2
6,27
haloarenes to initiate SRN1 reactions in DMSO.
The additive 13 was now applied to the transition metal-free
reaction conditions used in the coupling of iodoarenes to
benzene. The iodo-m-xylene 36 substrate was used to assess
whether an electron donor is formed from the DKP additive,
because in the transition metal-free coupling reactions the
substrate 36 is activated towards coupling exclusively through
1
8
a SET initiation step (Table 2).
Table 2. Aryl-aryl bond formation between iodo-m-xylene 36
and benzene using various additives.
Entry Additive
36
37
38
6
24
25
(
eq.)
--
(%)
(%)
(%)
(%)
(%)
(%)
a.
98
1
2
3
--
--
--
--
--
a.
a.
a.
a.
7 (0.2)
16
6
3
26
--
--
a
a.
a.
10
a.
a,b
28
a,b
53
4
13
20
13 (0.2)
c
c
(
27)
(14)
a
Yield calculated using 1,3,5-trimethoxybenzene as the internal standard in
1
b
H-NMR of the crude mixture. Yield calculated using the DKP additive 13 as
c
the limiting reagent. Isolated yield.
Scheme 4. A modification of the BHAS pathway for the reaction of substrate
iodo-m-xylene 36.
Three reactions were performed, under inert atmosphere, to
determine how efficiently the additive 13 can promote the coupling
between the iodo-m-xylene 36 and benzene: (i) The first reaction
1
8
t
exposed iodo-m-xylene 36 to KO Bu in the absence of any organic
o
To couple iodo-m-xylene 36 with benzene through the BHAS
reaction pathway, an additive, either 7 or 13, is required in the
additive (Table 2, entry 1) and after 18 h at 130 C, 98% of the
starting material 36 remained unreacted. (ii) Next, the iodo-m-
t
t
reaction because the reaction of 36 with KO Bu and no additive
xylene 36 was treated with KO Bu and sub-stoichiometric amounts
returned only starting material (Table 2, entry 1). Iodo-m-xylene –
of additive 7 under the same reaction conditions. This reaction gave
much higher conversion of the iodo-m-xylene 36 (only 16%
remained unreacted), and the rest of the products formed were 37
t
3
6 in the presence of KO Bu and either 7 or 13 (Table 2, entries 2–3)
formed products 37, 38 and 6, which are known products for the
reaction of iodo-m-xylene 36 via the BHAS pathway, thus providing
evidence that the additive 13 is capable of promoting the transition
(
6%), volatile m-xylene 38 (3%) and biphenyl 6 (26%) (Table 2, entry
). The ratio of yields of 37 to 6 (approximately 1: 4) was
characteristic of previous BHAS experiments performed in these
2
1
8
metal-free aryl-aryl bond formation, similarly to DKP 7. SET to 36
(Scheme 4) leads to cleavage of the C-I bond with the formation of
the aryl radical 39 and loss of an iodide anion. The aryl radical 39
can react in two ways: (i) it attacks a molecule of benzene to
ultimately form product 37 through the BHAS pathway. (ii) The aryl
radical 39 abstracts a hydrogen atom from a molecule of benzene
to form xylene 38 and the aryl radical 2. The aryl radical 2 will
1
7-19,28
transition metal-free reaction conditions.
(iii) The final
t
reaction was to expose 36 to KO Bu and sub-stoichiometric
amounts of additive 13 (Table 2, entry 3) whereupon the
compounds obtained were: unreacted starting material 36 (53%),
37 (4%), 38 (10%), 6 (13%), 24 (28%) and 25 (20%).
4
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undergo the BHAS mechanism and ultimately leads to radical anion The electron transfer reactions were carried out within a glove
. Finally, this converts to biphenyl product 6 through transfer of an box (Innovative Technology Inc., U.S.A.) under nitrogen
5
electron to substrate 36, which propagates the chain reaction.The atmosphere, and performed in oven-dried or flame-dried
formation of the product 25 supports the formation of the apparatus using anhydrous solvents, which were either
captodatively stabilised radical 15 in the reaction conditions. The degassed under reduced pressure, then purged with argon and
formation of the radical 15 (or 9) occurs through a SET from the dried over activated molecular sieves (3 Å), prior to being
enolate anion of the additive 14 (or 8), which provides evidence sealed and transferred to the glovebox. All solvents or samples
that the enolate anion donates a single electron to iodo-m-xylene introduced into the glovebox were transferred through the
36 to initiate the transition metal-free aryl-aryl bond formation. port, which was evacuated and purged with nitrogen ten times
Comparison of the reactions performed using the two possible before entry. When the reaction mixtures were prepared, the
additives, 7 and 13, suggests they both react through similar reaction vessel was removed from the glovebox and the rest of
reaction pathways. This is supported with the computational the reaction was performed in a fumehood.
1
analysis; SET from the enolate anion 8 (Scheme 4) to iodo-m-xylene Proton ( H) NMR spectra were recorded at 400.13, 400.03 and
ǂ
3
6 is possible under the reaction conditions, ꢀG = 23.0 kcal/mol 500.16 MHz on Bruker AV3, AV400 and AV500 spectrometers,
1
3
and ꢀGrxn = 10.3 kcal/mol, and SET from the enolate anion 14 to respectively. Carbon ( C) NMR spectra were recorded using
iodo-m-xylene 36 has the energy profile, ꢀG = 25.0 kcal/mol and broadband decoupled mode at 100.61, 100.59 and 125.75
ǂ
ꢀGrxn = 13.3 kcal/mol. Both these energy profiles for SET are MHz on Bruker AV3, AV400 and AV500 spectrometers,
accessible at 130 C, however the enolate anion of the DKP additive respectively. Spectra were recorded in either deuterated
o
8
has a more favourable overall energy profile for SET, which chloroform (CDCl ) or deuterated dimethyl sulfoxide (d -
6
3
suggests that the conversion of 36 into products would be more DMSO), depending on the solubility of the compounds. The
efficient using the DKP additive 7 rather than additive 13, which was chemical shifts are reported in parts per million (ppm)
borne out experimentally. These reactions simply provide initiation calibrated on the residual non-deuterated solvent signal, and
for the BHAS radical chain reaction, and it is likely that not many the coupling constants, J, are reported in Hertz (Hz). The peak
chains are needed to convert substrates to product.
multiplicities are denoted using the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; sx, sextet; m,
multiplet; br s, broad singlet; dd, doublet of doublets; dd,
doublet of triplets; td, triplet of doublets.
Conclusions
Infra-Red spectra were recorded on an ATR-IR spectrometer.
Melting points were determined on a Gallenkamp Melting
point apparatus. The mass spectra were recorded by either
gas-phase chromatography (GCMS) or liquid-phase
chromatography (LCMS), using various ionisation techniques,
as stated for each compound: atmospheric pressure chemical
ionisation (APCI), electron ionisation (EI), electrospray
ionisation (ESI). GCMS data were recorded using an Agilent
Technologies 7890A GC system coupled to a 5975C inert XL
EI/CI MSD detector. Separation was performed using the
DB5MS-UI column (30 m x 0.25 mm x 0.25 μm) at a
This study has provided evidence that the additive 13 behaves
analogously to 7, and that the enolate anion of additive 13
donates an electron to haloarenes under these transition
metal-free reaction conditions. Therefore, the role of the
additive
to form the enolate anion in situ and this enolate anion
electron donor species that initiates the BHAS mechanism
Scheme 4). This supports the growing body of evidence
7
in these transition metal-free reaction conditions, is
8
is the
(
relating to the role of organic electron donors in these
reactions.
o
temperature of 320 C, using helium as the carrier gas. LCMS
Experimental
data were recorded using an Agilent 6130 Dual source mass
spectrometer with Agilent 1200, Agilent Poroshell 120 EC-
C18 4.6mm x 75mm x 2.7μm column. High-resolution mass
spectrometry (HRMS) was performed at the University of
General experimental information.
All reagents were bought from commercial suppliers and used Wales, Swansea, in the EPSRC National Mass Spectrometry
without further purification unless stated otherwise. All the Centre. Accurate mass was obtained using atmospheric
reactions were carried out under argon atmosphere. Diethyl pressure chemical ionisation (APCI), chemical ionisation (CI),
ether, tetrahydrofuran, dichloromethane and hexane were electron ionisation (EI), electrospray ionisation (ESI) or
dried with a Pure-Solv 400 solvent purification system by nanospray ionisation (NSI) with a LTQ Orbitrap XL mass
Innovative Technology Inc., U.S.A. Organic extracts were, in spectrometer.
2 4
general, dried over anhydrous sodium sulphate (Na SO ). A
Büchi rotary evaporator was used to concentrate the reaction Synthesis of 1,4-dipropylpiperazine-2,5-dione 7. Anhydrous
2
7
mixtures. Thin layer chromatography (TLC) was performed dichloromethane (30 mL) was added to a round-bottomed
o
using aluminium-backed sheets of silica gel and visualised flask. Under an argon atmosphere, at 0 C, chloroacetyl
under a UV lamp (254 nm). The plates were developed using chloride (4 mL, 50 mmol) and n-propylamine (8.6 mL, 105
phosphomolybdic acid or KMnO4 solution. Column mmol, 2.1 eq.) were simultaneously added dropwise. The
o
chromatography was performed to purify compounds by using reaction mixture was stirred at 0 C for 15 min and then
diluted with diethyl ether (200 mL) and a solid precipitated.
silica gel 60 (200-400 mesh).
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o
The reaction mixture was filtered, and the solid was washed bottomed flask. Under an argon atmosphere, at 0 C, PBr
3
(0. 7
with diethyl ether. The filtered solution was concentrated in mL, 7.1 mmol, 0.4 eq.) was added slowly and the reaction
o
vacuo and diluted with diethyl ether (200 mL) and filtered a mixture was stirred at 0 C for 45 min, then at RT overnight.
second time. The filtered solution was concentrated in vacuo The reaction mixture was quenched with water (20 mL) and
2
to give 2-chloro-N-propylacetamide (6.72 g, 99%) as a pale extracted with diethyl ether (3 x 20 mL). The organic phases
8
+
11ClNO (M+H)
+
yellow oil [Found: (HRMS-ESI) 136.0521. C
5
H
2 4
were combined, dried over Na SO , filtered and concentrated
-1
requires 136.0524]; νmax(film) / cm 3292, 3084, 2965, 2936, in vacuo to give cis-4-bromobut-2-en-1-yl pivalate 10 (4.01 g,
1
876, 1651, 1539, 1460, 1439, 1258, 1240, 1155; H-NMR (500 96%) as a colourless oil [Found: (HRMS-APCI) 235.0330.
2
7
9
+
+
-1
MHz, CDCl
3
) δ 0.91 (3 H, t, J = 7.2 Hz, CH
3
), 1.50 (2 H, sx, J = 7.2
9 2
C H16 BrO (M+H) requires 235.0328]; νmax(film) / cm 2972,
1
Hz, CH
2
), 3.18 – 3.23 (2 H, m, CH
2
), 4.01 (2 H, s, CH
2
), 6.67 (1 H, 1724, 1479, 1396, 1279, 1140, 1032, 966, 939, 769, 725; H-
), 22.7 (CH ), NMR (400 MHz, CDCl ) δ 1.21 (9 H, s, 3 x CH ), 4.03 (2 H, d, J =
), 165.9 (C). 2-Chloro-N-propylacetamide 8.4 Hz, CH ), 4.68 (2 H, d, J = 6.8 Hz, CH ), 5.68 (1 H, dt, J =
6.78 g, 50 mmol) and anhydrous tetrahydrofuran (30 mL) 10.8, 6.8 Hz, cis-CH), 5.93 (1 H, dt, J = 10.8, 8.4 Hz, cis-CH); C-
1
3
br s, NH); C-NMR (100 MHz, CDCl
1.6 (CH ), 42.8 (CH
3
) δ 11.4 (CH
3
2
3
3
4
2
2
2
2
1
3
(
o
were added to a flame-dried round-bottomed flask. At 0 C, a NMR (125 MHz, CDCl
3 2 3
) δ 26.0 (CH ), 27.3 (3 x CH ), 38.9 (C),
suspension of sodium hydride (60% in mineral oil, 2.2 g, 55 59.3 (CH ), 128.6 (CH), 129.8 (CH), 178.4 (C); m/z (APCI)
2
+
81
+ 79
mmol, 1.1 eq.) in anhydrous tetrahydrofuran (20 mL) was 237.0310 [(M+H) , Br, 98%], 235.0330 [(M+H) , Br, 100].
added dropwise via cannula and the reaction mixture was
stirred at RT for 3.5 h. The reaction mixture was quenched by Synthesis of cis-4-(3,6-dioxo-1,4-dipropylpiperazin-2-yl)but-2-
dropwise addition of water and diluted with diethyl ether (150 en-1-yl pivalate 11. 1,4-Dipropylpiperazine-2,5-dione
mL). The organic phase was dried over Na SO , filtered and 13.0 mmol) and anhydrous tetrahydrofuran (110 mL) were
concentrated in vacuo. The crude material was purified by added to a flame-dried round-bottomed flask. Under an argon
7 (2.57 g,
2
4
o
column chromatography (0 - 100% ethyl acetate in hexane) to atmosphere, at
2
−
7 (2.66 g, 54%) as pale mmol, 1.1 eq.) in anhydrous tetrahydrofuran (40 mL) was
10 C, a solution of KHMDS (2.91 g, 14.5
9
give 1,4-dipropylpiperazine-2,5-dione
o
29
o
o
yellow crystals m.p. 54 – 59 C (lit: 40 – 42 C); [Found: added slowly and the reaction mixture was stirred at
−
10 C
78 C, cis-4-bromobut-2-
max(film) / cm 2964, 2932, 2872, 1647, 1483, 1335, 1308, en-1-yl pivalate 10 (3.67 g, 15.6 mmol, 1.2 eq.) was added
+
+
o
(
19 2 2
HRMS-ESI) 199.1438. C10H N O (M+H) requires 199.1438]; for 20 min, then at RT for 15 min. At −
-
1
ν
1
o
1
277, 1204, 1055; H-NMR (500 MHz, CDCl
), 1.59 (4 H, sx, J = 7.5 Hz, 2 x CH
2
3
) δ 0.92 – 0.95 (6 H, slowly and the reaction mixture was stirred at
), 3.37 (4 H, m, 2 x min, then at RT overnight. The reaction mixture was quenched
); C-NMR (125 MHz, CDCl ) δ 11.2 (2 x with saturated aqueous ammonium chloride solution (a few
), 47.7 (2 x CH ), 50.0 (2 x CH
−78 C for 30
m, 2 x CH
3
1
3
CH
2
), 3.96 (4 H, s, CH
), 20.0 (2 x CH
2
3
CH
3
2
2
2
), 163.6 (2 x C). drops) and the crude mixture was concentrated in vacuo. The
crude mixture was diluted with saturated aqueous ammonium
chloride solution (50 mL) and extracted with ethyl acetate (3 x
Synthesis of cis-4-bromobut-2-en-1-yl pivalate 10. Sodium
hydride (60% in mineral oil, 1.1 g, 27.4 mmol, 1.0 eq.) and
anhydrous tetrahydrofuran (120 mL) were added to a flame-
dried round-bottomed flask. Under an argon atmosphere, at 0
6
0 mL). The organic phases were combined, washed with
brine, dried over Na SO , filtered and concentrated in vacuo.
2
4
The crude material was purified by column chromatography (0
o
- 20% ethyl acetate in hexane) to give cis-4-(3,6-dioxo-1,4-
C, cis-2-butene-1,4-diol (2.3 mL, 27.4 mmol) was added slowly
o
and the reaction mixture was stirred at 0 C for 10 min, then at
dipropylpiperazin-2-yl)but-2-en-1-yl pivalate 11 (2.40 g, 53%)
+
32 2 4
as a yellow oil [Found: (HRMS-ESI) 375.2252. C19H N O Na
RT for 45 min. Trimethylacetyl chloride (3.4 mL, 27.4 mmol, 1.0
eq.) was added dropwise via syringe pump over a period of 30
min and the reaction mixture was stirred at RT overnight and
then quenched with saturated aqueous ammonium chloride
solution (100 mL) and extracted with ethyl acetate (3 x 100
mL). The organic phases were combined, washed with brine,
+
M+Na) requires 375.2254]; νmax(film) / cm 2965, 2874, 1724,
-1
(
1
1
655, 1464, 1329, 1148, 1065, 1032, 953; H-NMR (400 MHz,
CDCl ); δ 0.91 (6 H, t, J = 7.6 Hz, 2 x CH ), 1.18 (9 H, s, 3 x CH ),
.50 – 1.67 (4 H, m, 2 x CH ), 2.65 (1 H, dt, J = 14.8, 7.2 Hz,
CH ), 2.77 – 2.84 (2 H, m, 2 x CH ), 3.15 – 3.22 (1 H, m, CH ),
.47 – 3.52 (1 H, m, CH ), 3.78 (1 H, d, J = 17.6 Hz, CH ), 3.89 –
.09 (3 H, m, 2 x CH and CH), 4.56 (2 H, d, J = 7.2 Hz, CH ), 5.58
3
3
3
1
2
2
2
2
3
4
2
2
dried over Na
crude material was purified by column chromatography (0 –
0% ethyl acetate in hexane) to give cis-4-hydroxybut-2-en-1-
2 4
SO , filtered and concentrated in vacuo. The
2
2
(
1 H, dt, J = 11.2, 7.6 Hz, cis-CH), 5.70 (1 H, dt, J = 11.2, 6.8 Hz,
1
cis-CH); C-NMR (125 MHz, CDCl ) δ 11.3 (CH ), 11.4 (CH ),
3 3 3
2
3
2
9
yl pivalate (4.70 g, 99%) as a pale yellow oil [Found: (HRMS-
+
+
(M+H) requires 173.1172]; νmax(film) /
2 2 3 2
20.1 (CH ), 20.6 (CH ), 27.3 (3 x CH ), 30.4 (CH ), 38.9 (C), 46.2
ESI) 173.1169. C
9
H
17
O
3
-1
2 2 2 2
(CH ), 48.0 (CH ), 50.0 (CH ), 59.8 (CH ), 60.1 (CH), 126.8 (CH),
cm 3412, 2972, 2872, 1726, 1479, 1280, 1146, 1030, 983,
1
129.3 (CH), 164.2 (C), 165.9 (C), 178.4 (C).
9
39, 858, 772; H-NMR (400 MHz, CDCl
CH ), 4.26 (2 H, d, J = 6.4 Hz, CH ), 4.67 (2 H, d, J = 7.2 Hz, CH
.61 (1 H, dt, J = 11.2, 7.2 Hz, cis-CH), 5.85 (1 H, dt, J = 11.2, 6.4
3
) δ 1.19 (9 H, s, 3 x
Synthesis of cis-3-(4-hydroxybut-2-en-1-yl)-1,4-dipropylpiper-
azine-2,5-dione 12. Cis-4-(3,6-dioxo-1,4-dipropylpiperazin-2-
yl)but-2-en-1-yl pivalate 11 (2.37 g, 6.7 mmol) and methanol
3
2
2
),
5
1
3
3 3
Hz, cis-CH); C-NMR (125 MHz, CDCl ) δ 27.3 (3 x CH ), 38.9
(
40 mL) were added to a round-bottomed flask. Under an
o
argon atmosphere, at 0 C, K
(
C), 58.6 (CH ), 60.2 (CH ), 126.0 (CH), 133.3 (CH), 178.9 (C).
2
2
2 3
CO (1.11 g, 8.0 mmol, 1.2 eq.)
Cis-4-hydroxybut-2-en-1-yl pivalate (3.05 g, 17.7 mmol) and
was added and the reaction mixture was stirred at RT for 3 h.
o
The reaction was incomplete by TLC analysis. At 0 C, K CO
2 3
anhydrous diethyl ether (10 mL) were added to a round-
6
| J. Name., 2012, 00, 1-3
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Orga Pn l iec a s&e Bd oi o nmo to al ed cj uu sl ta mr Ca rhg ei nms istry
View Article Online
DOI: 10.1039/C7OB02209C
ARTICLE
(463 mg, 3.35 mmol, 0.5 eq.) was added and the reaction concentrated in vacuo. The crude mixture was diluted with
mixture was stirred at RT for 2 h. The reaction mixture was water (30 mL) and extracted with ethyl acetate (4 x 30 mL).
quenched with water (a few drops) and the crude mixture was The organic phases were combined, washed with brine, dried
2 4
concentrated in vacuo. The crude mixture was diluted with over Na SO , filtered and concentrated in vacuo. The crude
water (40 mL) and extracted with dichloromethane (4 x 40 material was purified by column chromatography (0 - 50%
mL). The organic phases were combined, washed with brine, ethyl acetate in hexane) to give cis-3-(4-(phenylthio)but-2-en-
dried over Na
2 4
SO , filtered and concentrated in vacuo. The 1-yl)-1,4-dipropylpiperazine-2,5-dione 13 (1.12 g, 90%) as a
+
crude material was purified by column chromatography pale yellow oil [Found: (HRMS-NSI) 361.1945. C20
+
29 2 2
H N O S
-1
(0ꢀ100% ethyl acetate in hexane) to give cis-3-(4-hydroxybut- (M+H) requires 361.1944]; νmax(film) / cm 2963, 2932, 2872,
1
-en-1-yl)-1,4-dipropylpiperazine-2,5-dione 12 (1.33 g, 73%) as 2361, 1655, 1468, 1437, 1327, 1271, 1120, 1065, 893, 739; H-
2
+
a pale yellow oil [Found: (HRMS-ESI) 291.1676. C14
H
24
N
2
3
O Na
NMR (400 MHz, CDCl
), 2.42 (1 H, dt, J = 14.4, 8.0 Hz, CH
), 2.73 – 2.76 (1 H, m, CH ), 3.18 – 3.21 (1 H,
), 3.41 – 3.56 (3 H, m, 3 x CH ), 3.75 (1 H, d, J = 17.2 Hz,
), 3.86 – 3.89 (1 H, m, CH ), 3.95 (1 H, t, J = 4.8 Hz, CH), 4.02
), 3.78 (1 H, d, J = 17.2 Hz, CH ), 5.47 (1 H, dt, J = 10.8, 8.4 Hz, cis-CH),
), 4.01 – 4.10 5.72 (1 H, dt, J = 10.8, 8.0 Hz, cis-CH), 7.23 (1 H, t, J = 7.2 Hz,
and the CH), 5.46 (1 H, dt, J = 10.8, 7.6 Hz, cis- ArH), 7.26 – 7.30 (2 H, m, ArH), 7.35 (2 H, d, J = 7.2 Hz, ArH);
3
) δ 0.88 – 0.92 (6 H, m, 2 x CH
3
), 1.52 –
+
-1
(
M+Na) requires 291.1679]; νmax(film) / cm 3410, 2963, 2932, 1.60 (4 H, m, 2 x CH
2
2
), 2.59
1
2
874, 1643, 1468, 1331, 1200, 1032, 718; H-NMR (400 MHz, – 2.62 (1 H, m, CH
CDCl ) δ 0.89 (6 H, t, J = 7.6 Hz, 2 x CH ), 1.52 – 1.63 (4 H, m, 2 m, CH
x CH ), 2.54 – 2.75 (2 H, m, CH and OH), 2.75 – 2.84 (2 H, m, CH
CH ), 3.15 – 3.22 (1 H, m, CH ), 3.40 – 3.47 (1 H, m, CH
1 H, d, J = 17.6 Hz, CH ), 3.87 – 3.94 (1 H, m, CH
4 H, m, 3 x CH
2
2
3
3
2
2
2
2
2
2
2
2
2
2
(
(
2
2
2
1
3
13
CH), 5.81 (1 H, dt, J = 10.8, 6.8 Hz, cis-CH); C-NMR (125 MHz,
CDCl ) δ 11.3 (CH ), 11.3 (CH ), 20.0 (CH ), 20.5 (CH ), 29.9 20.6 (CH
CH ), 46.2 (CH ), 48.0 (CH ), 49.9 (CH ), 58.1 (CH ), 60.2 (CH), (CH ), 60.2 (CH), 125.3 (CH), 126.9 (CH), 129.1 (CH), 130.1 (CH),
24.2 (CH), 134.6 (CH), 164.4 (C), 166.2 (C). 130.9 (CH), 135.7 (C), 164.2 (C), 165.9 (C); HSQC H/ C δ (0.88
0.92)/11.3, (0.88–0.92)/11.4, (1.52–1.60)/20.1, (1.52–
C-NMR (125 MHz, CDCl
3
) δ 11.3 (CH
3
), 11.4 (CH
3
), 20.1 (CH
2
),
3
3
3
2
2
2
), 29.8 (CH ), 31.5 (CH
2
2
), 46.3 (CH
2
), 48.0 (CH
2
), 50.0
(
2
2
2
2
2
2
1
13
1
–
Synthesis of cis-3-(4-(phenylthio)but-2-en-1-yl)-1,4-dipropyl- 1.60)/20.6, 2.42/29.8, (2.59–2.62)/29.8, (2.73–2.76)/46.3,
piperazine-2,5-dione 13. Cis-3-(4-hydroxybut-2-en-1-yl)-1,4- (3.18–3.21)/48.0, (3.41–3.56)/31.5, (3.41–3.56)/31.5, (3.41–
dipropylpiperazine-2,5-dione 12 (1.13 g, 4.2 mmol) and 3.56)/48.0, 3.75/50.0, (3.86–3.89)/46.3, 3.95/60.2, 4.02/50.0,
anhydrous diethyl ether (2 mL) were added to a round- 5.47/125.3, 5.72/130.1, 7.23/126.9, (7.26–7.30)/129.1,
o
bottomed flask. Under an argon atmosphere, at 0 C, PBr
3
7.35/130.9.
(
0.16 mL, 1.7 mmol, 0.4 eq.) was added slowly and the
3
0
reaction mixture was stirred at RT for 1 h 15 min. The reaction Synthesis of cis-4-methoxybut-2-en-1-ol 32.
mixture was quenched with water (10 mL) and extracted with (60% in mineral oil, 1.0 g, 25 mmol, 1.0 eq.) and anhydrous
Sodium hydride
diethyl ether (4 x 10 mL). The organic phases were combined, tetrahydrofuran (20 mL) were added to a flame-dried round-
o
, filtered and concentrated in vacuo to give bottomed flask. Under an argon atmosphere, at 0 C, cis-2-
dried over Na
2
SO
4
cis-3-(4-bromobut-2-en-1-yl)-1,4-dipropylpiperazine-2,5-dione
butene-1,4-diol 30 (6.2 mL, 75 mmol, 3 eq.) was added slowly
o
1.20 g, 86%) as a pale yellow oil [Found: (HRMS-ESI) 331.1018. and the reaction mixture was stirred at 0 C for 15 min, then at
(
7
9
+
+
(M+H) requires 331.1016]; νmax(film) / cm
-1
C
14
H24 BrN
2
O
2
RT for 1 h. Methyl iodide (1.6 mL, 25 mmol, 1.0 eq.) was added
2
963, 2932, 2874, 1655, 1466, 1327, 1202, 1155, 1063, 893, dropwise and the reaction mixture was stirred at RT overnight
1
7
43; H-NMR (400 MHz, CDCl
), 1.54 – 1.66 (4 H, m, 2 x CH
Hz, CH ), 2.79 – 2.86 (2 H, m, 2 x CH
CH ), 3.41 – 3.49 (1 H, m, CH ), 3.80 (1 H, d, J = 17.2 Hz, CH
.85 – 3.98 (3 H, m, 3 x CH ), 4.02 – 4.08 (2 H, m, CH and CH), mL). The organic phases were combined, dried over Na
.55 (1 H, dt, J = 10.8, 7.6 Hz, cis-CH), 5.92 (1 H, dt, J = 10.8, 8.4 filtered and concentrated in vacuo. The crude material was
3
) δ 0.92 (6 H, t, J = 7.6 Hz, 2 x and then quenched with saturated aqueous ammonium
), 2.63 (1 H, dt, J = 14.4, 7.2 chloride solution (100 mL) and concentrated in vacuo. The
), 3.20 – 3.28 (1 H, m, crude mixture was diluted with saturated aqueous ammonium
), chloride solution (20 mL) extracted with ethyl acetate (4 x 20
SO
CH
3
2
2
2
2
2
2
3
5
2
2
2
4
,
1
3
Hz, cis-CH); C-NMR (125 MHz, CDCl
0.1 (CH ), 20.6 (CH ), 25.9 (CH ), 29.7 (CH
CH ), 50.0 (CH ), 60.0 (CH), 127.3 (CH), 130.5 (CH), 164.1 (C), as a yellow oil [Found: (GCMS-EI) C
65.7 (C); m/z (ESI) 333.0997 [(M+H) , Br, 98%], 331.1018
3
) δ 11.3 (CH
3
), 11.4 (CH
3
), purified by column chromatography (0–100% ethyl acetate in
3
0
2
2
2
2
2
), 46.3 (CH
2
), 48.1 hexane) to give cis-4-methoxybut-2-en-1-ol 32 (2.20 g, 86%)
−
(M-H)− 100.7];
(
2
2
5 9 2
H O
+
81
-1
1
νmax(film) / cm 3364, 2873, 2817, 1450, 1411, 1190, 1084,
+
79
1
[
(M+H) , Br, 100]. Sodium hydride (60% in mineral oil, 167 1024, 985, 948; H-NMR (400 MHz, CDCl
mg, 4.2 mmol, 1.2 eq.) and anhydrous tetrahydrofuran (40 mL) Hz, OH), 3.35 (3 H, s, CH ), 4.01 (2 H, d, J = 6.0 Hz, CH
were added to a flame-dried round-bottomed flask. Under an H, t, J = 6.0 Hz, CH ), 5.70 (1 H, dtt, J = 11.2, 6.4, 1.2 Hz, cis-CH),
3
) δ 1.90 (1 H, t, J = 6.0
3
2
), 4.21 (2
2
o
13
argon atmosphere, at 0 C, thiophenol (0.39 mL, 3.8 mmol, 1.1 5.83 (1 H, dtt, J = 11.2, 6.4, 1.2 Hz, cis-CH); C-NMR (100 MHz,
eq.) was added slowly and the reaction mixture was stirred at CDCl ) δ 58.3 (CH ), 59.0 (CH ), 68.3 (CH ), 128.5 (CH), 132.4
3
3
2
2
RT for 1 h. A solution of cis-3-(4-bromobut-2-en-1-yl)-1,4- (CH).
dipropylpiperazine-2,5-dione (1.15 g, 3.5 mmol) in anhydrous
tetrahydrofuran (40 mL) was added dropwise and the reaction Synthesis of cis-1-bromo-4-methoxybut-2-ene 33. Cis-4-
mixture was stirred at RT overnight. The reaction mixture was methoxybut-2-en-1-ol 32 (2.0 g, 19.6 mmol) and anhydrous
quenched with water (a few drops) and the crude mixture was diethyl ether (10 mL) were added to a round-bottomed flask.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 11
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DOI: 10.1039/C7OB02209C
ARTICLE
Journal Name
o
Under an argon atmosphere, at 0 C, PBr
.4 eq.) was added slowly and the reaction mixture was stirred could not be identified).
at RT overnight. The reaction mixture was quenched with Table 1, entry 2. Cis-(4-methoxybut-2-en-1-yl)(phenyl)sulfane
water (10 mL) and extracted with diethyl ether (4 x 10 mL). 34 (97 mg, 0.5 mmol) and 1,4-dipropylpiperazine-2,5-dione
The organic phases were combined, dried over Na SO , filtered (99 mg, 0.5 mmol, 1.0 eq.) were added to an oven-dried
and concentrated in vacuo to give cis-1-bromo-4-methoxybut- pressure tube. In the glove box, KO Bu (112 mg, 1.0 mmol, 2.0
3
(0.73 mL, 7.8 mmol, diphenyl disulfide. (Other products formed in the reaction, but
0
7
2
4
t
2
-ene 33 (2.77 g, 86%) as an orange oil [Found: (HRMS-APCI) eq.) and anhydrous benzene (5 mL) were added and the
o
−
−
-
1
5 8
62.9756. C H BrO (M-H) requires 162.9759]; νmax(film) / cm reaction mixture was stirred at 130 C for 3 h in the dark. The
1
1
2
923, 2814, 1450, 1207, 1099, 959, 911, 736; H-NMR (400 reaction mixture was cooled to RT, quenched with aqueous
) δ 3.36 (3 H, s, CH ), 4.01 (2 H, d, J = 8.4 Hz, CH ), hydrochloric acid (1 M, 10 mL) and extracted with
.06 (2 H, d, J = 6.4 Hz, CH ), 5.70 (1 H, dt, J = 10.8, 6.4 Hz, cis- dichloromethane (3 x 10 mL). The organic phases were
CH), 5.89 (1 H, dtt, J = 10.8, 8.4, 1.6 Hz, cis-CH); C-NMR (100 combined, dried over Na
MHz, CDCl ) δ 26.5 (CH ), 58.5 (CH ), 67.6 (CH ), 128.5 (CH), vacuo. The yield of diphenyl disulfide 24
MHz, CDCl
3
3
2
4
2
1
3
2
4
SO , filtered and concentrated in
3
1
3
2
3
2
(6%) was
-
81
1
31.3 (CH); m/z (APCI) 164.9741 [(M-H) , Br, 100%], 162.9756 determined by adding 1,3,5-trimethoxybenzene to the crude
1
mixture as an internal standard for H-NMR. The product was
- 79
(M-H) , Br, 87].
[
1
identified by the following characteristic signals; H-NMR (400
3
Synthesis of cis-(4-methoxybut-2-en-1-yl)(phenyl)sulfane 34. MHz, CDCl ) δ 7.48–7.50 (4 H, m) for diphenyl disulfide 24.
Sodium hydride (60% in mineral oil, 728 mg, 18.2 mmol, 1.2 These signals are consistent with the literature values and
eq.) and anhydrous tetrahydrofuran (20 mL) were added to a reference samples. The compounds were all confirmed by
flame-dried round-bottomed flask. Under an argon GCMS trace, TLC and overlaying the NMR peaks to see if all the
o
atmosphere, at 0 C, thiophenol (1.87 mL, 18.2 mmol, 1.2 eq.) three data sets match with reference values.
was added slowly and the reaction mixture was stirred at RT Table 1, entry 3. Cis-(4-methoxybut-2-en-1-yl)(phenyl)sulfane
for 1 h. A solution of cis-1-bromo-4-methoxybut-2-ene 33 (1.15 34 (97 mg, 0.5 mmol) and pinacolone 35 (0.04 mL, 0.5 mmol,
g, 3.5 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1.0 eq.) were added to an oven-dried pressure tube. In the
t
dropwise and the reaction mixture was stirred at RT overnight. glove box, KO Bu (112 mg, 1.0 mmol, 2.0 eq.) and anhydrous
The reaction mixture was quenched with water (a few drops) benzene (5 mL) were added and the reaction mixture was
o
and the crude mixture was concentrated in vacuo. The crude stirred at 130 C for 3 h in the dark. The reaction mixture was
mixture was diluted with water (30 mL) and extracted with cooled to RT, quenched with aqueous hydrochloric acid (1 M,
ethyl acetate (4 x 30 mL). The organic phases were combined, 10 mL) and extracted with dichloromethane (3 x 10 mL). The
2 4 2 4
washed with brine, dried over Na SO , filtered and organic phases were combined, dried over Na SO , filtered and
3
concentrated in vacuo. The crude material was purified by concentrated in vacuo. The yield of diphenyl disulfide 24 (4%)
1
column chromatography (0 - 5% ethyl acetate in hexane) to was determined by adding 1,3,5-trimethoxybenzene to the
1
give cis-(4-methoxybut-2-en-1-yl)(phenyl)sulfane 34 (682.5 g, crude mixture as an internal standard for H-NMR. The product
1
3%) as a pale yellow oil [Found: (HRMS-APCI) 193.0687. was identified by the following characteristic signals; H-NMR
2
-
-
-1
C
11
H
13OS (M-H) requires 193.0693]; νmax(film) / cm 2920, (400 MHz, CDCl
3
) δ 7.48 – 7.50 (4 H, m) for diphenyl disulfide
812, 1582, 1480, 1439, 1192, 1103, 1026, 738, 692; H-NMR 24. These signals are consistent with the literature values and
400 MHz, CDCl ) δ 3.26 (3 H, s, CH ), 3.58 (2 H, d, J = 7.2 Hz, reference samples. (Other products formed in the reaction but
), 3.85 (2 H, d, J = 6.4 Hz, CH ), 5.60 – 5.74 (2 H, m, 2 x cis- could not be identified).
1
2
(
3
3
CH
2
2
CH), 7.19 – 7.23 (1 H, m, ArH), 7.26 – 7.31 (2 H, m, ArH), 7.36 –
1
3
7
5
1
.39 (2 H, m, ArH); C-NMR (100 MHz, CDCl
8.2 (CH ), 68.8 (CH ), 126.8 (CH), 128.2 (CH), 129.0 (2 x CH),
29.5 (CH), 130.8 (2 x CH), 135.8 (C).
3 2
) δ 31.9 (CH ),
Reduction of iodo-m-xylene 36 (Table 2).
3
2
Table 2, entry 1. Iodo-m-xylene 36 (0.07 mL, 0.5 mmol) was
t
added to an oven-dried pressure tube. In the glove box, KO Bu
(
112 mg, 1.0 mmol, 2.0 eq.) and anhydrous benzene (5 mL)
Reactions of cis-(4-methoxybut-2-en-1-yl)(phenyl)sulfane 34
Table 1).
o
were added and the reaction was stirred at 130 C for 18 h in
the dark. The reaction mixture was cooled to RT, quenched
with water (10 mL) and extracted with diethyl ether (3 x 10
(
Table 1, entry 1. Cis-(4-methoxybut-2-en-1-yl)(phenyl)sulfane
(97 mg, 0.5 mmol) was added to an oven-dried pressure
34
mL). The organic phases were combined, dried over Na
2 4
SO ,
t
tube. In the glove box, KO Bu (56 mg, 0.5 mmol, 1.0 eq.) and
anhydrous benzene (5 mL) were added and the reaction
filtered and concentrated in vacuo to give iodo-m-xylene 36
1
H-NMR (400 MHz, CDCl
8.0 Hz, ArH), 7.13 (1 H, t, J = 8.0 Hz, ArH); C-NMR (100 MHz,
CDCl ) δ 29.9 (2 x CH ), 108.6 (C), 127.1 (2 x CH), 127.7 (CH),
42.2 (C). (The yield of iodo-m-xylene 36 (98%) was
3 3
) δ 2.48 (6 H, s, 2 x CH ), 7.05 (2 H, d, J
o
mixture was stirred at 130 C for 3 h in the dark. The reaction
13
=
mixture was cooled to RT, quenched with aqueous
hydrochloric acid (1 M, 10 mL) and extracted with
dichloromethane (3 x 10 mL). The organic phases were
3
3
1
determined by adding 1,3,5-trimethoxybenzene to the crude
1
mixture as an internal standard for H-NMR.) These signals are
combined, dried over Na
2
SO
4
, filtered and concentrated in
1
vacuo. Analysis of the H-NMR spectrum did not identify
consistent a commercial sample.
8
| J. Name., 2012, 00, 1-3
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Journal Name
Orga Pn l iec a s&e Bd oi o nmo to al ed cj uu sl ta mr Ca rhg ei nms istry
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DOI: 10.1039/C7OB02209C
ARTICLE
Table 2, entry 2. Iodo-m-xylene 36 (0.07 mL, 0.5 mmol) and δ 2.48 (6 H, s), 7.05 (2 H, d, J = 8.0 Hz), 7.11 (1 H, t, J = 8.0 Hz)
,4-dipropylpiperazine-2,5-dione (194 mg, 0.1 mmol, 0.2 eq.) for iodo-m-xylene 36; δ 2.03 (6 H, s), 7.14–7.20 (5 H, m), 7.40–
1
7
were added to an oven-dried pressure tube. In the glove box, 7.49 (3 H, m) (partly obscured by biphenyl peaks) for 2,6-
t
KO Bu (112 mg, 1.0 mmol, 2.0 eq.) and anhydrous benzene (5 dimethylbiphenyl 37; δ 2.32 (6 H, s) for xylene 38; δ 7.36 (2 H,
o
mL) were added and the reaction was stirred at 130 C for 18 h t, J = 8.0 Hz), 7.45 (4 H, t, J = 8.0 Hz), 7.60 (4 H, d, J = 8.0 Hz) for
3
5
in the dark. The reaction mixture was cooled to RT, quenched biphenyl
with water (10 mL) and extracted with diethyl ether (3 x 10 diphenyl disulfide 24; δ 0.84 (3 H, t, J = 7.2 Hz), 0.91 (3 H, t, J =
mL). The organic phases were combined, dried over Na SO 7.2 Hz), 1.38–1.74 (5 H, m), 1.75–1.84 (1 H, m), 1.88–1.96 (1 H,
filtered and concentrated in vacuo. The yields of iodo-m-xylene m), 2.85–2.95 (3 H, m), 3.87 (1 H, d, J = 4.0 Hz), 4.01 (1 H, s),
6
;
δ 7.21–7.26 (2 H, m), 7.48–7.50 (4 H, m) for
2
4
,
3
3
34
36 (16%), 2,6-dimethylbiphenyl 37 (6%), xylene 38 (3%) 7.19–7.23 (1 H, m) for 7-(2-(phenylthio)ethyl)-2,5-dipropyl-2,5-
3
5
and biphenyl
6
(26%) were determined by adding 1,3,5- diazabicyclo[2.2.2]octane-3,6-dione 25. These signals are
trimethoxybenzene to the crude mixture as an internal consistent with the literature values and reference samples.
1
standard for H-NMR. The products were identified by the The crude material was purified by column chromatography (0
1
following characteristic signals; H-NMR (400 MHz, CDCl
3
) δ - 100% ethyl acetate in hexane) to yield both diphenyl disulfide
3
1
o
32
o
.48 (6 H, s), 7.05 (2 H, d, J = 8.0 Hz), 7.11 (1 H, t, J = 8.0 Hz) for 24 (3 mg, 27%) as white crystals m.p. 54–56 C (lit : 57 C);
2
+
-1
iodo-m-xylene 36; δ 2.03 (6 H, s), 7.14–7.20 (5 H, m), 7.40–7.49 [Found: (GCMS-EI) C12
3 H, m) (partly obscured by biphenyl peaks) for 2,6-dimethyl- 1474, 1437, 1070, 1020, 995, 733; H-NMR (400 MHz, CDCl
biphenyl 37; δ 2.32 (6 H, s) for xylene 38; δ 7.36 (2 H, t, J = 8.0 7.21–7.25 (2 H, m, ArH), 7.28–7.33 (4 H, m, ArH), 7.48–7.51 (4
10 2
H S (M) 218.0]; νmax(film) / cm 1574,
1
(
3
) δ
1
3
Hz), 7.45 (4 H, t, J = 8.0 Hz), 7.60 (4 H, d, J = 8.0 Hz) for biphenyl H, m, ArH); C-NMR (100 MHz, CDCl
. (GCMS-CI) 9.78 min (m/z 231.9) for iodo-m-xylene 36; time (4 x CH), 129.2 (4 x CH), 137.2 (2 x C) and 7-(2-
0.96 min (m/z 182.1) for 2,6-dimethylbiphenyl 37; 10.62 min (phenylthio)ethyl)-2,5-dipropyl-2,5-diazabicyclo[2.2.2]octane-
m/z 154.1) for biphenyl . These signals are consistent with 3,6-dione 25 (4.9 mg, 14%) as a brown oil [Found: (HRMS-EI)
3
) δ 127.3 (2 x CH), 127.7
6
1
(
6
+
-
the literature values and reference samples.
360.1870. C20
1
2961, 2926, 2872, 1668, 1456, 1429 1290, 1258, 1120, 1070,
H
28
N
2
O
2
S (M) requires 360.1871]; νmax(film) / cm
Table 2, entry 3. Iodo-m-xylene 36 (0.07 mL, 0.5 mmol) and
cis-3-[4-(phenylthio)but-2-en-1-yl]-1,4-dipropylpiperazine-2,5-
1
1024, 739; H-NMR (400 MHz, CDCl
), 0.91 (3 H, t, J = 7.2 Hz, CH ), 1.38 – 1.46 (1 H, m, CH
dried pressure tube was added. In the glove box, KO Bu (112 1.47–1.63 (4 H, m, CH ), 1.64–1.72 (1 H, m, CH), 1.75–1.84 (1
mg, 1.0 mmol, 2.0 eq.) and anhydrous benzene (5 mL) were H, m, CH ), 1.88–1.96 (1 H, m, CH
added and the reaction was stirred at 130 C for 18 h in the 2.85–2.95 (3 H, m, 2 x CH and CH
dark. The reaction mixture was cooled to RT, quenched with 3.46–3.54 (2 H, m, CH
water (10 mL) and extracted with diethyl ether (3 x 10 mL). s, CH), 7.19–7.23 (1 H, m, ArH), 7.28–7.36 (4 H, m, ArH); C-
3
) δ 0.84 (3 H, t, J = 7.2 Hz,
dione 13 (36 mg, 0.1 mmol, 0.2 eq.) were added to an oven- CH
3
3
2
),
t
2
2
2
), 1.99–2.10 (1 H, m, CH
2
), 3.16–3.20 (1 H, m, CH
2
),
),
o
2
2
2
), 3.87 (1 H, d, J = 4.0 Hz, CH), 4.01 (1 H,
1
3
The organic phases were combined, dried over Na
2
SO
4
, filtered NMR (100 MHz, CDCl
21.6 (CH ), 25.2 (CH ), 27.4 (CH
CH ), 47.1 (CH ), 59.9 (CH), 62.6 (CH), 126.7 (CH), 129.3 (2 x
CH), 129.7 (2 x CH), 135.4 (C), 167.3 (C), 170.4 (C); HSQC
3
) δ 11.2 (CH
3
), 11.4 (CH
3 2
), 21.0 (CH ),
and concentrated in vacuo.
2
2
2
), 37.2 (CH
2
), 37.7 (CH), 46.4
(
2
2
1
13
(
H/ C) δ 0.84/11.2, 0.91/11.4, (1.38–1.46)/27.4, (1.47–
1.63)21.0,
1.84)/25.2,
2.95)/37.2,
(1.47–1.63)/21.6,
(1.88–1.96)/27.4,
(2.85–2.95)/46.4,
(1.64–1.72)/37.7,
(1.99–2.10)/25.2,
(3.16–3.20)/47.1,
(1.75–
(2.85–
(3.46–
Entry Additive
eq.)
13 (0.2)
36
37
38
6
24
25
3.54)/46.4, (3.46–3.54)/47.1, 3.87/59.9, 4.01/62.6, (7.19–
.23)/126.7, (7.28–7.36)/129.3, (7.28 – 7.36)/129.7. (The yields
7
(
(%)
(%)
(%)
(%)
(%)
(%)
of 24 and 25 were determined based on 0.1 mmol of DKP as
the limiting reagent).
a
3
a.
4
a.
10
a.
13
a,b
28
a,b
5
20
3
c
c
(
27)
(14)
a
Yield calculated using 1,3,5-trimethoxybenzene as the internal
1
standard H-NMR of the crude mixture. Yield calculated using
c
the DKP additive 13 as the limiting reagent. Isolated yield.
b
Conflicts of interest
There are no conflicts to declare.
The yields of iodo-m-xylene 36 (53%), 2,6-dimethylbiphenyl
3
3
34
(4%), xylene 38 (10%), biphenyl
35
6
Acknowledgements
37
(13%), diphenyl
disulfide 24 (28%) and 7-(2-(phenylthio)ethyl)-2,5-dipropyl-2,5- We thank the EPSRC and University of Strathclyde for the funding.
Grant Number: EP/L505080/1. Further thanks to EPSRC National
Mass Spectrometry Service Centre, Swansea, for the high resolution
mass spectra results. Results were obtained using the EPSRC funded
ARCHIE-WeSt High Performance Computer (www.archie-
diazabicyclo[2.2.2]octane-3,6-dione 25 (20%) were determined
by adding 1,3,5-trimethoxybenzene to the crude mixture as an
1
internal standard for H-NMR. The products were identified by
1
the following characteristic signals; H-NMR (400 MHz, CDCl
3
)
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J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02209C
ARTICLE
Journal Name
west.ac.uk) through EPSRC grant no. EP/K000586/1. We thank Allan Since 13 might behave in a similar way, a blank experiment
o
was conducted with KOtBu at 130 C; this afforded diphenyl
Young for help during the revision of this manuscript.
disulfide in minute amounts (2%).
2
8. J. P. Barham, G. Coulthard, K. J. Emery, E. Doni, F. Cumine, G.
Nocera, M. P. John, L. E. A. Berlouis, T. McGuire, T. Tuttle and J.
A. Murphy, J. Am. Chem. Soc., 2016, 138, 7402 7410.
9. W. Dai; Y. Lv; L. Wang; S. Shang; B. Chen; G. Li; S. Gao, Chem.
Commun. 2015, 51, 11268 11271.
0. E. Tayama, S. Otoyama, W. Isaka, Chem. Commun., 2008,
216 4218.
1. M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, A. Zare, H. G.
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7. When 34 receives an electron, C-S bond cleavage to occur
−
,
−
2
to form thiophenate anion and a carbon radical might be
expected Seeing PhSSPh as a product might imply either (a)
that the radical anion of 34 undergoes fragmentation to
methoxide anion, butadiene and phenylthiyl radical, or more
likely, that slow addition of a carbon radical to the allyl sulfide
of 34 occurs, leading to the expulsion of phenylthiyl radical ;
this radical can then dimerise to form PhSSPh.
1
0 | J. Name., 2012, 00, 1-3
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Page 11 of 11
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB02209C
Evidence of single electron transfer from the enolate anion of an N,N’-
dialkyldiketopiperazine additive in BHAS coupling reactions
a
a
a
Katie J. Emery, Tell Tuttle* and John A. Murphy*
TOC Entry
SPh
O
SPh
Pr
SPh
Pr
N
O
N
O
e
PrN
N
O
N
O
N
O
Pr
Pr
Pr
I
2
5
(
(
i)
Ar
I
Ar
Ar
ii) KOtBu
Initiation of Coupling Reaction