Application of copper(II)-mediated radical cross-dehydrogenative coupling to prepare spirocyclic oxindoles and to a formal total synthesis of Satavaptan

Article abstract of DOI:10.1016/j.tet.2018.09.026

Application of radical cross-dehydrogenative coupling (CDC) procedures to prepare a range of novel spirocyclic oxindoles and to a formal total synthesis of the vasopressin V₂ receptor antagonist Satavaptan is reported. The key step involves a c

Full text of DOI:10.1016/j.tet.2018.09.026

Accepted Manuscript
Application of copper(II)-mediated radical cross-dehydrogenative coupling to prepare
spirocyclic oxindoles and to a formal total synthesis of Satavaptan
Timothy E. Hurst, Ryan Gorman, Pauline Drouhin, Richard J.K. Taylor
PII:
S0040-4020(18)31095-0
10.1016/j.tet.2018.09.026
TET 29798
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2018
Accepted Date: 12 September 2018
Please cite this article as: Hurst TE, Gorman R, Drouhin P, Taylor RJK, Application of copper(II)-
mediated radical cross-dehydrogenative coupling to prepare spirocyclic oxindoles and to a formal total
synthesis of Satavaptan, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.09.026.
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Application of copper(II)-mediated radical
cross-dehydrogenative coupling to prepare
spirocyclic oxindoles and to a formal total
synthesis of Satavaptan
Leave this area blank for abstract info.
Timothy E. Hurst, Ryan Gorman,
Pauline Drouhin and Richard J. K. Taylor
Department of Chemistry, University of York, Heslington,
York, YO10 5DD, UK
O
H
N
O
O
O
Cu(OAc)
2
•H
2
O (10–100 mol%)
(
)
n
O
N
R
O
EtO
toluene or mesitylene, 110-165 °C
air or O2 atmosphere
n
(
)
N
R
O
N
9
examples
SO
OMe
Satavaptan
2
5
2-68% yield
R = Me, Bn, DMB, PMB
n = 1,2,3
t-BuHN
O

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Application of copper(II)-mediated radical cross-dehydrogenative coupling to prepare
‡
spirocyclic oxindoles and to a formal total synthesis of Satavaptan
∗
Timothy E. Hurst, Ryan Gorman, Pauline Drouhin and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Application of radical cross-dehydrogenative coupling (CDC) procedures to prepare a range of
novel spirocyclic oxindoles and to a formal total synthesis of the vasopressin V receptor
2
Received in revised form
Accepted
Available online
antagonist Satavaptan is reported. The key step involves a copper-mediated oxidative cyclisation
of a simple linear anilide precursor to give the spirocyclic oxindole core. This synthetic
approach was also used to prepare novel Satavaptan scaffolds and analogues.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
copper
cross-dehydrogenative coupling
total synthesis
analogue synthesis
vasopressin antagonists
—
——
∗
Corresponding author. Tel.: +1-1904-322543; e-mail: richard.taylor@york.ac.uk
‡
Dedicated to Professor Léon Ghosez in recognition of his many contributions to science and to the Tetrahedron journals, and to acknowledge
his friendship and advice.

2
Tetrahedron
ACCEPTED MANUSCRIPT
1
. Introduction
O
H
N
Hyponatremia, or low blood sodium levels, is a common
O
complication in several diseases including congenital heart
failure, cirrhosis of the liver, and syndrome of inappropriate
antidiuretic hormone (SIADH); common diuretics typically used
EtO
O
1
N
in the treatment of such diseases often lead to loss of essential
SO
2
2
sodium and potassium salts. Several vasopressin V receptor
2
OMe
antagonists have been developed to address this problem (Figure
t-BuHN
1
). Selective vasopressin V receptor antagonists (e.g. 1-3) work
2
O
by blocking the production of vasopressin, an anti-diuretic
hormone responsible for causing the kidneys to retain water.
Thus, administration of Tolvaptan 2 alongside traditional
diuretics has been shown to increase fluid excretion without
Satavaptan, 1
HO
N
Cl
3
causing hyponatremia in patients suffering from heart failure.
N
N
O
Our interest concerned Satavaptan 1 and improved analogues.
The synthesis of Satavaptan 1 was first reported by Sanofi in
O
O
Cl
Me
O
N
1
999 and involves formation of the oxindole core via a classical
Me
H
N
H
Fischer cyclisation under harsh conditions (180 °C reaction
temperature), while tedious late-stage separation of the syn- and
F
4
anti-stereoisomers was also required. These shortcomings were
Tolvaptan, 2
Lixivaptan, 3
addressed in a subsequent synthesis by Liotta in 2001 (Scheme
Figure 1. Examples of vasopressin V receptor antagonists.
5
2
1
). Thus, in the Liotta synthesis, the key oxindole 6 was
prepared via a Rh-catalysed annulation of diazo compound 5 at
room temperature. Construction of the spirocyclic ketone 11 was
achieved through subsequent double alkylation with
dibromide 10, itself prepared in 3 steps from methyl 3-

3
Liotta's Synthesis of Satavaptan
ACCEPTED MANUSCRIPT
EtO
N
2
H
EtO
EtO
Rh (OAc)
2
4
O
N
Bn
O
N
NHBn
Bn
4
5
6
4
steps, 69% (from 4)
O
Ti(Oi-Pr)4
HO
O
O
O
NaH
EtMgBr
Br
Br
OMe
Br
Br
Br
Br
7
8
9
10
3
steps, 51% (from 7)
H
O
O
O
OH
O
L-Selectride
EtO
EtO
EtO
O
O
N
N
N
Bn
12
Bn
Bn
11
1
3
66:1 syn:anti
1
2
. Alkylation
. Li, NH
3
O
O
SO
2
Cl
OMe
H
N
H
N
O
O
+
EtO
EtO
O
O
O
NHt-Bu
N
N
H
2
SO Ar
14
15
Satavaptan, 1
5
steps, 46% (from 6)
4 steps, 25%
85%
Radical Cross-Dehydrogenative Coupling (CDC)
via
H
O
R'
EWG
[9a]
R'
EWG
O
EWG = CO R
2
∑
H
cat. Cu(II)
[
9b]
EWG
O
CONR
2
N
toluene, reflux
[9c-d]
N
R
R
N
R
COR
air
R'
16
17
18
This Work - Formal Synthesis of Satavaptan
O
O
EtO
H
O
O
O
O
H
EtO
EtO
N
Bn
O
O
O
O
N
Bn
N
Bn
19
12
20
Scheme 1. Previous synthesis of Satavaptan and new approach via copper-mediated cross-dehydrogenative coupling
in this process. We now wish to report the application of this
highly atom-economical approach to the preparation of Liotta’s
key spirocyclic oxindole intermediate 12, thus representing a new
formal synthesis of Satavaptan. In our approach, the target
molecule 12 would be derived by deoxygenation of selectively
protected ketone 19, produced by the radical CDC cyclisation of
anilide 20. This synthetic approach is also applied to prepare
novel Satavaptan scaffolds and analogues (see later).
bromopropionate 7. Crucially, conditions were established for the
syn-selective reduction of ketone 12 using L-Selectride as the
hydride source, obviating the need for separation of a mixture of
isomers at a later stage in the synthesis. The origin of this
selectivity was proposed to be trapping of the cyclohexane in the
twist-boat conformation via coordination of both carbonyl
oxygen atoms to the lithium cation, thus revealing the correct
face for hydridic attack. Alkylation of the cyclohexanol and
removal of the benzyl protecting group under Birch conditions
gave N-H oxindole 14, which was treated with arylsulfonyl
chloride 15 to deliver Satavaptan 1. Several other formal
syntheses of Satavaptan have also been reported, invoking either
2
. Results and Discussion
In order to establish the feasibility of preparing the key
spirocyclic oxindole core of Satavaptan via our radical cross-
dehydrogenative coupling procedure, initial studies focused on
9c
6
7
the cyclisation of simple anilides 21 (Scheme 2). In the event,
treatment of linear precursors 21a-f with inexpensive
Cu(OAc) ·H O in refluxing toluene under an atmosphere of O
a radical or hypervalent iodine-mediated spirocyclisation, or
8
alkylation/Dieckmann condensation as the key step.
2
2
2
We have previously reported the synthesis of oxindoles 17
through the intramolecular Cu(II)-catalysed radical cross-
dehydrogenative coupling (CDC) of simple anilides 16, which
proceeds via homolytic aromatic substitution of stabilised radical
delivered a range of spirocyclic oxindoles 22a-f featuring 5-, 6-,
and 7-membered ring ketones. Crucially, several different
removable N-protecting groups (including Bn, DMB and PMB)
were well-tolerated in this process. Furthermore, groups allowing
for further functionalisation such as an alkene (22e) or epoxide
9
a
,10
1
8 (Scheme 1).
A range of electron-withdrawing groups,
9
9b 9c-e
including esters, lactams and ketones, were well tolerated

4
Tetrahedron
ACCEPTED MAtre
N
at
U
me
S
ntCRofIP
a
T
nilide 25 with
a
catalytic quantity of
O
O
O
Cu(OAc)
2
•H
2
O (10–100 mol%)
( )
n
Cu(OAc) ·2H O in refluxing mesitylene to give spirocyclic
2
2
N
O
toluene, 110 °C , O
2
atmosphere
oxindole 26 in 52% yield. To facilitate the carbonyl
deoxygenation, ketone 26 was first reduced to the corresponding
alcohol 27 in excellent yield. In the first instance, deoxygenation
was successfully carried out using a classical Barton-McCombie
reaction via the corresponding imidazole-1-thiocarbonyl
R
n(
)
N
R
22a-f
2
1a-f
13
O
O
O
O
O
derivative.
However, an alternative route which negates the
O
need for the use of highly toxic tin reagents was considered
desirable. Thus, cleavage of the acetal and concomitant
dehydration was achieved under acidic conditions to give enone
N
Bn
N
N
Me
Me
2
2a, 56%
22b, 65%
22c, 66%
2
9, which could be hydrogenated to give the desired ketone 30 in
O
high yield.
O
O
O
O
O
O
Having successfully established protocols for the key oxindole
spirocyclisation and deoxygenation reactions, attention finally
turned to the formal synthesis of Satavaptan 1 (Scheme 4).
Coupling of the appropriately substituted aniline 4 with ketoacid
N
DMB
N
N
PMB
PMB
22d, 68%
22e, 55%
22f, 62%
2
4 was carried out in the presence of propylphosphonic
Scheme 2. Substrate scope in the copper-mediated synthesis
of spirocyclic oxindoles.
14
anhydride (T3P) to give β-ketoamide 20, which, on treatment
with stoichiometric Cu(OAc) ·H O in refluxing mesitylene or
2
2
ethylene carbonate delivered the requisite spirocyclic keto-
oxindole 19 in 58-62% yield. Ethylene carbonate has been shown
to be an excellent green replacement for traditional organic
solvents due to its low cost, ready availability, high flash point,
low (eco)toxicity and excellent biodegradability. Pleasingly, in
this instance, mesitylene was easily substituted for ethylene
carbonate without a significant change in yield. Finally,
deoxygenation was performed without incident via the 3-step
sequence developed above to give Liotta’s spirocyclic oxindole
12. This route therefore represents a new formal synthesis of
Satavaptan, whilst removing the potentially dangerous diazo
intermediates and costly rhodium salts used by Liotta et al.
(
22f) were also successfully incorporated into the spirocyclic
products. With conditions for the oxindole spirocyclisation in
hand, a simple model system was next examined to establish the
viability of the deoxygenation required for the formal synthesis
of Satavaptan (Scheme 3). Synthesis of the model system began
with selectively protected ketoester 23, which was saponified to
acid 24 in a two-step procedure involving first transesterification
to the benzyl ester followed by hydrogenolysis. Next, coupling
of acid 24 with N-methylaniline in the presence of Mukaiyama’s
reagent delivered linear precursor 25 primed for the cross-
dehydrogenative coupling. Rapid cyclisation occurred on
15
11
12
O
O
O
O
O
O
EtO
1
. BnOH, PhMe, 4Å MS
. H , Pd/C, EtOAc
EtO
HO
HO
T3P
O
O
O
2
2
+
NH
Bn
EtOAc, rt, 16 h
O
O
O
O
2
3
24, 73%
4
24
Mukaiyama
Et
O
H
EtO
3
N, CH
2 2
Cl
O
O
O
Cu(OAc)2•H2O
100 mol%)
O
H
(
EtO
N
ethylene carbonate
165 °C , 1 h
Bn
O
O
H
N
O
O
Cu(OAc)
2
•H
2
O
O
O
N
O
H
(10 mol%)
Bn
1
9, 62%
20, 76%
O
mesitylene
165 °C , 25 min
air bubbled through
Me
O
N
NaBH4
Me
6, 52%
O
MeOH, 0 °C , 2 h
2
25, 60%
O
NaBH , EtOH
O
4
HO
O
1. HCl (aq), THF
0 °C , 1.5 h
7
O
O
O
O
EtO
EtO
HO
2. H2, Pd/C
EtOAc, rt, 16 h
O
O
O
1
. Im
2
C=S, 1,2-DCE
N
N
Bn
Bn
2
. Bu
PhMe, reflux
3
SnH, AIBN
O
31, 80%
12, 82%
N
N
Me
7, 93%
Me
Scheme 4. Formal total synthesis of Satavaptan.
2
28, 69%
1
0% aq HCl
THF, reflux, 1 h
In a final aspect to this work we wished to demonstrate the
versatility of our route by applying it to the synthesis of a novel
analogue of Satavaptan featuring a changed sulfonamide and a
novel triazole side chain (Scheme 5). Mindful of the requirement
to use the Birch reduction for cleavage of the benzyl protecting
group used by Liotta, a different protecting group strategy was
therefore adopted. In the event, the para-methoxybenzyl (PMB)
group was chosen due to its potential removal under a wide
variety of conditions (oxidation, acid, hydrogenolysis). In
O
O
H
2
, 10% Pd/C
EtOAc, rt, 18 h
O
O
N
N
Me
Me
2
9, 74%
30, 94%
Scheme 3. Model system for the deoxygenation of spirocyclic
oxindoles.

5
analogous fashion to the benzyl analogue above
A
, a
C
m
C
ide
E
f
P
or
TED
on MANUSCRIPT
ma
ti
(32→33), cross-dehydrogenative coupling using either
EtO
H
N
O
O
EtO
O
O
H
T3P
HO
+
O
NH
EtOAc, rt, 16 h
PMB
O
PMB
O
O
32
24
33, 52%
Cu(OAc)
2 2
•H O (10 mol%)
mesitylene, 165 °C , 20 min
O
O
O
1
. HCl (aq), THF
HO
O
O
O
70 °C , 2 h
NaBH
4
EtO
EtO
EtO
2. H , Pd/C
2
MeOH, 0 °C , 1 h
O
O
O
EtOAc, rt, 18 h
N
PMB
N
N
PMB
35, 89%
PMB
36, 84% (2 steps)
34, 52%
L-Selectride, THF
78 °C , 2 h
–
NBn
N
NaH
Br
OH
O
BnN , CuI
3
DIPEA
O
N
EtO
EtO
EtO
O
THF
50 °C , 20 h
O
THF, rt, o/n
N
PMB
O
N
PMB
N
PMB
37, 84%
38, 77%
39
TFA, reflux, 2 d
NBn
N
N
O
NBn
N
EtO
KOt-Bu, ArSO
2
Cl
O
N
O
N
THF, rt, 3 h
EtO
SO
2
O
N
H
Cl
3
F C
41, 54%
40, 89% (2 steps)
Scheme 5. Synthesis of a novel Satavaptan analogue.
versatility of this approach was demonstrated by the synthesis of
Cu(OAc) ·H O or Cu(2-ethylhexanoate) as catalyst (33→34),
a novel Satavaptan analogue 41.
2
2
2
and deoxygenation (34→36) proceeded without incident. Syn-
selective reduction of ketone 36 was accomplished under Liotta’s
conditions (L-Selectride, THF, –78 °C) to give alcohol 37, which
was subjected to alkylation with propargyl bromide. Huisgen
cycloaddition of the subsequent alkyne 38 with benzyl azide in
the presence of CuI delivered triazole 39. Contrary to the benzyl
deprotection above, removal of the PMB group was achieved on
simple reflux with TFA to give N-H oxindole 40 (57% yield over
4
. Experimental section
4
.1. General Methods
Except where stated, all reagents were purchased from
1
commercial sources and used without further purification. H and
13
C NMR spectra were recorded on a JEOL ECX400 or ECS400
spectrometer, operating at 400 MHz and 100 MHz, respectively.
All spectral data was acquired at 295 K. Chemical shifts (δ) are
quoted in parts per million (ppm). The residual solvent peak, δH
7.27 and δ 77.0 for CDCl was used as a reference. Coupling
2
steps from 38). Finally, deprotonation of 40 followed by
addition of the aryl sulfonyl chloride delivered the novel
Satavaptan analogue 41.
C
3
constants (J) are reported in Hertz (Hz). The multiplicity
abbreviations used are: s singlet, d doublet, t triplet, q quartet, m
multiplet. Signal assignment was achieved by analysis of DEPT,
COSY, HMBC and HSQC experiments where required. Infrared
3
. Conclusions
The highly atom-economical radical cross-dehydrogenative
coupling (CDC) of simple linear β-ketoamides 21 to give
spirocyclic oxindoles 22 bearing 5-, 6- and 7-membered ring
ketones has been established (Schemes 2 and 3). This approach
was subsequently employed in the formal total synthesis of the
(
IR) spectra were recorded on a PerkinElmer UATR 2
spectrometer as a thin film dispersed from either CH Cl or
2
2
CDCl . Mass-spectra (low and high-resolution) were obtained by
3
the University of York Mass Spectrometry Service, using
electrospray ionisation (ESI) on a Bruker Daltonics, Micro-tof
vasopressin V receptor antagonist Satavaptan (Scheme 4). CDC
2
of linear anilide 20, followed by deoxygenation in a three-step
sequence involving reduction to the alcohol, dehydration, and
hydrogenation delivered the key spirocyclic oxindole
intermediate previously prepared by Liotta et al., and thus
represents a new formal synthesis of Satavaptan. Finally, the
spectrometer. Melting points were determined using
a
Gallenkamp apparatus. Thin layer chromatography was carried
out on Merck silica gel 60F254 pre-coated aluminium foil sheets
and were visualised using UV light (254 nm) and stained with
basic aqueous potassium permanganate. Flash column
chromatography was carried out using slurry packed Fluka silica

6
Tetrahedron
gel (SiO ), 35–70 ꢀm, 60 Å, under a light
A
po
C
sit
C
iv
E
e
P
pres
T
E
su
D
re, MA37
N
.5
U
(M
S
e
C
),
R
30
I
.5 (CH ), 26.9 (CH ), 23.8 (CH ); HRMS (ESI):
2 2 2
P
T
2
+
eluting with the specified solvent system.
MNa , found 254.1149. C H NNaO requires 254.1151.
14
17
2
4
.2.1.4. N-Methyl-2-oxo-N-
phenylcycloheptanecarboxamide (21c)
4
.2. Experimental procedures and compound characterisation
A suspension of Pd/C (3 wt% on activated carbon, 84 mg) in
EtOAc (10 mL) was thoroughly degassed three times while
stirring. Benzyl 2-oxocycloheptanecarboxylate (0.247 g, 1.00
4
4
.2.1. Synthesis of spirocyclic oxindoles
.2.1.1. General procedure 1: Synthesis of linear
anilides 21a-f
mmol) was added and the mixture stirred under an atmosphere of
®
H for 1 h. The suspension was filtered through Celite , washed
2
The cyclic ketone (1 equiv) was added to a solution of
magnesium methyl carbonate (2 M in DMF, 8 equiv). The
reaction mixture was stirred at 130 °C for 6 h. After cooling to rt,
with EtOAc, and concentrated in vacuo to give the crude acid as
a colourless oil.
1
0% HCl solution was added until the pH became acidic. The
To a solution of the crude acid in CH Cl (10 mL) at 0 °C was
added N-methylaniline (0.062 mL, 0.570 mmol), 2-
2
2
aqueous phase was extracted with Et O, and the combined
organic layers washed with H O and sat. brine, dried over
MgSO , filtered, and concentrated in vacuo to give the carboxylic
acid.
2
2
chloromethylpyridinium iodide (0.210 g, 0.812 mmol) and Et N
3
4
(0.400 mL, 2.64 mmol). The reaction was stirred at rt for 1 h,
then quenched by the addition of 10% HCl (10 mL). The layers
were separated, and the aqueous phase was extracted with EtOAc
To a solution of the crude acid in CH Cl (0.06 M) at 0 °C was
2
2
(
2 × 10 mL). The combined organic extracts were washed with
added the aniline (1.15 equiv), 2-chloro-1-methylpyridinium
iodide (1.4 equiv) and Et N (4.6 equiv). The reaction mixture was
stirred at rt for 18 h, then quenched by the addition of 10% HCl.
The layers were separated, and the aqueous phase extracted with
CH Cl . The combined organic layers washed with H O and sat.
brine, dried over MgSO , filtered, and concentrated in vacuo to
give the crude product. Purification by column chromatography
on silica gel (Hexane/EtOAc, 3:1 to 1:4) gave the title compound.
brine (2 × 10 mL), dried over MgSO , filtered and concentrated
4
3
in vacuo to give the crude product as a yellow oil. Purification by
column chromatography on silica gel (Hexane/EtOAc, 6:1) gave
the title compound 21c (81 mg, 52%) as a colourless oil; ν
max
2
2
2
-1
2
884, 1678, 1624, 1570, 1472, 1359, 1097 cm ; δ (400 MHz;
H
4
CDCl ) 7.45-7.29 (3H, m), 7.22-7.16 (2H, m), 3.45 (1H, dd, J
3
1
2
0.6, 3.9 Hz), 3.25 (3H, s), 2.55 (1H, ddd, J 14.6, 11.6, 3.3 Hz),
.14-2.04 (1H, m), 2.02-1.92 (1H, m), 1.92-1.81 (2H, m), 1.80-
4
.2.1.2. N-Benzyl-2-oxo-N-phenylcyclopentane-1-
1.71 (2H, m), 1.40-1.03 (3H, m); δ (100 MHz; CDCl ) 210.9
C
3
carboxamide (21a)
(
C), 170.6 (C), 143.6 (C), 129.9 (CH), 128.2 (CH), 128.0 (CH),
5
6.6 (CH), 43.3 (CH ), 37.6 (Me), 29.6 (CH ), 28.6 (CH ), 28.4
2
2
2
Following general procedure 1 from cyclopentanone (0.290 g,
.26 mmol), methyl magnesium carbonate (2 M in DMF, 9.04
mL, 18.1 mmol) was obtained the carboxylic acid. Formation of
the amide was carried out using N-benzylaniline (0.154 mL,
+
(CH ), 24.60 (CH ); HRMS (ESI): MH , found 246.1497.
2 2
2
C H NO requires 246.1489.
15
20
2
4.2.1.5. N-(2,4-Dimethoxybenzyl)-2-oxo-N-
0
0
.831 mmol), 2-chloro-1-methylpyridinium iodide (0.255 g,
phenylcycloheptanecarboxamide (21d)
.997 mmol) and Et N (0.462 mL, 3.32 mmol) to give the title
3
A suspension of Pd/C (3 wt% on activated carbon, 0.403 g) in
EtOAc (48 mL) was thoroughly degassed three times while
stirring. Benzyl 2-oxocycloheptanecarboxylate (1.18 g, 4.80
compound 21a (43 mg, 15%) as a colourless solid; mp. 97-99 °
C; νmax 2966, 1739, 1644, 1595, 1495, 1405, 700 cm ; δ (400
MHz; CDCl ) 7.32-7.27 (3H, m), 7.27-7.23 (3H, m), 7.23-7.18
-
1
H
3
mmol) was added and the mixture stirred under an atmosphere of
(2H, m), 7.13 (2H, br s), 5.01 (1H, d, J 14.4 Hz), 4.82 (1H, d, J
®
H for 1 h. The suspension was filtered through Celite , washed
2
1
2
4.4 Hz), 3.08 (1H, dd, J 10.2, 9.2 Hz), 2.48-2.36 (1H, m), 2.35-
.24 (1H, m), 2.24-2.16 (1H, m), 2.14-2.03 (2H, m), 1.77-1.58
with EtOAc, and concentrated in vacuo to give the crude acid as
a colourless oil.
(1H, m); δ (100 MHz; CDCl ) 214.8 (C), 170.1 (C), 142.1 (C),
C
3
1
1
37.1 (C), 129.6 (CH), 128.7 (2 × CH), 128.5 (CH), 128.3 (CH),
27.4 (CH), 53.3 (CH ), 52.9 (CH), 38.6 (CH ), 28.4 (CH ), 21.1
To a solution of the crude acid in CH Cl (48 mL) at 0 °C was
added N-(2,4-dimethoxybenzyl)aniline (0.666 g, 2.74 mmol), 2-
2
2
2
2
2
+
(CH ); HRMS (ESI): MNa , found 316.1297. C H NNaO
2
1
9
1
9
2
chloromethylpyridinium iodide (0.980 g, 3.84 mmol) and Et N
3
requires 316.1308.
(
1.76 mL, 12.6 mmol). The reaction was stirred at rt for 1 h, then
quenched by the addition of 10% HCl (50 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (2 ×
4
.2.1.3. N-Methyl-2-oxo-N-phenylcyclohexane-1-
carboxamide (21b)
5
0 mL). The combined organic extracts were washed with brine
Following general procedure 1 from cyclohexanone (0.21 mL,
.04 mmol), methyl magnesium carbonate (2 M in DMF, 8.15
mL, 16.3 mmol) was obtained the carboxylic acid. Formation of
the amide was carried out using N-methylaniline (0.254 mL, 2.34
mmol), 2-chloro-1-methylpyridinium iodide (0.720 g, 2.82
(2 × 50 mL), dried over MgSO , filtered and concentrated in
4
2
vacuo to give the crude product as a yellow oil. Purification by
column chromatography on silica gel (Hexane/EtOAc, 6:1) gave
the title compound 21d (0.470 g, 45%) as a colourless solid; mp.
66-68 °C; νmax 1705, 1650, 1614, 1594, 1508, 1495, 1454, 1262,
-
1
mmol) and Et N (1.31 mL, 9.38 mmol) to give the title
1209, 1157, 1037, 702 cm ; δ (400 MHz; CDCl ) 7.28-7.25
3
H
3
compound 21b (65 mg, 30%) as a yellow oil; νmax 2941, 2865,
(3H, m), 7.26 (1H, d, J 8.3 Hz), 7.00 (2H, dd, J 7.6, 2.0 Hz), 6.42
(1H, dd, J 8.3, 2.4 Hz), 6.29 (1H, d, J 2.4 Hz), 4.90 (1H, d, J 14.5
Hz), 4.81 (1H, d, J 14.5 Hz), 3.76 (3H, s), 3.50 (3H, s), 3.44 (1H,
dd, J 10.6, 3.9 Hz), 2.54 (1H, dd, J 8.8, 5.5 Hz), 2.10-1.95 (3H,
m), 1.93-1.82 (2H, m), 1.75 (2H, dd, J 11.2, 4.6 Hz), 1.31-1.12
(2H, m); δ (100 MHz; CDCl ) 211.0 (C), 170.4 (C), 160.2 (C),
-
1
1
710, 1652, 1595, 1495, 1450, 1421, 1382, 1126, 775, 702 cm ;
δ (400 MHz; CDCl ) 7.37-7.35 (2H, m), 7.34-7.31 (1H, m), 7.15
H
3
(2H, dd, J 8.2, 1.3 Hz), 3.28 (3H, s), 3.21 (1H, dd, J 11.7, 5.9
Hz), 2.44-2.37 (1H, m), 2.16 (1H, ddd, J 15.4, 12.9, 3.6 Hz),
2
1
.04-1.94 (2H, m), 1.94-1.83 (2H, m), 1.78-1.64 (1H, m), 1.51-
C
3
.37 (1H, m); δ (100 MHz; CDCl ) 207.5 (C), 169.7 (C), 143.8
158.5 (C), 142.1 (C), 131.0 (CH), 129.3 (CH), 129.1 (CH), 127.9
(CH), 117.9 (C), 104.2 (CH), 98.3 (CH), 56.9 (CH), 55.4 (Me),
C
3
(C), 129.9 (CH), 128.2 (CH), 127.3 (CH), 55.3 (CH), 41.7 (CH2),
5
5.1 (Me), 47.1 (CH ), 43.4 (CH ), 29.6 (CH ), 28.7 (CH ), 28.5
2 2 2 2

7
+
(
CH ), 24.6 (CH ); HRMS (ESI): MNa ,
A
fo
C
un
C
d
E
4
P
04
T
.1
E
83
D
1; MACD
N
C 7
U
l )
S
C
.3
J 6.6, 3.1 Hz), 6.77 (2H, d, J 8.6 Hz), 5.75-5.58 (2H, m), 5.05-
.90 (4H, m), 4.82 (2H, s), 3.77 (3H, s), 3.35 (1H, dd, J 8.4, 5.9
Hz), 2.64 (1H, ddd, J 15.3, 8.4, 7.2 Hz), 2.47 (1H, ddd, J 15.3,
.2, 5.9 Hz), 2.42-2.35 (1H, m), 2.29-2.21 (1H, m), 2.22-2.14
2H, m); δ (100 MHz; CDCl ) 204.9 (C), 168.7 (C), 159.1 (C),
R
4-7
I
.
P
29
T
(3H, m), 7.09 (2H, d, J 8.6 Hz), 6.90 (2H, dd,
2
2
3
C H NNaO requires 404.1832.
23
27
4
4
4
.2.1.6. 5-(1-Hydroxypent-4-enylidene)-2,2-
dimethyl-1,3-dioxane-4,6-dione
7
(
1
1
1
A solution of DCC (4.74 g, 23.0 mmol) in CH Cl (10 mL)
C
3
2
2
41.5 (C), 137.0 (CH), 135.1 (CH), 130.4 (CH), 129.8 (CH),
29.4 (C), 129.2 (CH), 128.5 (CH), 117.3 (CH ), 115.3 (CH ),
was added slowly to a stirred solution of Meldrum’s acid (3.01 g,
0.9 mmol), 4-pentenoic acid (2.13 mL, 20.9 mmol), and 4-
dimethylamino)pyridine (2.81 g, 23.0 mmol) in CH Cl (30 mL)
at 0 °C. The reaction mixture was allowed to warm to rt and
stirred for 16 h. The suspension was filtered through Celite, and
then washed with CH Cl (50 mL). The filtrate was washed
2
(
2
2
13.8 (CH), 56.9 (CH), 55.3 (Me), 52.8 (CH ), 40.3 (CH ), 33.6
CH ), 27.4 (CH ); HRMS (ESI): MNa , found 400.1878.
2
2
2
2
+
(
2 2
C H NNaO requires 400.1883.
24 27
3
2
2
4
.2.1.9. Z-N-(4-Methoxybenzyl)-7-oxo-N-
subsequently with 10% HCl (50 mL). The aqueous phase was
extracted with CH Cl (2 × 20 mL). The combined organic
phenylcyclohept-3-enecarboxamide (21e)
2
2
phases were washed with water (2 × 30 mL) and brine (2 × 30
To degassed solution of N-(4-methoxybenzyl)-2-(2-
a
mL), dried over MgSO , filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
methylallyl)-3-oxo-N-phenylhept-6-enamide (0.493 g, 1.33
mmol) in CH Cl (100 mL) was added Grubbs 2nd generation
4
2
2
(
EtOAc) to give the title compound (3.32 g, 70%) as a yellow oil;
catalyst (52 mg, 0.067 mmol). The reaction mixture was stirred at
45 °C for 1 h. After cooling to rt, the solvent was removed in
vacuo, and the residue was purified by column chromatography
on silica gel (Petrol/EtOAc, 5:1 to 2:1) to give the title compound
21e (0.264 g, 57%) as a colourless oil; νmax 1709, 1661, 1648,
-
1
νmax 1739, 1665, 1574, 1408, 1282, 1154, 1031, 919 cm ; δ (400
MHz; CDCl ) 5.84 (1H, ddt, J 16.9, 10.2, 6.6 Hz), 5.08 (1H, dtd,
J 16.9, 1.4, 1.3 Hz), 5.02 (1H, dtd, J 10.2, 1.4, 1.3 Hz), 3.19 (2H,
dd, J 7.7, 6.6 Hz), 2.48 (1H, ddd, J 6.6, 6.6, 1.4 Hz), 2.45 (1H,
ddd, J 7.7, 6.6, 1.4 Hz), 1.72 (6H, s); δ (100 MHz; CDCl ) 197.2
H
3
-
1
1594, 1512, 1396, 1244, 1176, 1033, 702 cm ; δ (400 MHz;
C
3
H
(
C), 170.6 (C), 160.3 (C), 136.1 (CH), 116.3 (CH ), 105.0 (C),
CDCl ) 7.30-7.26 (3H, m), 7.12 (2H, d, J 8.7 Hz), 6.94 (2H, dd, J
2
3
9
1.7 (C), 35.1 (CH ), 29.9 (CH ), 26.9 (2 x Me); HRMS (ESI):
5.8, 3.8 Hz), 6.77 (2H, d, J 8.7 Hz), 5.68-5.56 (2H, m), 4.88 (1H,
d, J 14.2 Hz), 4.77 (1H, d, J = 14.2 Hz), 3.80 (1H, dd, J 11.9, 3.9
Hz), 3.75 (3H, s), 2.79-2.71 (1H, m), 2.67 (1H, dd, J 14.9, 7.3
Hz), 2.43-2.34 (1H, m), 2.08-2.02 (2H, m), 2.01-1.93 (1H, m); δC
2
2
+
MNa , found 249.0742. C H NaO requires 249.0733.
11
14
5
4
6
.2.1.7. N-(4-Methoxybenzyl)-3-oxo-N-phenylhept-
-enamide
(
100 MHz; CDCl ) 209.2 (C), 169.5 (C), 159.0 (C), 141.6 (C),
3
1
1
30.2 (CH), 129.6 (CH), 129.4 (C), 129.2 (CH), 129.1 (CH),
28.4 (CH), 128.2 (CH), 113.8 (CH), 55.3 (CH or Me), 55.2 (CH
To a stirred solution of 5-(1-hydroxypent-4-enylidene)-2,2-
dimethyl-1,3-dioxane-4,6-dione (2.16 g, 9.55 mmol) in 1,4-
dioxane (14 mL) was added N-(4-methoxybenzyl)aniline (2.04 g,
.55 mmol). The reaction mixture was stirred for 4 h at 110 °C,
or Me), 52.5 (CH ), 42.2 (CH ), 28.4 (CH ), 23.9 (CH ); HRMS
2
2
2
2
+
(ESI): MNa , found 372.1573. C H NNaO requires 372.1570.
9
22 23 3
then the solvent was removed in vacuo and the residual oil was
purified by column chromatography on silica gel
4
.2.1.10. N-(4-Methoxybenzyl)-4-oxo-N-phenyl-8-
oxabicyclo[5.1.0]octane-3-carboxamide (21f)
(Hexane/EtOAc, 5:1) to give the title compound (2.81 g, 87%) as
a yellow oil; νmax 1720, 1651, 1594, 1512, 1395, 1244, 1175,
To a stirred solution of (Z)-N-(4-methoxybenzyl)-7-oxo-N-
phenylcyclohept-3-enecarboxamide 21e (0.122 g, 0.348 mmol) in
acetone (2 mL) at 0 °C was added a solution of DMDO (0.06 M
in acetone, 11.1 mL, 0.696 mmol). The reaction mixture was
stirred at 0 °C for 1 h and allowed to warm to rt for a further 1 h.
The solvent was removed in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/Petrol 2:1) to give
the title compound 21f (0.108 g, 85%) as a colourless oil and
-
1
1
7
8
1
3
033, 821, 701 cm ; δ (400 MHz; CDCl ) 7.32-7.28 (3H, m),
H 3
.12 (2H, d, J 8.7 Hz), 6.94 (2H, dd, J 6.5, 3.1 Hz), 6.78 (2H, d, J
.7 Hz), 5.70 (1H, ddt, J 16.8, 10.2, 6.6 Hz), 4.94 (1H, dd, J 16.8,
.5 Hz), 4.91 (1H, dd, J 10.2, 1.5 Hz), 4.83 (2H, s), 3.76 (3H, s),
.27 (2H, s), 2.41 (2H, t, J 7.1 Hz), 2.21 (2H, td, J 7.1, 6.6 Hz);
δ (100 MHz; CDCl ) 203.7 (C), 166.7 (C), 159.0 (C), 141.9 (C),
C
3
1
1
4
3
36.8 (CH), 130.3 (CH), 129.7 (CH), 129.2 (C), 128.6 (CH),
28.5 (CH), 115.4 (CH ), 113.8 (CH), 55.3 (Me), 52.5 (CH ),
inseparable 1:1.5 mixture of diastereoisomers; νmax 1710, 1657,
2
2
+
-1
9.5 (CH ), 42.3 (CH ), 27.5 (CH ); HRMS (ESI): MNa found
1594, 1594, 1512, 1396, 1244, 1176, 1031, 730, 702 cm ; δ
2
2
2
H
60.1561. C H NNaO requires 360.1570.
(400 MHz; CDCl ) 7.31-7.26 (3H, m), 7.14-7.06 (2H, m), 6.92-
21
23
3
3
6
(
3
.84 (2H, m), 6.80-6.74 (2H, m), 4.84 (1H, d, J 14.3 Hz), 4.77
0.4H, d, J 14.3 Hz), 4.75 (0.6H, d, J 14.3 Hz), 3.75 (3H, s),
.66-3.58 (1H, m), 3.17 (1H, td, J 4.6, 1.7 Hz), 3.06-3.01 (1H,
m), 2.54- 2.34 (2H, m), 2.09 (0.6H, ddd, J 12.1, 7.5, 4.4 Hz),
.01-1.93 (2H, m), 1.82 (1.4H, ddd, J 12.1, 9.8, 4.4 Hz); δ (100
4
.2.1.8. N-(4-Methoxybenzyl)-2-(2-methylallyl)-3-
oxo-N-phenylhept-6-enamide
To a stirred solution of NaH (60% in mineral oil, 0.336 g, 8.41
mmol) in DMF (100 mL) was added N-(4-Methoxybenzyl)-3-
oxo-N-phenylhept-6-enamide (2.58 g, 7.65 mmol) at 0 °C. The
reaction mixture was stirred for 15 min and allyl bromide (0.695
mL, 8.03 mmol) was added slowly. The resulting light green
solution was stirred for 30 min and then allowed to warm to room
temperature where it slowly turned yellow. The reaction mixture
2
C
MHz; CDCl ) 209.3 and 207.4 (C), 168.9 and 168.7 (C), 159.0
3
(C), 141.3 and 141.2 (C), 130.2 and 130.1 (CH), 129.74 and
1
1
5
2
3
29.70 (CH), 129.4 (CH), 129.31 and 129.26 (C), 128.5 (CH),
13.8 (CH), 55.3 (Me), 54.4 (CH), 54.0 and 53.3 (CH), 52.6 and
2.5 (CH ), 51.7 and 51.4 (CH), 38.0 and 36.3 (CH ), 28.6 and
2
2
+
7.3 (CH ), 24.0 and 22.7 (CH ); HRMS (ESI): MNa , found
was stirred overnight and quenched with sat. NH Cl (100 mL).
2
2
4
88.1504. C H NNaO requires 388.1519.
The aqueous layer was extracted with EtOAc (2 × 100 mL). The
combined organic phases were washed with water (5 × 50 mL)
22 23
4
4
.2.1.11. General procedure 2: Copper(II)-mediated
and sat. brine (2 × 50 mL), dried over MgSO , filtered and
4
synthesis of spirocyclic oxindoles 22a-f
concentrated in vacuo. Purification by column chromatography
on silica gel (Petrol/EtOAc, 6:1) gave the title compound (3.21 g,
quant.) as a light yellow oil; νmax 1717, 1650, 1613, 1594, 1512,
To a stirred solution of linear amide 21 (1 equiv) in toluene
(0.04 M) was added Cu(OAc) ꢁH O (10 mol%-1 equiv) under an
2
2
-
1
1
394, 1302, 1245, 1176, 1033, 916, 702 cm ; δ (400 MHz;
O atmosphere. The reaction mixture was heated at 110 °C for
2
H

8
Tetrahedron
1
.5 h then cooled to room temperature and
A
t
C
he
C
so
E
lv
P
e
T
nt
E
was MA3:
D
NU
1);
ν
SC17
R
1
I
6
P
, 1692, 1609, 1590, 1508, 1465, 1361, 1208, 1156,
T
max
®
-1
removed in vacuo. The residue was filtered through Celite ,
washed with CH Cl and concentrated in vacuo to give the crude
1035, 746 cm ; δ (400 MHz; CDCl ) 7.24 (1H, dd, J 7.5, 1.0
H
3
Hz), 7.17 (1H, td, J 7.5, 1.0 Hz), 7.06 (1H, d, J 8.4 Hz), 7.01 (1H,
td, J 7.5, 1.0 Hz), 6.77 (1H, d, J 7.5 Hz), 6.44 (1H, d, J 2.4 Hz),
6.38 (1H, dd, J 8.4, 2.4 Hz), 4.89 (1H, d, J 16.0 Hz), 4.80 (1H, d,
J 16.0 Hz), 3.84 (3H, s), 3.75 (3H, s), 3.05 (1H, td, J 9.0, 2.1 Hz),
2
2
product. Purification by column chromatography on silica gel
Hexane/EtOAc, 4:1) gave the title compound.
(
4
.2.1.12. 1’-Benzyl-1’,2’-
dihydrospiro[cyclopentane-1,3’-indole] -2’,5-dione
22a)
2
2
.76 (1H, td, J 9.0, 2.1 Hz), 2.37 (1H, dd, J 14.7, 8.8 Hz), 2.22–
.12 (1H, m), 2.05 (1H, dd, J 14.7, 9.4 Hz), 1.97–1.73 (5H, m);
(
δ (100 MHz; CDCl ) 207.7 (C), 175.7 (C), 160.4 (C), 158.1 (C),
C
3
Following general procedure 2 from N-benzyl-2-oxo-N-
143.0 (C), 130.7 (C), 129.1 (CH), 128.6 (CH), 123.4 (CH), 122.5
(CH), 116.0 (C), 109.8 (CH), 104.4 (CH), 98.5 (CH), 65.6 (C),
phenylcyclopentane-1-carboxamide 21a (11.0 mg, 0.037 mmol)
was obtained the title compound 22a (6.0 mg, 56%) as a
colourless oil; νmax 2969, 1747, 1702, 1611, 1489, 1466, 1360,
5
(CH
5.5 (Me), 55.4 (Me), 42.5 (CH ), 38.2 (CH ), 34.9 (CH ), 31.0
2 2 2
+
), 26.7 (CH
), 25.4 (CH
H25NNaO requires 402.1676.
4
); HRMS (ESI): MNa , found
2
2
2
-
1
1
183, 1107, 754, 697 cm ; δ (400 MHz; CDCl ) 7.34–7.24 (5H,
402.1665. C23
H
3
m), 7.16 (1H, td, J 7.7, 1.3 Hz), 7.09 (1H, dd, J 7.2, 1.2 Hz), 7.00
1H, td, J 7.6, 1.0 Hz), 6.69 (1H, d, J 7.9 Hz), 5.00 (1H, d, J 15.8
Hz), 4.80 (1H, d, J 15.8 Hz), 2.79–2.70 (1H, m), 2.70–2.61 (1H,
m), 2.60–2.48 (2H, m), 2.46–2.37 (1H, m), 2.32–2.19 (1H, m); δC
4
.2.1.16. (Z)-1'-(4-
(
Methoxybenzyl)spiro[cyclohept[3]ene-1,3'-
indoline] -2',7-dione (22e)
(
100 MHz; CDCl ) 212.7 (C), 175.4 (C), 143.5 (C), 135.4 (C),
Following
general
procedure
2
from
(Z)-N-(4-
3
1
1
30.5 (C), 128.9 (CH), 128.7 (CH), 127.7 (CH), 127.1 (CH),
methoxybenzyl)-7-oxo-N-phenylcyclohept-3-enecarboxamide
21e (0.024 g, 0.068 mmol) at 100 °C was obtained the title
compound 22e (0.013 g, 55%) as a colourless solid; mp. 125-127
23.0 (CH), 122.6 (CH), 109.6 (CH), 63.1 (C), 43.9 (CH ), 38.4
2
+
(CH ), 34.2 (CH ), 20.4 (CH ); HRMS (ESI): MNa , found
2
2
2
3
14.1154. C H NNaO requires 314.1151.
°C; ν 1697, 1610, 1514, 1487, 1466, 1352, 1248, 1178, 1033,
19
17
2
max
-
1
7
50 cm ; δ (400 MHz; CDCl ) 7.28 (1H, dd, J 7.6, 1.0 Hz), 7.20
H 3
4
.2.1.13. 1’-Methyl-1’-2’-
(2H, d, J 8.7 Hz), 7.17 (1H, td, J 7.6, 1.0 Hz), 6.99 (1H, td, J 7.6,
dihydrospiro[cyclohexane-1,3’-indole] -2’,6-dione
22b)
1
.0 Hz), 6.83 (2H, d, J 8.7 Hz), 6.72 (1H, d, J 7.6 Hz), 5.95–5.80
(
(
(
2H, m), 4.88 (1H, d, J 15.5 Hz), 4.77 (1H, d, J 15.5 Hz), 3.76
3H, s), 3.60 (1H, dd, J 14.2, 8.1 Hz), 3.41 (1H, ddd, J 15.4, 4.7,
Following general procedure 2 from N-methyl-2-oxo-N-
2
.2 Hz), 2.76–2.65 (2H, m), 2.63–2.50 (1H, m), 2.35 (1H, dd, J
15.4, 7.4 Hz); δ (100 MHz; CDCl ) 206.6 (C), 174.2 (C), 159.1
C), 142.9 (C), 131.0 (CH), 130.6 (C), 128.8 (CH), 128.5 (CH),
phenylcyclohexane-1-carboxamide 21b (0.016 g, 0.067 mmol)
was obtained the title compound 22b (0.010 g, 65%) as a
colourless oil; νmax 2940, 2867, 1730, 1697, 1613, 1494, 1471,
C
3
(
-
1
1
27.5 (C), 125.6 (CH), 124.2 (CH), 122.8 (CH), 114.3 (CH),
), 39.0 (CH ), 31.4
CH ), 27.7 (CH ); HRMS (ESI): MNa found 370.1410.
1
373, 1348, 1127, 754 cm ; δ (400 MHz; CDCl ) 7.30 (1H, td,
H
3
J 7.6, 1.1 Hz), 7.28 (1H, d, J 7.3 Hz), 7.09 (1H, td, J 7.5, 0.9 Hz),
109.6 (CH), 67.8 (C), 55.3 (Me), 43.4 (CH
(
2
2
+
6
5
4
2
2
.83 (1H, d, J 7.8 Hz), 3.19 (3H, s), 3.05 (1H, ddd, J 14.2, 10.5,
.5 Hz), 2.58 (1H, dt, J 14.2, 5.5 Hz), 2.41 (1H, dtt, J 14.2, 10.5,
.0 Hz), 2.27–2.13 (2H, m), 2.08 (1H, ddd, J 14.2, 10.5, 4.0 Hz),
.03–1.92 (1H, m), 1.90–1.81 (1H, m); δ (100 MHz; CDCl )
2
2
C H NNaO requires 370.1414.
22 21
3
4
.2.1.17. 1'-(4-Methoxybenzyl)-8-
C
3
oxaspiro[bicyclo[5.1.0]octane-3,3'-indoline] -2',4-
dione (22f)
05.4 (C), 174.4 (C), 143.3 (C), 129.5 (C), 128.8 (CH), 124.7
(
2
2
CH), 122.8 (CH), 108.5 (CH), 63.8 (C), 39.9 (CH ), 37.4 (CH ),
2 2
+
7.0 (CH ), 26.6 (CH ), 20.4 (CH ); HRMS (ESI): MNa , found
Following general procedure 2 from N-(4-methoxybenzyl)-4-
oxo-N-phenyl-8-oxabicyclo[5.1.0]octane-3-carboxamide (0.027
g, 0.073 mmol) was obtained the title compound 22f (0.015 g,
2
3
2
52.0998. C H NNaO requires 252.0995.
14
15
2
4
.2.1.14. 1'-Methylspiro[cycloheptane-1,3'-
6
1
2%) as a pale yellow oil; νmax 1698, 1611, 1514, 1488, 1466,
indoline] -2,2'-dione (22c)
-1
362, 1248, 1178, 1033, 751 cm ; δ (400 MHz; CDCl ) 7.55
H
3
(
8
(
1H, dd, J 7.6, 1.0 Hz), 7.20 (1H, td, J 7.6, 1.0 Hz), 7.17 (2H, d, J
.8 Hz), 7.08 (1H, td, J 7.6, 1.0 Hz), 6.83 (2H, d, J 8.8 Hz), 6.73
1H, d, J 7.6 Hz), 4.87 (1H, d, J 15.6 Hz), 4.76 (1H, d, J 15.6
Following general procedure 2 from N-methyl-2-oxo-N-
phenylcycloheptanecarboxamide 21c (0.037 g, 0.152 mmol) was
obtained the title compound 22c (0.024 g, 66%) as a colourless
-
1
Hz), 3.75 (3H, s), 3.43 (1H, ddd, J 6.9, 3.9, 2.4 Hz), 3.31 (1H, dt,
J 3.9, 2.8 Hz), 3.19 (1H, dd, J 8.4, 3.0 Hz), 3.13 (1H, dd, J 15.7,
2
oil; νmax 2889, 1703, 1668, 1585, 1471, 1447, 1352, 1325 cm ; δ
H
(
400 MHz; CDCl ) 7.29 (1H, td, J 7.7, 1.2 Hz), 7.25 (1H, ddd, J
3
.4 Hz), 2.54–2.47 (3H, m), 2.41 (1H, dd, J 15.7, 6.9 Hz); δC
7
.7, 1.2, 0.5 Hz), 7.06 (1H, td, J 7.7, 1.2 Hz), 6.83 (1H, d, J 7.7
(100 MHz; CDCl ) 204.0 (C), 173.9 (C), 159.2 (C), 142.9 (C),
Hz), 3.19 (3H, s), 3.09–3.01 (1H, m), 2.78–2.67 (1H, m), 2.31
1H, dd, J 14.8, 9.1 Hz), 2.17–2.09 (1H, m), 2.07–1.95 (1H, m),
3
1
(
5
30.3 (C), 128.8 (CH), 128.5 (CH), 127.4 (C), 125.6 (CH), 123.4
CH), 114.3 (CH), 109.5 (CH), 63.8 (C), 55.3 (Me), 55.2 (CH),
4.3 (CH), 43.5 (CH ), 35.8 (CH ), 32.8 (CH ), 25.9 (CH );
(
1
2
.94–1.84 (1H, m), 1.84–1.73 (4H, m); δ (100 MHz; CDCl )
07.6 (C), 175.3 (C), 143.5 (C), 130.8 (C), 128.7 (CH), 123.6
C
3
2
2
2
2
+
HRMS (ESI): MNa found 386.1369. C H NNaO requires
3
(
CH), 122.7 (CH), 108.6 (CH), 65.6 (C), 42.3 (CH ), 34.8 (CH ),
22 21
4
2
2
86.1363.
3
0.9 (CH ), 26.8 (CH ), 26.5 (Me), 25.4 (CH ); HRMS (ESI):
2 2 2
+
MH , found 244.1334. C H NO requires 244.1332.
15
18
2
4
.2.2. Synthesis of a Satavaptan model system
4
.2.1.15. 1'-(2,4-
Dimethoxybenzyl)spiro[cycloheptane-1,3'-indoline]-
,2'-dione (22d)
4.2.2.1. N-Methyl-N-phenyl 7-oxo-1,4-
dioxaspiro[4.5]decane-8-carboxamide (25)
2
A solution of benzyl 7-oxo-1,4-dioxaspiro[4.5]decane-8-
carboxylate (2.07 g, 7.13 mmol) and 10% Pd/C (0.414 g) in
Following general
procedure
2
from
N-(2,4-
dimethoxybenzyl)-2-oxo-N-phenylcycloheptanecarboxamide 21d
EtOAc (71 mL) was evacuated and backfilled with H four times.
2
(
0.306 g, 0.798 mmol) was obtained the title compound 22d
The reaction mixture was stirred under an atmosphere of H2
(balloon) for 16 h, then filtered through a pad of Celite which
(0.206 g, 68%) as a colourless solid; R 0.40 (Hexane/EtOAc,
f

9
was washed with EtOAc (3 × 15 mL). The c
A
om
C
bi
C
ne
E
d
P
or
T
ga
E
n
D
ics MA16
N
09
U
, 1
S
4
C
91
R
, 1
I
4
P
7
T
0, 1417, 1377, 1358, 1238, 1126, 1095, 1070,
-
1
were concentrated in vacuo to afford 7-oxo-1,4-
dioxaspiro[4.5]decane-8-carboxylic acid 24 (1.40 g, 98%) as a
colourless solid which was used directly in the next step without
further purification.
1039 cm ; δ (400 MHz; CDCl ) 7.51 (1H, dd, J 7.5, 0.4 Hz),
H
3
7.31 (1H, td, J 7.8, 1.1 Hz), 7.06 (1H, td, J 7.6, 0.9 Hz), 6.86
(1H, d, J 7.7 Hz), 4.10-3.98 (5H, m), 3.21 (3H, s), 2.50-2.46 (1H,
m), 2.20-2.17 (1H, m), 2.05-1.84 (4H, m); δ (100 MHz; CDCl )
C
3
1
78.3 (C), 143.7 (C), 130.4 (C), 128.2 (CH), 125.6 (CH), 122.2
To
a
solution of 7-oxo-1,4-dioxaspiro[4.5]decane-8-
(CH), 108.8 (C), 107.9 (CH), 71.0 (CH), 64.5 (CH ), 64.4 (CH ),
2
2
carboxylic acid 24 (1.40 g, 6.99 mmol) in CH Cl (71 mL) at 0
C was added N-methylaniline (0.93 mL, 8.56 mmol), 2-chloro-
-methylpyridinium iodide (2.73 g, 10.7 mmol) and Et N (2.98
2
2
5
2.7 (C), 37.9 (CH ), 30.0 (CH ), 28.1 (CH ), 26.3 (Me); HRMS
2 2 2
+
°
1
(ESI): MNa , found 312.1212. C H NNaO requires 312.1206.
16 19 4
3
mL, 21.4 mmol). The reaction mixture was stirred at 0 °C for 30
4.2.2.4. 1’-Methyl-1’,2’-dihydrospiro[cyclohexane-
min, then at rt for 19 h. H O (150 mL) was then added, the
1,3’-indol] -2-ene-2’,4-dione (29)
2
organics separated, and the aqueous phase further extracted with
CH Cl (2 × 150 mL). The combined organics were washed with
To
a
solution
of
3’-hydroxy-1’’-methyl-1’’,2’’-
2
2
dihydrodispiro[1,3-dioxolane-2,1’-cyclohexane-4’,3’’-indole]-
’’-one 27 (29.0 mg, 0.100 mmol) in THF (0.5 mL) was added
0% aqueous HCl (0.2 mL). The reaction mixture was heated at
reflux for 1 h, then cooled to rt and partitioned between saturated
NaHCO (10 mL) and EtOAc (3 × 10 mL). The combined
organics were dried over MgSO , filtered, and concentrated in
vacuo. Purification by flash column chromatography, eluting
with EtOAc/Hexane (1:9 to 1:1), afforded the title compound as a
colourless oil (16.9 mg, 74%); νmax 3056, 2934, 1704, 1674,
607, 1491, 1469, 1418, 1383, 1370, 1344, 1301, 1267, 1255,
237, 1189, 1126, 1089 cm ; δ (400 MHz; CDCl ) 7.35 (1H, td,
J 7.7, 1.2 Hz), 7.19 (1H, dd, J 7.4, 0.7 Hz), 7.09 (1H, td, J 7.6,
0.7 Hz), 6.90 (1H, d, J 7.7 Hz), 6.46 (1H, d, J 10.1 Hz), 6.24 (1H,
d, J 10.1 Hz), 3.25 (3H, s), 3.11 (1H, ddd, J 17.2, 9.8, 5.3 Hz),
.60 (1H, ddd, J 17.2, 9.8, 5.3 Hz), 2.43-2.36 (1H, m), 2.27 (1H,
ddd, J 14.0, 9.8, 5.1 Hz); δ (100 MHz; CDCl ) 198.1 (C), 176.3
C), 146.2 (CH), 143.1 (C), 131.5 (CH), 131.2 (C), 129.2 (CH),
23.7 (CH), 123.1 (CH), 108.7 (CH), 49.7 (C), 33.2 (CH ), 32.0
saturated NaHCO (150 mL), dried over MgSO , filtered, and
3
4
2
1
concentrated in vacuo. Purification by flash column
chromatography, eluting with EtOAc/Hexane (1:1), afforded the
title compound 25 (1.24 g, 60%) as a pale yellow solid; mp 105–
3
1
1
07 °C; νmax 2918, 1715, 1656, 1595, 1489, 1421, 1385, 1307,
-1
4
237, 1131, 1091, 1032 cm ; δ (400 MHz; CDCl ) 7.40-7.31
H
3
(3H, m), 7.18-7.16 (2H, m), 3.95-3.86 (4H, m), 3.29 (3H, s), 3.21
(1H, dd, J 10.2, 6.0 Hz), 2.70 (1H, dd, J 14.1, 2.1 Hz), 2.32 (1H,
d, J 14.1 Hz), 2.27-2.17 (1H, m), 2.09-2.03 (1H, m), 1.92-1.84
1
1
(
1H, m), 1.74-1.67 (1H, m).; δ (100 MHz; CDCl ) 203.0 (C),
C
3
-1
H
3
1
68.8 (C), 143.4 (C), 129.7 (CH), 128.1 (CH), 127.1 (CH), 109.4
(
3
C), 64.55 (CH ), 64.51 (CH ), 53.2 (CH), 51.0 (CH ), 37.3 (Me),
2
2
2
+
2.7 (CH ), 23.9 (CH ).; HRMS (ESI): MNa , found 312.1196.
2 2
C H NNaO requires 312.1206.
16
19
4
2
4
.2.2.2. 1’’-Methyl-1’’,2’’-dihydrodispiro[1,3-
C
3
dioxolane-2,1’-cyclohexane-4’,3’’-indole] -2’’,3’-
dione (26)
(
1
(
2
+
CH ), 26.6 (Me); HRMS (ESI): MNa , found 250.0843.
2
A
solution
of
N-methyl-N-phenyl
7-oxo-1,4-
C H NNaO requires 250.0838.
1
4
13
2
dioxaspiro[4.5]decane-8-carboxamide 25 (0.430 g, 1.49 mmol)
and Cu(OAc) ·H O (30.0 mg, 0.150 mmol) in mesitylene (30
4.2.2.5. 1’-Methyl-1’,2’-dihydrospiro[cyclohexane-
2
2
mL) was heated at reflux for 15 min whilst compressed air (dried
over H SO ) was bubbled through the mixture. After cooling to
rt, the reaction mixture was concentrated in vacuo. Purification
by flash column chromatography, eluting with EtOAc/Hexane
1,3’-indole] -2’,4-dione (30)
2
4
A solution of 1’-methyl-1’,2’-dihydrospiro[cyclohexane-1,3’-
indol]-2-ene-2’,4-dione 29 (16.9 mg, 0.074 mmol) and 10% Pd/C
(3.4 mg) in EtOAc (1 mL) was evacuated and backfilled with H2
(1:9 to 1:4), afforded the title compound (0.222 g, 52%) as a
4
times. The reaction mixture was stirred under an atmosphere of
colourless solid; mp 124–125 °C; νmax 2969, 1723, 1694, 1656,
-
1
H (balloon) for 16 h, then filtered through a pad of Celite which
2
1
606, 1489, 1348, 1309, 1236, 1122, 1089, 1066 cm ; δ (400
H
was washed with EtOAc (3 × 15 mL). The combined organics
were concentrated in vacuo to afford the title compound as a
colourless solid (16.0 mg, 94%); mp 128–130 °C; νmax 2927,
MHz; CDCl ) 7.32 (1H, td, J 7.7, 1.3 Hz), 7.24 (1H, dd, J 7.4, 0.7
3
Hz), 7.13 (1H, td, J 7.6, 0.9 Hz), 6.85 (1H, d, J 7.7 Hz), 4.06-
4
.00 (4H, m), 3.50 (1H, d, J 13.5 Hz), 3.20 (3H, s), 2.81 (1H, td,
J 12.9, 4.9 Hz), 2.77 (1H, dd, J 13.5, 2.4 Hz), 2.26 (1H, td, J
2.5, 4.4 Hz), 2.10 (1H, dt, J 14.0, 4.1 Hz), 1.97-1.93 (1H, m); δC
100 MHz; CDCl ) 200.9 (C), 173.4 (C), 143.3 (C), 128.9 (CH),
1
1
1
700, 1609, 1493, 1467, 1443, 1377, 1347, 1330, 1301, 1228,
-1
186, 1131, 1085 cm ; δ (400 MHz; CDCl ) 7.32 (1H, td, J 7.7,
H
3
1
.0 Hz), 7.24 (1H, d, J 7.3 Hz), 7.09 (1H, td, J 7.6, 0.6 Hz), 6.89
(
3
(1H, d, J 7.8 Hz), 3.25 (3H, s), 3.17 (2H, ddd, J 16.1, 8.8, 8.8
1
28.8 (C), 125.1 (CH), 123.1 (CH), 110.0 (C), 108.5 (CH), 65.1
Hz), 2.48 (2H, ddd, J 15.0, 5.4, 5.4 Hz), 2.15 (4H, dd, J 8.8, 5.4
Hz); δ (100 MHz; CDCl ) 210.9 (C), 179.3 (C), 142.9 (C), 133.3
(
2
CH ), 64.8 (CH ), 62.4 (C), 49.8 (CH ), 31.6 (CH ), 30.4 (CH ),
6.6 (Me).; HRMS (ESI): MNa , found 310.1040. C H NNaO
16 17 4
2
2
2
2
2
+
C
3
(C), 128.4 (CH), 122.8 (CH), 122.6 (CH), 108.5 (CH), 45.6 (C),
requires 310.1050.
+
3
2
7.0 (CH ), 33.7 (CH ), 26.3 (Me).; HRMS (ESI): MNa , found
2 2
4
.2.2.3. 3’-Hydroxy-1’’-methyl-1’’,2’’-
dihydrodispiro[1,3-dioxolane-2,1’-cyclohexane-
’,3’’-indole] -2’’-one (27)
52.0983. C H NNaO requires 252.0995.
14
15
2
4
4
.2.3. Formal total synthesis of Satavaptan
.2.3.1. N-Benzyl-N-(4-ethoxyphenyl)-7-oxo-1,4-
4
To solution of 1’’-methyl-1’’,2’’-dihydrodispiro[1,3-
a
dioxaspiro[4.5]decane-8-carboxamide (20)
dioxolane-2,1’-cyclohexane-4’,3’’-indole]-2’’,3’-dione 26 (0.197
g, 0.686 mmol) in MeOH (6.9 mL) at 0 °C was added NaBH4
To stirred solution of ethyl
a
7-oxo-1,4-
dioxaspiro[4.5]decane-8-carboxylate 24 (0.577 g, 1.41 mmol), N-
benzyl-4-ethoxyaniline 4 (0.141 g, 0.705 mmol) and DIPEA (311
µL, 1.83 mmol) in EtOAc (9 mL) at room temperature was added
T3P (0.897 g, 1.41 mmol, 50% w/w solution in EtOAc). The
reaction mixture was stirred at room temperature for 16 h.
(
39.0 mg, 1.03 mmol). Stirring was continued at 0 °C for 1 h,
then saturated NH Cl (20 mL) was added and the aqueous phase
4
extracted with EtOAc (3 × 20 mL). The combined organics were
dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash column chromatography, eluting with
EtOAc/Hexane (1:1), afforded the title compound (0.185 g, 93%)
as a colourless solid; mp 169–171 °C; νmax 3394, 2896, 1673,
Saturated NaHCO (10 mL) was added and the aqueous phase
3
extracted with EtOAc (10 × 5 mL). The combined organic

1
0
Tetrahedron
extracts were washed with saturated NaHC
A
O
C
(1
C
0
E
m
P
L)
T
, b
E
ri
D
ne MAph
NU
as
e w
S
a
C
s
R
ex
I
tracted with EtOAc (2 × 10 mL). The combined
P
T
3
(10 mL), dried over MgSO , filtered and concentrated in vacuo.
organic phases were dried (MgSO ), filtered and concentrated in
4
4
Purification
by flash
column
chromatography (1:1
vacuo. Purification by flash column chromatography (1:1
hexane/EtOAc) afforded the title compound 20 (0.220 g, 76%) as
hexane/EtOAc) afforded a single diastereoisomer of the title
a colourless oil; ν 2978, 1718, 1657, 1511, 1401, 1301, 1247
compound 31 (0.284 g, 80%) as a colourless powder; m.p. 174–
max
-
1
-
cm ; δ (400 MHz; CDCl ): 7.28-7.16 (5H, m), 6.83 (2H, d, J
175 °C; ν 3452, 2933, 1698, 1597, 1496, 1455, 1442, 1351 cm
H
3
max
1
8
.9 Hz), 6.73 (2H, d, J 8.9 Hz), 5.00 (1H, d, J 14.4 Hz), 4.73 (1H,
d, J 14.4 Hz), 3.98-3.85 (6H, m), 3.21 (1H, dd, J 5.95, 4.12 Hz),
.66 (1H, d, J 14.0 Hz), 2.31 (1H, d, J 14.0 Hz), 2.34-2.20 (1H,
m), 2.07-2.20 (1H, m), 1.96-1.87 (1H, m), 1.72 (1H, td, J 12.8,
.12 Hz), 1.37 (3H, t, J 6.9 Hz); δ (100 MHz, CDCl ): 203.3
; δ (400 MHz, CDCl ): 7.31-7.19 (5H, m), 7.16 (1H, d, J 2.5
H
3
Hz), 6.68 (1H, dd, J 8.5, 2.5 Hz), 6.57 (1H, d, J 8.5 Hz), 4.98
(1H, d, J 16.0 Hz), 4.81 (1H, d, J 16.0 Hz), 4.20-3.91 (7H, m),
2.60-2.46 (1H, m), 2.25-2.13 (1H, m), 2.09-1.96 (3H, m), 1.94-
1.86 (1H, m), 1.37 (3H, t, J 7.0 Hz); δ (100 MHz, CDCl ): 178.3
2
4
C
3
C
3
(
1
(
C), 169.4 (C), 158.7 (C), 137.4 (C), 134.3 (C), 129.5 (CH),
28.9 (CH), 128.4 (CH), 127.4 (CH), 115.1 (CH), 109.7 (C), 64.9
CH ), 63.7 (CH ), 53.7 (CH), 53.3 (CH ), 51.4 (CH ), 33.1
(C), 154.9 (C), 136.3 (C), 136.0 (C), 128.8 (CH), 127.5 (CH),
127.1 (C), 127.0 (CH), 114.5 (CH), 112.7 (CH), 109.3 (CH),
108.9 (C), 73.4 (CH), 71.3 (C), 64.6 (CH ), 64.5 (CH ), 64.1
2
2
2
2
2
2
+
(CH ), 24.1 (CH ), 14.8 (Me); HRMS [ESI]: MNa , found
(CH ), 43.7 (CH ), 38.1 (CH ), 30.1 (CH ), 28.4 (CH ), 15.0
2 2 2 2 2
+
2
2
4
32.1776. C H NNaO requires 432.1781.
(Me); HRMS [ESI]: MH , found 410.1957. C H NO requires
24 28 5
24
27
5
4
10.1962.
4
.2.3.2. 1''-Benzyl-5''-ethoxy-2'H-dispiro[1,3-
dioxolane-2,4'-cyclohexane-1',3''-indole] -
',2''(1''H)-dione (19)
4.2.3.4. 1'-Benzyl-5'-ethoxyspiro[cyclohex[2]ene-
1,3'-indoline] -2',4-dione
2
In mesitylene: N-Benzyl-N-(4-ethoxyphenyl)-7-oxo-1,4-
To 1''-benzyl-5''-ethoxy-3'-hydroxydispiro[1,3-dioxolane-2,1'-
cyclohexane-4',3''-indol]-2''(1''H)-one 31 (0.261 g, 0.638 mmol)
was added THF (3 mL) and 10% aqueous HCl solution (1.2 mL)
and the mixture stirred at 70 °C for 90 min. The reaction mixture
was allowed to cool to room temperature then quenched with sat.
dioxaspiro[4.5]decane-8-carboxamide 20 (80.0 mg, 0.196 mmol)
and Cu(OAc) ꢁH O (3.9 mg, 10 mol%) in mesitylene (4 mL) was
2
2
stirred at 165 °C with compressed air bubbled through for 30
min. Upon completion of the reaction, mesitylene was removed
under reduced pressure and EtOAc (5 mL) was added. The
organic phase was washed with 10% HCl solution (2 × 5 mL),
NaHCO (6mL). The aqueous phase was extracted with EtOAc
3
(2 × 5 mL). The combined organic phases were dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash column
chromatography (7:3 hexane/EtOAc) afforded the title compound
1
0% NH OH solution (2 × 5 mL), brine (5 ml), dried over
4
MgSO , filtered and concentrated in vacuo. Purification by flash
4
column chromatography (7:3 petrol/EtOAc) afforded the title
compound 19 (46.0 mg, 58%) as a yellow oil.
(0.188 g, 85%) as a colourless oil; ν 2979, 1705, 1675, 1560,
max
-
1
1495, 1453, 1384, 1341 cm ; δ (400 MHz; CDCl ): 7.34-7.23
H
3
(
(
5H, m), 6.80 (1H, d, J 2.4 Hz), 6.73 (1H, dd, J 8.4, 2.4 Hz), 6.67
1H, d, J 8.4 Hz), 6.57 (1H, d, J 10.0 Hz), 6.27 (1H, d, J 10.0
In ethylene carbonate: N-Benzyl-N-(4-ethoxyphenyl)-7-oxo-
,4-dioxaspiro[4.5]decane-8-carboxamide 20 (55.0 mg, 0.134
1
Hz), 4.95 (1H, d, J 15.7 Hz), 4.85 (1H, d, J 15.7 Hz), 3.94 (2H, q,
J 7.0 Hz), 3.16 (1H, ddd, J 17.2, 10.0, 5.3 Hz), 2.63 (1H, ddd, J
1
5
1
mmol) and Cu(OAc) ꢁH O (26.8 mg, 0.134 mmol) in ethylene
2
2
carbonate (3.3 mL) was stirred at 165 °C under an atmosphere of
air for 1 h. The reaction mixture was removed from heat and
7.2, 6.9, 5.0 Hz), 2.51-2.42 (1H, m), 2.31 (1H, ddd, J 13.8, 10.0,
.0 Hz), 1.36 (3H, t, J 7.0 Hz); δ (100 MHz, CDCl ): 198.0 (C),
C
3
allowed to cool to rt, then H O (8 mL) and EtOAc (8 mL) were
2
76.0 (C), 155.6 (C), 146.2 (CH), 135.5 (C), 135.4 (C), 132.5
added and the reaction mixture allowed to cool to room
temperature. The reaction mixture was transferred to a separating
funnel to which EtOAc (15 mL) was added and the organic phase
washed with H O (5 × 10 mL), 10% aqueous NH OH solution (3
(C), 131.6 (CH), 128.9 (CH), 127.8 (CH), 127.2 (CH), 113.8
(CH), 111.8 (CH), 110.1 (CH), 64.1 (CH ), 50.1 (C), 44.1 (CH ),
2
2
+
3
3
3.2 (CH ), 32.3 (CH ), 14.9 (Me); HRMS [ESI]: MH , found
2 2
2
4
48.1588. C H NO requires 348.1594.
22
22
3
×
5 mL), brine (5 mL), dried (MgSO ), filtered and concentrated
4
in vacuo. Purification by flash column chromatography (7:3
hexane/EtOAc) afforded the title compound 19 (34.0 mg, 62%)
4.2.3.5. 1'-Benzyl-5'-ethoxyspiro[cyclohexane-1,3'-
indoline] -2',4-dione (12)
as a yellow oil; ν 2978, 1718, 1698, 1496, 1455, 1352, 1300
max
-
1
To
ethoxyspiro[cyclohex[2]ene-1,3'-indoline]-2',4-dione (0.166 g,
.478 mmol) in EtOAc (6.5 mL) was added 10 wt% Pd/C (21.7
a
stirred
solution
of
1'-benzyl-5'-
cm ; δ (400 MHz, CDCl ): 7.25-7.12 (5H, m), 6.77 (1H, d, J 2.3
H
3
Hz), 6.63 (1H, dd, J 8.4, 2.3 Hz), 6.51 (1H, d, J 8.4 Hz), 4.79
2H, s), 4.01-3.83 (6H, m), 3.46 (1H, d, J 13.7 Hz), 2.77 (1H, td,
J 12.9, 4.9 Hz), 2.72 (1H, d, J 13.7 Hz), 2.29-2.16 (1H, m), 2.09
1H, dt, J 14.1, 4.6 Hz), 1.93-1.86 (1H, m), 1.30 (3H, t, J 6.9 Hz);
δ (100 MHz, CDCl ): 200.8 (C), 173.2 (C), 155.5 (C), 135.54
0
(
mg). The vessel was placed under vacuum and back-filled with
H three times before being stirred at room temperature for 16 h
2
(
under an atmosphere of H (balloon). The reaction mixture was
2
C
3
filtered through celite. The celite was washed with EtOAc (3 × 5
mL) then the combined organics were concentrated in vacuo.
(C), 135.47 (C), 129.9 (C), 128.8 (CH), 127.6 (CH), 127.0 (CH),
1
14.1 (CH), 113.9 (CH), 112.6 (CH), 109.8 (C), 65.0 (CH ), 64.7
2
Purification
by flash
column
chromatography (7:3
(
3
CH ), 64.0 (CH ), 62.6 (C), 49.8 (CH ), 43.9 (CH ), 31.8 (CH ),
2
2
2
2
2
+
hexane/EtOAc) afforded the title compound 12 (0.162 g, 97%) as
0.4 (CH ), 14.8 (Me); HRMS [ESI]: MNa , found 430.1620.
2
5
a colourless powder; m.p. 140–143 °C (Lit. 125–128 °C); ν
max
C H NNaO requires 430.1625.
24
25
5
3
1
033, 2977, 2928, 1710, 1692, 1600, 1495, 1477, 1449, 1369,
-1
4
.2.3.3. 1''-Benzyl-5''-ethoxy-3'-
345 cm ; δ (400 MHz; CDCl ): 7.32-7.21 (5H, m), 6.84 (1H,
H
3
hydroxydispiro[1,3-dioxolane-2,1'-cyclohexane-
d, J 2.5 Hz), 6.68 (1H, d, J 8.6 Hz), 6.62 (1H, d, J 8.6 Hz), 4.90
2H, s), 3.94 (2H, q, J 6.9 Hz), 3.25-3.14 (2H, m), 2.58-2.44 (2H,
4
',3''-indol] -2''(1''H)-one (31)
(
m), 2.25-2.09 (4H, m), 1.36 (3H, t, J 6.9 Hz); δ (100 MHz,
C
To a stirred solution of 1''-benzyl-5''-ethoxy-2'H-dispiro[1,3-
CDCl ): 210.6 (C), 179.1 (C), 155.3 (C), 135.8 (C), 135.1 (C),
3
dioxolane-2,4'-cyclohexane-1',3''-indole]-2',2''(1''H)-dione
19
1
1
34.4 (C), 128.7 (CH), 127.6 (CH), 127.0 (CH), 112.5 (CH),
11.1 (CH), 109.6 (CH), 64.0 (CH ), 45.8 (C), 43.5 (CH ), 36.8
(
0.355 g, 0.872 mmol) in MeOH (10.5 mL) at 0 °C was added
2
2
NaBH (49.5 mg, 1.31 mmol) and stirred for 2 h. The reaction
+
4
(CH ), 33.7 (CH ), 14.8 (Me); HRMS [ESI]: MH , found
2 2
mixture was quenched with NH Cl (10 mL) then the aqueous
4
3
50.1741. C H NO requires 350.1751.
22 24 3

1
1
4
4
.2.4. Synthesis of a Satavaptan analogue
.2.4.1. N
(4
Ethoxyphenyl)
N
[(4

109.7 (CH), 64.9 (CH ), 64.7 (CH ), 64.0 (CH ), 62.5 (C),
ACCEPTED MANUSCRIPT
2
2
2
55.2 (Me), 49.7 (CH
), 43.3 (CH
), 31.7 (CH
), 30.4 (CH ), 14.8
2
2
2
2
+
methoxyphenyl)methyl]
7
oxo
1,4

(Me).; HRMS (ESI): MNa , found 460.1732. C25
H
27NNaO
6
dioxaspiro[4.5]decane
8
carboxamide (33)
requires 460.1731.
4
.2.4.3. 5''
Ethoxy
5'
hydroxy
1''
[(4

methoxyphenyl)methyl]
1'',2''

dihydrodispiro[1,3
dioxolane
2,1'
cyclohexane

',3''
indol]
2''
one (35)
To
a
solution
of
4� ethoxy� N� [(4�
methoxyphenyl)methyl]aniline 32 (1.99 g, 7.75 mmol) and 7�
oxo� 1,4� dioxaspiro[4.5]decane� 8� carboxylic acid 24 (3.10 g,
4
1
2
5.5 mmol) in EtOAc (77.5 mL) was added DIPEA (3.51 mL,
0.2 mmol) and T3P (50wt% in EtOAc, 9.86 g, 15.5 mmol). The
To solution
a
of
5''� ethoxy� 1''� [(4�
reaction mixture was stirred at rt for 20 h, then diluted with
methoxyphenyl)methyl]� 1'',2''� dihydrodispiro[1,3� dioxolane�
EtOAc (50 mL), washed with H O (2 × 50 mL) and sat. brine (50
2
2
0
,1'� cyclohexane� 4',3''� indole]� 2'',5'� dione 34 (0.260 g,
mL), dried over MgSO , filtered and concentrated in vacuo.
4
.594 mmol) in MeOH (5.9 mL) at 0 °C was added NaBH (34.0
4
Purification by flash column chromatography, eluting with
EtOAc/hexane (1:4 to 1:1), afforded the title compound 33 (1.77
g, 52%) as a colourless solid; mp. 38–40 °C; νmax 2934, 2837,
mg, 0.891 mmol) in one portion. The reaction mixture was stirred
at 0 °C for 2 h, then quenched at the same temperature with sat.
NH Cl (20 mL). The aqueous phase was extracted with EtOAc (3
4
1
1
716, 1650, 1610, 1585, 1509, 1477, 1454, 1440, 1400, 1356,
×
20 mL), and the combined organics were dried over MgSO4,
-1
318, 1292, 1243, 1174, 1113, 1092, 1031 cm ; δ (400 MHz;
H
filtered, and concentrated in vacuo. Purification by flash column
chromatography, eluting with EtOAc/Hexanes (1:1) afforded the
title compound 35 (0.231 g, 89%) as a colourless solid; mp 54–
CDCl ) 7.15 (2H, d, J 8.7 Hz), 6.82-6.73 (6H, m), 4.94 (1H, d, J
3
1
3
4.2 Hz), 4.67 (1H, d, J 14.2 Hz), 3.97 (2H, q, J 6.9 Hz), 3.96-
.87 (4H, m), 3.77 (3H, s), 3.19 (1H, dd, J 10.5 and 6.0 Hz), 2.68
5
1
6 °C; νmax 3448, 2932, 2885, 1691, 1596, 1513, 1489, 1440,
(
(
1H, dd, J 14.2 and 2.3 Hz), 2.32 (1H, d, J 13.7 Hz), 2.31-2.21
1H, m), 2.08-2.02 (1H, m), 1.94-1.87 (1H, m), 1.72 (1H, ddd, J
-1
345, 1290, 1245, 1177, 1144, 1110, 1049 cm ; δ (400 MHz;
H
CDCl ) 7.17-7.14 (2H, m), 6.84-6.81 (3H, m), 6.71 (1H, dd, J
3
1
2
2.8, 12.8, 4.5 Hz), 1.39 (3H, t, J 6.9 Hz); δ (100 MHz; CDCl )
03.2 (C), 169.1 (C), 158.8 (C), 158.5 (C), 134.1 (C), 130.1
C
3
8
.5, 2.5 Hz), 6.61 (1H, d, J 8.5 Hz), 4.79 (2H, s), 4.05-3.92 (6H,
m), 3.76 (3H, s), 3.52 (1H, d, J 13.6 Hz), 2.83 (1H, td, J 12.9, 5.0
Hz), 2.79 (1H, dd, J 13.4, 1.9 Hz), 2.26 (1H, td, J 13.2, 4.4 Hz),
(CH), 129.5 (CH), 115.0 (CH), 113.6 (CH), 109.6 (C), 64.7
(
CH ), 64.6 (CH ), 63.6 (CH ), 55.2 (Me), 53.6 (CH), 52.5 (CH ),
2
2
2
2
2
.14 (1H, dt, J 13.8, 4.4 Hz), 1.99-1.94 (1H, m), 1.37 (3H, t, J 7.0
5
1.3 (CH ), 33.0 (CH ), 24.0 (CH ), 14.7 (Me).; HRMS (ESI):
2 2 2
+
Hz); δ (100 MHz; CDCl ) 177.0 (C), 157.7 (C), 153.6 (C), 127.1
C
3
MNa , found 462.1874. C H NNaO requires 462.1887.
25
29
6
(CH), 126.8 (C), 113.2 (CH), 112.9 (CH), 111.4 (CH), 108.0
(
CH), 107.6 (C), 70.0 (C), 63.3 (CH ), 63.2 (CH ), 62.8 (CH ),
4
.2.4.2. 5''
Ethoxy
1''
[(4

2
2
2
methoxyphenyl)methyl]
1'',2''

dihydrodispiro[1,3
dioxolane
2,1'
cyclohexane

4
54.0 (Me), 41.9 (CH
HRMS (ESI): MNa , found 462.1870. C25
462.1887.
2
), 28.8 (CH
2
), 27.1 (CH
2
), 13.7 (Me);
H29NNaO requires
6
+
',3''
indole]
2'',5'
dione (34)
4
.2.4.4. 5''
Ethoxy
1''
[(4

methoxyphenyl)methyl]
1'',2''

dihydrodispiro[1,3
dioxolane
2,1'
cyclohexane

',3''
indol]
2'
en
2''
one
In mesitylene: N� (4� Ethoxyphenyl)� N� [(4�
methoxyphenyl)methyl]� 7� oxo� 1,4� dioxaspiro[4.5]decane�
� carboxamide 33 (0.659 g, 1.50 mmol) and Cu(OAc) ·H O
8
2
2
4
(29.9 mg, 10 mol%) in mesitylene (30 mL) was stirred at 165 °C
with compressed air bubbled through for 20 min. Upon
completion of the reaction, the mesitylene was removed under
reduced pressure. Purification by flash column chromatography,
eluting with EtOAc/Hexanes (1:4 to 2:3) afforded the title
compound 34 (0.341 g, 52%) as a colourless oil.
A
solution of 5''� ethoxy� 5'� hydroxy� 1''� [(4�
methoxyphenyl)methyl]� 1'',2''� dihydrodispiro[1,3� dioxolane�
,1'� cyclohexane� 4',3''� indol]� 2''� one 35 (0.210 g, 0.478
mmol) in THF (2.4 mL) and 10% HCl (0.96 mL) was heated at
reflux for 2 h. After cooling to rt, the reaction mixture was
2
partitioned between sat. NaHCO (25 mL) and EtOAc (3 × 25
In ethylene carbonate: N� (4� Ethoxyphenyl)� N� [(4�
methoxyphenyl)methyl]� 7� oxo� 1,4� dioxaspiro[4.5]decane�
3
mL). The combined organics were dried over MgSO , filtered,
4
and concentrated in vacuo. Purification by flash column
chromatography, eluting with EtOAc/Hexanes (1:4 to 1:3)
afforded the title compound (0.156 g, 87%) as a colourless solid;
mp 142–143 °C; νmax 2979, 2932, 1697, 1674, 1611, 1599, 1513,
8
� carboxamide 33 (0.650 g, 1.48 mmol) and Cu(2-
ethylhexanoate) (53.0 mg, 10 mol%) in ethylene carbonate (15
mL) was stirred at 165 °C with compressed air bubbled through
for 20 min. The reaction mixture was cooled to rt, then sat.
NH Cl (30 mL) was added and the aqueous phase was extracted
with EtOAc (3 × 30 mL). The combined organics were washed
with 10% NH OH solution (30 mL), H O (10 × 30 mL) and sat.
brine (30 mL), dried over MgSO , filtered and concentrated in
vacuo. Purification by flash column chromatography, eluting
with EtOAc/Hexanes (1:4 to 2:3) afforded the title compound 34
2
1
1
6
2
493, 1476, 1443, 1384, 1335, 1290, 1275, 1245, 1221, 1176,
4
-1
109, 1033 cm ; δ (400 MHz; CDCl ) 7.22 (2H, d, J 8.7 Hz),
H
3
.85 (2H, d, J 8.7 Hz), 6.80 (1H, d, J 2.8 Hz), 6.75 (1H, dd, J 8.2,
.3 Hz), 6.70 (1H, d, J 8.2 Hz), 6.51 (1H, d, J 10.1 Hz), 6.28 (1H,
4
2
4
d, J 10.1 Hz), 4.89 (1H, d, J 15.1 Hz), 4.79 (1H, d, J 15.1 Hz),
3
5
2
.95 (2H, q, J 6.9 Hz), 3.78 (3H, s), 3.17 (1H, ddd, J 17.0, 10.1,
.0 Hz), 2.63 (1H, ddd, J 17.4, 6.9, 5.0 Hz), 2.49-2.42 (1H, m),
(0.265 g, 41%) as a colourless oil; mp 40–42 °C; νmax 2926, 1718,
.30 (1H, ddd, J 14.6, 9.6, 5.0 Hz), 1.38 (3H, t, J 6.9 Hz); HRMS
1
1
693, 1603, 1513, 1494, 1478, 1454, 1440, 1397, 1352, 1300,
+
-1
(ESI): MNa , found 400.1511. C H NNaO requires 400.1519.
275, 1245, 1182, 1163, 1129, 1097, 1033, 1013 cm ; δ (400
23 23
4
H
MHz; CDCl ) 7.15 (2H, d, J 8.7 Hz), 6.84-6.80 (3H, m), 6.71
3
4
.2.4.5. 5''
Ethoxy
1''
[(4

(1H, dd, J 8.7, 2.3 Hz), 6.61 (1H, d, J 8.7 Hz), 4.79 (2H, s), 4.07-
methoxyphenyl)methyl]
1'',2''

dihydrodispiro[1,3
dioxolane
2,1'
cyclohexane

',3''
indol]
2''
one (36)
3
.92 (6H, m), 3.76 (3H, s), 3.53 (1H d, J 13.7 Hz), 2.83 (1H, ddd,
J 12.9, 12.8, 4.6 Hz), 2.78 (1H, dd, J 13.7, 1.8 Hz), 2.26 (1H,
ddd, J 13.7, 13.7, 4.6 Hz), 2.14 (1H, ddd, J 13.7, 4.6, 4.6 Hz),
4
2
2
1
.00-1.94 (1H, m), 1.37 (3H, t, J 6.9 Hz); δ (100 MHz; CDCl )
00.8 (C), 173.1 (C), 159.0 (C), 155.4 (C), 135.6 (C), 129.9 (C),
28.4 (CH), 127.5 (C), 114.2 (CH), 113.9 (CH), 112.6 (CH),
To stirred solution
a
of
5''� ethoxy� 1''� [(4�
C
3
methoxyphenyl)methyl]� 1'',2''� dihydrodispiro[1,3� dioxolane�
2,1'� cyclohexane� 4',3''� indol]� 2'� en� 2''� one (0.145 g, 0.384

1
2
Tetrahedron
mmol) in EtOAc (3.8 mL) was added 10% P
A
d/
C
C
C
(7
E
7 m
P
g).
T
E
T
D
he MA12
NU
48
, 1
S
1
C
87
R
, 1176, 1153, 1130, 1114, 1102, 1088, 1069, 1052,
I
P
T
-1
vessel was placed under vacuum and back-filled with H four
1034, 1011 cm ; δ (400 MHz; CDCl ) 7.18 (2H, d, J 8.7 Hz),
2
H
3
times before being stirred at room temperature for 18 h under an
6.88 (1H, d, J 2.3 Hz), 6.83 (2H, d, J 8.7 Hz), 6.65 (1H, dd, J 8.7,
2.3 Hz), 6.59 (1H, d, J 8.7 Hz), 4.80 (2H, s), 4.26 (2H, d, J 2.3
Hz), 3.95 (2H, q, J 6.9 Hz), 3.87-3.79 (1H, m), 3.76 (3H, s), 2.43
(1H, t, J 2.3 Hz), 2.28-2.20 (2H, m), 2.06-1.95 (4H, m), 1.67-
1.61 (2H, m), 1.38 (3H, t, J 6.9 Hz); δ (100 MHz; CDCl ) 179.8
atmosphere of H . The reaction mixture was filtered through
2
celite. The celite was washed with EtOAc (2 × 15 mL) then the
combined organics concentrated in vacuo to afford the title
compound 36 (0.143 g, 96%) as a colourless solid; mp 123–125
C
3
°
1
C; νmax 2978, 2929, 1711, 1691, 1600, 1513, 1494, 1477, 1443,
395, 1368, 1343, 1291, 1274, 1245, 1177, 1110, 1044, 1033.
(C), 159.0 (C), 155.0 (C), 136.1 (C), 135.4 (C), 128.6 (CH),
128.4 (C), 114.2 (CH), 112.0 (CH), 111.7 (CH), 109.2 (CH), 80.5
(C), 74.4 (CH), 74.0 (C), 64.1 (CH ), 55.3 (Me), 55.0 (CH ), 46.6
-
1
cm ; δ (400 MHz; CDCl ) 7.21 (2H, d, J 8.7 Hz), 6.87-6.82
H
3
2
2
(
(
3H, m), 6.70 (1H, dd, J 8.7, 1.8 Hz), 6.67 (1H, d, J 8.7 Hz), 4.85
2H, s), 3.96 (2H, q, J 7.3 Hz), 3.77 (3H, s), 3.21 (2H, ddd, J
(C), 43.0 (CH ), 30.7 (CH ), 26.0 (CH ), 15.0 (Me).; HRMS
2 2 2
+
(ESI): MNa , found 442.1980. C H NNaO requires 442.1989.
26
29
4
1
6.0, 10.5, 6.4 Hz), 2.50 (2H, ddd, J 14.7, 4.6, 4.6 Hz), 2.24-2.11
4
.2.4.8. 4-[(1-Benzyl-1H-1,2,3-triazol-4-
(4H, m), 1.38 (3H, t, J 6.9 Hz); δ (100 MHz; CDCl ) 210.7 (C),
C
3
yl)methoxy]-5’-ethoxy-1’-[(4-
methoxyphenyl)methyl] -1,2’-
dihydrospiro[cyclohexane-1,3’-indole] -2’-one (39)
1
78.9 (C), 159.1 (C), 155.3 (C), 135.2 (C), 134.5 (C), 128.5
(CH), 127.9 (C), 114.2 (CH), 112.6 (CH), 111.1 (CH), 109.6
(CH), 64.1 (CH ), 55.2 (Me), 45.8 (C), 43.0 (CH ), 36.9 (CH ),
2
2
2
+
3
3.7 (CH ), 14.8 (Me).; HRMS (ESI): MNa , found 402.1680.
To
a
solution
of
5'� ethoxy� 1'� [(4�
2
C H NNaO requires 402.1676.
methoxyphenyl)methyl]� 4� (prop� 2� yn� 1� yloxy)� 1',2'�
dihydrospiro[cyclohexane� 1,3'� indol]� 2'� one 38 (30.0 mg,
0
0
mmol). The reaction mixture was stirred at rt for 22 h, then
partitioned between H O (20 mL) and EtOAc (3 × 20 mL). The
23
25
4
4
.2.4.6. 5'
Ethoxy
4
hydroxy
1'
[(4

.072 mmol) in THF (2 mL) was added benzyl azide (14 ꢀL,
.108 mmol), CuI (2.7 mg, 14.4 ꢀmol) and DIPEA (25 ꢀL, 0.144
methoxyphenyl)methyl]
1',2'

dihydrospiro[cyclohexane
1,3'
indol]
2'
one
(
37)
2
To
a
solution
of
5''� ethoxy� 1''� [(4�
combined organics were dried over MgSO , filtered, and
4
methoxyphenyl)methyl]� 1'',2''� dihydrodispiro[1,3� dioxolane�
,1'� cyclohexane� 4',3''� indol]� 2''� one 36 (0.140 g, 0.369
mmol) in THF (2 mL) at –78 °C was added L-Selectride (1.0 M
in THF, 0.55 mL, 0.550 mmol). The reaction mixture was stirred
at –78 °C for 2 h, then quenched at the same temperature by the
concentrated in vacuo. Purification by flash column
chromatography, eluting with EtOAc/Hexanes (1:4 to 2:3)
afforded the title compound 39 (40.2 mg, quant.) as a colourless
solid; mp 148–150 °C; νmax 2928, 2865, 1694, 1603, 1510, 1493,
2
-
1449, 1364, 1335, 1289, 1271, 1244, 1172, 1109, 1051, 1032 cm
1
addition of H O (20 mL). The aqueous phase was extracted with
; δ (400 MHz; CDCl ) 7.54 (1H, s), 7.40-7.34 (3H, m), 7.30-
2
H
3
EtOAc (3 × 20 mL), and the combined organics dried over
7.28 (2H, m), 7.19-7.15 (2H, m), 6.86 (1H, d, J 2.4 Hz), 6.84-
6.80 (2H, m), 6.64 (1H, dd, J 8.5, 2.4 Hz), 6.58 (1H, d, J 8.5 Hz),
5.52 (2H, s), 4.79 (2H, s), 4.72 (2H, s), 3.95 (2H, q, J 7.0 Hz),
3.75 (3H, s), 3.73-3.69 (1H, m), 2.27-2.18 (2H, m), 2.06-1.93
MgSO , filtered, and concentrated in vacuo. Purification by flash
4
column chromatography, eluting with EtOAc/Hexanes (1:1)
afforded the title compound 37 (0.119 g, 84%) as a colourless oil;
νmax 3406, 2925, 2855, 1688, 1612, 1598, 1513, 1495, 1476,
(4H, m), 1.65-1.60 (2H, m), 1.38 (3H, t, J 7.0 Hz); δ (100 MHz;
C
1
1
6
4
442, 1393, 1365, 1341, 1289, 1273, 1245, 1177, 1109, 1050,
CDCl ) 179.8 (C), 159.0 (C), 155.0 (C), 146.8 (C), 136.1 (C),
3
-
1
035 cm ; δ (400 MHz; CDCl ) 7.18 (2H, d, J 8.2 Hz), 6.85-
135.4 (C), 134.8 (C), 129.2 (CH), 128.8 (CH), 128.6 (CH), 128.4
(C), 128.2 (CH), 122.4 (CH), 114.2 (CH), 112.1 (CH), 111.6
(CH), 109.2 (CH), 75.5 (CH), 64.1 (CH ), 61.9 (CH ), 55.3 (Me),
H
3
.81 (3H, m), 6.65 (1H, dd, J 8.7, 2.3 Hz), 6.59 (1H, d, J 8.2 Hz),
.80 (2H, s), 3.95 (2H, q, J 6.9 Hz), 3.98-3.87 (1H, m), 3.76 (3H,
2
2
s), 2.28-2.18 (2H, m), 2.05-1.94 (4H, m), 1.74-1.66 (2H, m), 1.37
54.2 (CH ), 46.6 (C), 42.9 (CH ), 30.8 (CH ), 26.3 (CH ), 15.0
2 2 2 2
+
(
3H, t, J 6.9 Hz); δ (100 MHz; CDCl ) 179.7 (C), 158.8 (C),
(Me); HRMS (ESI): MNa , found 575.2612. C H N NaO
33 36 4 4
C
3
1
55.0 (C), 135.9 (C), 135.1 (C), 128.4 (CH), 128.2 (C), 114.0
requires 575.2629.
(
CH), 112.0 (CH), 111.1 (CH), 109.1 (CH), 68.8 (CH), 64.0
4
.2.4.9. 4
[(1
Benzyl
1H
1,2,3
triazol
4

(CH ), 55.1 (Me), 46.1 (C), 42.7 (CH ), 31.1 (CH ), 29.6 (CH ),
2
2
2
2
+
yl)methoxy]
5'
ethoxy
1',2'

dihydrospiro[cyclohexane
1,3'
indol]
2'
one
40)
1
4.8 (Me).; HRMS (ESI): MNa , found 404.1822. C H NNaO
23 27 4
requires 404.1832.
(
4
.2.4.7. 5'
Ethoxy
1'
[(4

A solution of 4-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]-5’-
ethoxy-1’-[(4-methoxyphenyl)methyl]-1,2’-
methoxyphenyl)methyl]
4
(prop
2
yn
1

yloxy)
1',2'
dihydrospiro[cyclohexane
1,3'

indol]
2'
one (38)
dihydrospiro[cyclohexane-1,3’-indole]-2’-one 39 (33.7 mg, 0.061
mmol) in TFA (3 mL) was heated at reflux for 2 d. After cooling
to rt, the reaction mixture was partitioned between sat. NaHCO3
(35 mL) and CH Cl (3 × 35 mL). The combined organics were
To
a
solution of 5'� ethoxy� 4� hydroxy� 1'� [(4�
methoxyphenyl)methyl]� 1',2'� dihydrospiro[cyclohexane� 1,3'�
2
2
indol]� 2'� one 37 (0.091 g, 0.239 mmol) in THF (3 mL) was
added NaH (60% in mineral oil, 0.038 g, 0.956 mmol) in one
portion. The reaction mixture was heated at reflux for 1 h before
the addition of propargyl bromide (106 ꢀL, 0.717 mmol). Stirring
was maintained at reflux for a further 17 h. After cooling to rt,
dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash column chromatography, eluting with
EtOAc/Hexanes (1:1) afforded the title compound (23.5 mg,
89%) as a colourless solid; mp 70–72 °C; νmax 3211, 2925, 2854,
1697, 1603, 1494, 1456, 1392, 1364, 1328, 1307, 1245, 1196,
-
1
the reaction mixture was partitioned between sat. NH Cl (20 mL)
1112, 1081, 1047 cm ; δ (400 MHz; CDCl ) 8.41 (1H, br s),
4
H
3
and EtOAc (3 × 20 mL). The combined organics were dried over
7.53 (1H, s), 7.38-7.34 (2H, m), 7.3-7.28 (2H, m), 6.83 (1H, d, J
2.4 Hz), 6.79 (1H, d, J 8.5 Hz), 6.70 (1H, dd, J 8.4, 2.5 Hz), 5.53
(2H, s), 4.72 (2H, s), 3.98 (2H, q, J 7.0 Hz), 3.72-3.66 (1H, m),
2.22-2.14 (2H, m), 2.03-1.94 (4H, m), 1.63-1.57 (2H, m), 1.40
(3H, t, J 7.0 Hz).; δ (100 MHz; CDCl ) 182.5 (C), 154.9 (C),
MgSO , filtered, and concentrated in vacuo. Purification by flash
4
column chromatography, eluting with EtOAc/Hexanes (1:9 to
1
:1) afforded the title compound (0.077 g, 77%) as a colourless
oil; νmax 3226, 2978, 2941, 2114, 1689, 1611, 1594, 1513, 1485,
475, 1457, 1438, 1387, 1369, 1340, 1318, 1300, 1287, 1270,
C
3
1
146.7 (C), 136.6 (C), 134.7 (C), 133.4 (C), 129.2 (CH), 128.8

1
3
2
.
Palm, C.; Pistrosch, F.; Herbrig, K.; Gross, P. Am. J. Med.
2006, 119, S87-S92.
(
CH), 128.3 (CH), 122.5 (CH), 112.5 (CH), 1
A
11
C
.5
C
(C
EP
H
),
TED
1
09
.9 MANUSCRIPT
(CH), 75.5 (CH), 64.2 (CH ), 61.9 (CH ), 54.3 (CH ), 47.1 (C),
2
2
2
+
3. Torres, V. E.; Chapman, A. B.; Devuyst, O.; Gansevoort, R. T.;
Grantham, J. J.; Higashihara, E.; Perrone, R. D.; Krasa, H. B.;
Ouyang, J.; Czerwiec, F. S. New. Eng. J. Med. 2012, 367, 2407–
3
4
0.6 (CH ), 26.2 (CH ), 15.0 (Me); HRMS (ESI): MNa , found
2 2
55.2040. C H N NaO requires 455.2054.
25
28
4
3
2
418. b) Shoaf, S. E.; Elizari, M. V.; Wang, Z.; Sekar, K.;
4
.2.4.10. 4
[(1
benzyl
1H
1,2,3
triazol
4

Grinfeld, L. R.; Barbagelata, N. A.; Lerman, J.; Bramer, S. L.;
Trongé, J.; Orlandi, C. J. Cardiovasc. Pharmacol. Therapeut.
yl)methoxy]
1'
[2
chloro
4

trifluoromethyl)benzenesulfonyl]
5'
ethoxy

',2'
dihydrospiro[cyclohexane
1,3'
indol]
2'

one (41)
(
1
2005, 10, 165–171. c) Gheorghiade, M.; Gattis, W. A.; O’Connor,
C. M.; Adams, Jr, K. F.; Elkayam, U.; Barbagelata, A.; Ghali, J.
K.; Benza, R. L.; McGrew, F. A.; Klapholz, M.; Ouyang, J.;
Orlandi, C. J. Amer. Med. Assoc. 2004, 291, 1963–1971.
Loïc Foulon, P.; Georges Garcia, F.; Claudine Serradeil-Le Gal,
E.; Gérard Valette, L.-F. US Patent 5 994 350, 1999.
Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta, D.
C. J. Org. Chem. 2001, 66, 3653-3661.
a) Lanza, T.; Minozzi, M.; Monesi, A.; Nanni, D.; Spagnolo, P.;
Zanardi, G. Adv. Synth. Catal. 2010, 352, 2275–2280. b)
González-López de Turiso, F.; Curran, D. P. Org. Lett. 2005, 7,
4
5
6
.
.
.
To a solution of 4� [(1� benzyl� 1H� 1,2,3� triazol� 4�
yl)methoxy]� 5'� ethoxy� 1',2'� dihydrospiro[cyclohexane�
,3'� indol]� 2'� one 40 (20.6 mg, 0.048 mmol) in THF (1.5 mL)
1
at 0 °C was added KOt-Bu (16.2 mg, 0.144 mmol). The reaction
mixture was stirred at rt for 20 min before the addition of 2-
chloro-4-(trifluoromethyl)benzenesulfonyl chloride (40.2 mg,
1
51–154.
0
.144 mmol). Stirring was continued at rt for 16 h, then sat.
7
.
a) Hayashi, K.; Takayama, J.; Xuan, M.; Suda, M.; Teramae, H.;
Sakamoto, T. Heterocycles, 2016, 92, 1785–1795. b) Yu, Z.; Ju,
X.; Wang, J.; Yu, W. Synthesis 2011, 860–866.
NH Cl (15 mL) was added. The aqueous phase was extracted
with EtOAc (3 × 15 mL), dried over MgSO , filtered, and
4
4
concentrated in vacuo. Purification by flash column
chromatography, eluting with EtOAc/Hexanes (1:1) afforded the
title compound 41 (17.4 mg, 54%) as a colourless solid; mp 56–
8. Sánta-Csutor, A.; Mucsi, Z.; Finta, Z.; Gönczi, C.; Halász, J.;
Csikós, E.; Hermecz, I. Eur. J. Org. Chem. 2006, 1769–1778. b)
Hermecz, I.; Sánta-Csutor, A.; Gönczi, C.; Héja, G.; Csikós, E.;
Simon, K.; Smelkó-Esek, A.; Podányi, B. Pure. Appl. Chem.
5
8 °C; νmax 2980, 2933, 1746, 1690, 1594, 1487, 1471, 1393,-
2
001, 73, 1401–1409.
1
371, 1321, 1289, 1247, 1228, 1177, 1142, 1116, 1080, 1043 cm
9
.
a) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249–3251.
b) Moody, C. L.; Franckevičius, V.; Drouhin, P.; Klein, J. E. M.
N.; Taylor, R. J. K. Tetrahedron Lett. 2012, 53, 1897–1899. c)
Hurst, T. E.; Gorman, R.; Drouhin, P.; Perry, A.; Taylor, R. J. K.
Chem. Eur. J. 2014, 20, 14063-14073. d) Drouhin, P.; Hurst, T.
E.; Whitwood, A. C.; Taylor, R. J. K. Org. Lett. 2014, 16, 4900–
4903. e) Drouhin, P.; Hurst, T. E.; Whitwood, A. C.; Taylor, R. J.
K. Tetrahedron 2015, 71, 7124–7136.
1
;
δ (400 MHz; CDCl ) 8.46 (1H, d, J 8.1 Hz), 7.78-7.73 (3H,
H 3
m), 7.43 (1H, s), 7.39-7.34 (3H, m), 7.28-7.25 (2H, m), 6.83 (1H,
dd, J 8.9, 2.6 Hz), 6.78 (1H, d, J 2.6 Hz), 5.50 (2H, s), 4.03 (2H,
q, J 7.0 Hz), 3.61-3.55 (1H, m), 1.94-1.88 (6H, m), 1.67-1.59
(
2H, m), 1.43 (3H, t, J 7.0 Hz); δ (100 MHz; CDCl ) 177.7 (C),
C
3
1
56.7 (C), 146.4 (C), 139.6 (C), 136.5 (C, q, J 34.0 Hz), 134.6
(
1
3
C), 134.5 (C), 134.1 (CH), 133.4 (C), 131.4 (C), 129.2 (CH),
28.9 (CH), 128.8 (CH, q, J 3.9 Hz), 128.2 (CH), 124.2 (CH, q, J
.7 Hz), 122.4 (C, q, J 272 Hz), 122.3 (CH) 115.1 (CH), 113.3
10. For a related copper-based approach see: a) Dey, C.; Larinov, E.;
Kündig, E. P. Org. Biomol. Chem. 2013, 11, 6735–6743 and
references therein. For other approaches see: b) Donald, J. R.;
Taylor, R. J. K.; Petersen, W. F. J. Org. Chem. 2017, 82, 11288–
11294. c) Wu, Z.-J.; Xu, H.-C. Angew. Chem. Int. Ed. 2017, 56,
4734–4738.
(CH), 110.4 (CH), 75.3 (CH), 64.0 (CH ), 61.7 (CH ), 54.3
2 2
(
CH ), 46.4 (C), 31.8 (CH ), 26.1 (CH ), 14.9 (Me); HRMS
2 2 2
+ 35
(ESI): MNa , found 697.1477. C H ClF NNaO S requires
11. Sparrow, K.; Barker, D.; Brimble, M. A. Tetrahedron 2012, 68,
32
30
3
5
1
017–1028.
6
97.1470.
1
2. Standard hydrolysis under basic conditions led to poor and
irreproducible yields of product due to extensive decomposition of
the starting material.
Acknowledgements
1
1
3. Barton., D. H. R.; Motherwell, W. B.; Strange, A. Svnthesis 1981
743-744.
4. (a) Wissmann, H.; Kleiner, H.-J. Angew. Chem. Int. Ed. 1980, 19,
We thank the University of York Wild Fund for postgraduate
support (P. D.) and the EPSRC for postdoctoral support (T. E. H.,
EP/J000124/1). We also thank CHEM21 for postgraduate support
1
33–134;
(b) For recent applications see Unsworth, W. P.; Kitsiou, C.;
(R. M. G.). The research for this work has received funding from
Taylor, R. J. K. Org. Lett. 2013, 15, 258–261; Unsworth, W. P.;
Gallagher, K. A.; Jean, M.; Schmidt, J. P.; Diorazio, L. J.; Taylor,
R. J. K. Org. Lett. 2013, 15, 262–265.
the Innovative Medicines Initiative joint undertaking project
CHEM21 (https://www.chem21.eu/) grant agreement no.
1
5. Parker, H. L.; Sherwood, J.; Hunt, A. J.; Clark, J. H. ACS
Sustainable Chem. Eng. 2014, 2, 1739–1742; for a recent review
on green solvents see Clarke, C. J.; Tu, W.-C.; Levers, O.; Bröhl,
A.; Hallett, J. P. Chem. Rev. 2018, 118, 747–800.
1
15360, resources of which are composed of financial
contribution from the European Union’s Seventh Framework
Programme (FP7/2007–2013) and EFPIA companies in kind
contribution.
References
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