Dearomatisation approaches to spirocyclic dienones via the electrophilic activation of alkynes

Article abstract of DOI:10.1039/c6ob02426b

Two complementary dearomatising spirocyclisation protocols to generate spirocyclic dienones from anisole and phenol-tethered ynones are described, each proceeding via electrophilic alkyne activation. The first approach focuses on the spirocyclisation of p

Full text of DOI:10.1039/c6ob02426b

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ARTICLE
Dearomatisation Approaches to Spirocyclic Dienones via the
Electrophilic Activation of Alkynes.
Received 00th January 20xx,
Accepted 00th January 20xx
Aimee K. Clarke, John T. R. Liddon, James D. Cuthbertson, Richard J. K. Taylor* and William P.
Unsworth*
DOI: 10.1039/x0xx00000x
Two complementary dearomatising spirocyclisation protocols to generate spirocyclic dienones from anisole and phenol-
tethered ynones are described, each proceeding via electrophilic alkyne activation. The first approach focuses on the
www.rsc.org/
2 2 2
spirocyclisation of para-substituted anisoles using either SnCl ·2H O or Cu(OTf) . The second approach, which enables the
3
spirocyclisation of both ortho- and para-substituted phenols, uses silica-supported AgNO to generate similar scaffolds
with much greater efficiency. Initial asymmetric studies are also outlined.
cyclisation reaction can take place with a range of C-
2
a
2b
nucleophiles including alkenes/alkynes, enamides, allyl
Introduction
2
c,d
2e
enols/enolates, aromatics, nitro compounds
2f
2g
silanes,
Spirocyclic dienones are key structural features in numerous
bioactive natural products isolated from a variety of trees,
2h,i
and diazo compounds. Alternatively, the flow of electron
density can be reversed and a substituted phenol/anisole can
react directly with a tethered electrophilic species (Scheme
plants and bacteria, with representative examples
1
in Figure 1.
1
–
6
shown
a-e
1
b); examples of electrophilic ipso-cyclisation with
3f
HO
HO
3
a-c
3d
3e
sulfonates,
nitriles,
epoxides,
activated allenes,
O
3g
activated aryl halides, propargyl bromides/carbonates,
3h
O
3
i-k
3l,m
OH
activated alkynes/alkenes and allylic carbonates
been reported.
have all
O
OH
O
HO
R2
R2
[
O]
OH
OH
(a)
N
HO
O
N
R1
R1
HO
O
H N
2
O
O
Nucleophilic
ipso-cyclisation
Spirocalcaridine A 1
Argutosine D 2
Hopeanol A 3
O
O
Spirocyclic
dienone
R2
R1
O
O
OH
OH
HO
Electrophilic
ipso-cyclisation
N
O
O
N
O
R2
NH2
(b)
O
N
N
H
R
2
H
R1
3
R1
3
R O
R O
Glaziovine 4
Spirocalcaridine B 5
Spirobacillene A 6
(
c) This work
O
O
Figure 1. Natural products containing spirocyclic dienone motifs.
O
O
Sn(II), Cu(II) or Ag(I)
R1 = Me or H
A popular approach to synthesise spirocyclic dienones is via
the dearomatisation and ipso-cyclisation of a phenol or anisole
derivative, with this typically achieved using one of two
methods (Scheme 1). The most common method is based on
the oxidation of a substituted phenol (Scheme 1a); following
oxidation of the phenol, an intramolecular nucleophilic ipso-
or
R2
R2
R2
1
O
R O
Scheme 1. General methods for spirocyclic dienone synthesis.
In this manuscript, two complementary protocols which
generate spirocyclic dienones are outlined (Scheme 1c), with
both methods promoted by the activation of a tethered alkyne
4
moiety. The first approach focuses on the spirocyclisation of
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para-substituted anisoles using either SnCl
2
·2H
2
O or Cu(OTf)
2
improvement in the reactivity of substrates 9a–9c, forcing us
to activate the alkyne towards nucleophilic attack, while the to concede that an electron donating group on the alkyne
second uses silica-supported AgNO to generate similar terminus is a requirement for this transformation.
3
scaffolds from analogous phenol precursors with greater
efficiency and scope. Substrate scoping studies are described
for each reaction series, while comparisons between the two
reaction types, synthetic extensions and preliminary
asymmetric results are also outlined.
Table 1. Optimisation of the spirocyclisation of anisole-tethered ynones
Results and discussion
This research program began during a project to synthesise the
5
6, Figure 1). In
,6
spirocyclic natural product spirobacillene A (
this published work, it was found that treating anisole-
7
tethered ynone
CH Cl resulted in its efficient conversion into spirocyclic
dienone , which was isolated in 89% yield (Scheme 2). The
ease and scalability of this key step was instrumental in
allowing us to complete the synthesis of spirobacillene A
2 2
7 with five equivalents of SnCl ·2H O at RT in
[
a],[b]
Equiv/
Conversion
2
2
Reagent
Time [h]/
Temp [°C]
(isolated yield in
brackets)
8
1
2
3
4
5
6
9a
9b
9c
9c
9d
9d
SnCl
SnCl
SnCl
SnCl
SnCl
2
2
2
2
2
·2H
·2H
·2H
·2H
·2H
2
2
2
2
2
O
O
O
O
O
5/20/RT or 45
5/20/RT or 45
5/20/RT
No Reaction
No Reaction
No Reaction
10%
6
,
5
,8
which was published in 2013.
5/20/45
5/20/RT
75% (57%)
Cu(OTf)
2
1/1/RT
>95% (80%)
[
2 2
a] All reactions were performed using 0.09–0.20 mmol of the ynone 9a-d in CH Cl (0.1
1
M); [b] Conversion measured by analysis of the H NMR spectra of the unpurified
reaction mixture.
With this in mind, a series of anisoles tethered to electron-rich
ynones (9d
–
l
) were made and tested using both SnCl
2 2
·2H O
Scheme 2. Sn(II)-mediated synthesis of spirobacillene A.
and Cu(OTf)
2
to activate the alkyne (Table 2). Spirocycle 10e
was formed in just 1 h from aniline-substituted ynone 9e using
one equivalent of SnCl ·2H O. Alternatively, the same product
could be made using catalytic Cu(OTf) (0.1 equivalents), albeit
This initial discovery inspired the development of a number of
9
other classes of dearomatising spirocyclisation reactions in
2
2
1
0,11
2
our group in the following years.
publication, the conversion of ynone
remained the only reported reaction of its type in the
However, prior to this
with a longer reaction time. Thiophene-substituted ynone 9f
7
into spirocycle
8
reacted more slowly; the cyclisation was incomplete following
1
2
treatment with SnCl
but proceeded more efficiently with Cu(OTf)
3% yield. Substitution around either ring system is well
tolerated, evidenced by the efficient syntheses of compounds
0g . Vinyl sulfide product 10j could also be isolated in a
reasonable yield using Cu(OTf) , demonstrating compatibility
2
·2H
2
O at room temperature for 3 days,
literature, hence it was decided to further optimise this
process and to evaluate its scope.
2
to afford 10f in a
7
Initial results were disappointing, with unsubstituted and
alkyl substituted ynones 9a and 9b both failing to react with
1
–i
2 2
SnCl ·2H O under the conditions used during the total
2
synthesis of spirobacillene A (Table 1, entries 1 and 2). Phenyl
with non-aromatic-tethered ynones. Additionally, the reaction
is not limited to the synthesis of spirocyclic cyclopentenones;
spirocyclic cyclohexenones 10k and 10l were both formed in
good yields, although the reactions were slower and thus
required additional heating or a longer reaction time.
substituted ynone 9c also failed to react at room temperature
(entry 3), although a small amount of cyclisation was observed
upon heating at reflux (entry 4). A plausible explanation for
this poor reactivity is that the more electron-rich the alkyne,
the more readily it can interact with acidic additives,
promoting spirocyclisation. Support for this theory was found
when examining the cyclisation of anisole-substituted ynone
2 2
9d; under the standard SnCl ·2H O mediated conditions, a
more respectable 75% conversion into spirocyclic dienone 10d
was observed (entry 5, 57% isolated yield). Pleasingly, the
spirocyclisation was improved significantly by changing the
catalyst; full details of reaction optimisation are included in the
Supplementary Information, with the highlight being the
discovery that Cu(OTf)
ynone 9d within 1 h, with spirocycle 10d isolated in 80%
isolated yield (entry 6). However, Cu(OTf) did not lead to any
2
promoted the complete cyclisation of
2
2
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Table 2. Substrate scope of spirocyclisation of anisole-tethered ynones using indeed be formed, and with Ag(I) catalysts now viable for this
2 2 2
SnCl ·2H O (A) and Cu(OTf) (B).
transformation, significant improvements in the scope and
efficiency soon emerged. The use of silica-supported AgNO
10 mol%) in CH Cl at RT was found to be a particularly active
3
(
2
2
and convenient catalyst system and was chosen for the
substrate scoping studies, which were performed on ynone
tethered phenols (11c
,d,m–v). For clarity, five of these
examples (denoted in the table with a *) were included in an
1
0c
earlier publication, while the other seven substrates are
novel examples (Table 3). It should also be noted that
AgNO
3
·SiO
; ynones 11c,d,m,o,q-v did not react in the presence of
and only a 7% conversion to spirocyclic
dienone 10n was observed for ynone 11n when using
2
is a much more reactive catalyst than unsupported
AgNO
3
unsupported AgNO
3
1
3
3
unsupported AgNO .
3 2
Table 3. Substrate scope of AgNO ·SiO -catalysed dearomatisation/spirocyclisations.
[
a] All reactions were performed in CH
specified. Where stated, reaction conversions were measured by analysis of the
NMR spectra of the unpurified reaction mixture; [b] 5 equiv. of SnCl ·2H O used; [c] 0.1
equiv. of Cu(OTf) used; [d] Reaction performed at 50 °C.
2 2
Cl (0.1 M) at RT with 1 equiv. of reagent unless
1
H
2
2
2
To summarise this reaction series, para-substituted anisoles
tethered to electron-rich ynones can be converted into
spirocyclic dienones in high yield using either a Sn(II) or Cu(II)
reagent. The simplicity of the synthetic procedure and mild
reaction conditions are the most pleasing aspects of this
method, although the use of relatively large quantities of Sn(II)
and Cu(II) reagents and the requirement to use electron-rich
ynones were both identified as areas with potential for
improvement.
It was reasoned that both of the above limitations might be
addressed by using a more active catalyst. Silver(I) catalysts
were identified as particularly promising candidates, given that
they have generally been found to be the best catalyst class in
1
0
3 2 2 2
related alkyne activation processes, but disappointingly, the [a] All reactions were performed using 1 wt. % AgNO ·SiO in CH Cl (0.1 M) at RT
unless specified otherwise; [b] Reaction performed at 40 °C. Compounds highlighted
with a * were featured in our earlier publication (see reference 10c); all other examples
are novel.
Ag(I) catalysts tested were ineffective for the spirocyclisation
of anisole system 9d. However, by switching the nucleophilic
component in the starting material from an anisole to the
analogous phenol, the desired spirocyclic product 10d could
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O
It quickly became apparent that by changing the catalyst and
starting material, the requirement for an electron-donating
substituent on the ynone had been removed; simple alkyl
O
TFA, CH2Cl2
RT, 2 h
1
N
H
chains and aromatic substituents in the R position were all
BocN
well tolerated, generating spirocyclic dienone products 10c
,
O
O
1
0o
14, 68%
10d, 10n in high yields. Alkyl substituted ynones bearing
O
O
protected amine and alcohol groups (11o and 11p) also
reacted smoothly to furnish their corresponding spirocyclic
dienones (10o and 10p). The incorporation of terminal
cyclopropane and cyclopentane rings appeared to increase the
reactivity of the ynone; dienones 10q and 10r were produced
in near-quantitative yields in 2–6 h which is notably faster than
1
0% aq. HCl,
THF
RT, 1.5 h
O
H
TBSO
O
O
1
0p
15, 75%
most of the other reactions explored in this study. Pleasingly, Scheme 4. One-pot deprotection and cyclisation of spirocyclic dienones 10o and
0p
we were also able to perform the spirocyclisation on ortho-
1
.
substituted phenols 11s–v; there are relatively few literature
Finally, having shown that ortho-substituted phenols can be
converted into chiral spirocyclic dienones, the possibility of
performing this reaction asymmetrically has also been briefly
examined. Preliminary studies show that spirocyclisation can
be achieved with a modest amount of asymmetric induction
examples of dearomatisation and ipso-cyclisation reactions of
ortho-substituted phenols, and so the efficient syntheses of
chiral spirocyclic products 12s–v in 90–99% yields are
2
especially pleasing.
d,14
The superior reactivity of the Ag(I) mediated reaction
system compared to the earlier Sn(II)/Cu(II) reactions is best
demonstrated by a direct comparison. Thus, our published
(
23% ee) using the BINOL-based chiral phosphoric acid silver(I)
salt 16 (Scheme 5). It is envisaged that optimisation of the
15
reaction conditions and the nature of the silver(I) catalyst
synthesis of spirocyclic dienone
8, which is a key intermediate
should lead to improve enatioselectivity in this process.
en route to spirobacillene A, required five equivalents of
5
SnCl
contrast, the same product was generated from phenol 13 in
near-quantitative yield in just 7 h using 10 mol% AgNO ·SiO
Scheme 3).
2 2
·2H O and 18 h to generate the product in 89% yield. In
3
2
(
Scheme 5. Asymmetric spirocyclisation reaction using silver salt of CPA 16
.
Conclusions
In summary, two mild and efficient methods for the synthesis
of spirocyclic dienones are described. Both were briefly
introduced by our group in previous publications, but the
significantly expanded substrate scoping studies outlined in
this manuscript mean that each can now be considered as
general and versatile synthetic approach to this important
compound class. Both methods work well on a variety of easy-
to-synthesise ynone precursors. The use of catalytic
Scheme 3. Previous and improved routes to spirobacillene A precursor 8.
The potential of the spirocyclic dienone products to undergo
additional complexity generating reactions has also been
briefly demostrated; spirocyclic products 10o and 10p were
each found to undergo protecting group cleavage and
cyclisation in one-pot to furnish novel tricyclic products 14 and
3 2
AgNO ·SiO to promote the spirocyclisation of ynone tethered
phenols is likely to be of particular interest, in view of the
excellent isolated yields in this series, the simple product
purification and the capacity to recover the active catalyst by
filtration.
15
as single diastereomers and in reasonable, unoptimised
yields (Scheme 4).
Experimental
Except where stated, all reagents were purchased from
1
commercial sources and used without further purification. H
4
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1
3
NMR and C NMR spectra were recorded on a JEOL ECX400 or To a solution of terminal alkyne (1.50 mmol) in THF (10 mL) at
JEOL ECS400 spectrometer, operating at 400 MHz and 100 −78 °C was added n-BuLi (0.875 mL, 1.4 mmol, 1.6 M in
MHz respectively. All spectral data were acquired at 295 K. hexanes). The resulting yellow solution was stirred at −78 °C
Chemical shifts (δ) are quoted in parts per million (ppm). The for 30 min, then transferred via cannula to a cooled (−78 °C)
residual solvent peak, δ
and δ 39.5 for DMSO-d
Hertz (Hz) to the nearest 0.5 Hz. The multiplicity abbreviations and stirred for a further 1 h. The reaction was then re-cooled
used are: s (singlet), d (doublet), t (triplet), q (quartet), m to −78 °C and quenched with sat. aq. NH
Cl (30 mL), allowed to
multiplet), br (broad). Signal assignment was achieved by warm to RT, diluted with water (70 mL), extracted with EtOAc
H
7.26 and δ
. Coupling constants (J) are reported in mixture was stirred at −78 °C for 5 min then warmed to −10 °C
6
C 3 H
77.0 for CDCl and δ 2.50 solution of Weinreb amide (1.00 mmol) in THF (5 mL). The
C
4
(
4
analysis of DEPT, COSY, NOESY, HMBC and HSQC experiments (3 × 100 mL), dried over MgSO and concentrated in vacuo.
where required. Infrared (IR) spectra were recorded on a Purification by flash column chromatography (10:1
PerkinElmer UATR 2 Spectrometer as a thin film dispersed petrol:EtOAc to elute the excess alkyne, then 5:1 petrol:EtOAc
from either CH
2
Cl
2 3
or CDCl and are reported in wavenumbers to elute the product) afforded the ynone product.
−
1
cm ). Mass-spectra were obtained by the University of York
(
Mass Spectrometry Service, using electrospray ionisation (ESI) General Procedure B2: Ynone Formation II
on a Bruker Daltonics, Micro-tof spectrometer. Melting points To a stirred solution of alkyne (3.00 mmol) in THF (3 mL) at −78
were determined using Gallenkamp apparatus and are °C under argon was added n-BuLi (1.00 mL, 2.5 mmol, 2.5 M in
uncorrected. Reactions were monitored using thin layer hexanes) dropwise. The mixture was stirred for 30 min at −78
chromatography (TLC), which was carried out on Merck silica °C and then transferred via cannula to a −78 °C soluꢀon of
gel 60F254 pre-coated aluminium foil sheets and were Weinreb amide (1.00 mmol) in THF (5 mL). Upon complete
visualised using UV light (254 nm) and stained with basic transfer the mixture was warmed to RT and stirred for the
aqueous
potassium
permanganate.
Flash
column specified amount of time. The reaction was quenched with sat.
chromatography was carried out using slurry packed Fluka aq. NH Cl (30 mL), diluted with water (70 mL) and extracted
4
2
silica gel (SiO ), 35–70 µm, 60 Å, under a light positive with EtOAc (3 × 100 mL). The organics were combined, washed
pressure, eluting with the specified solvent system. with brine (100 mL), dried over MgSO , concentrated in vacuo
4
1
Compounds 9d and 9e
6
10a
were prepared according to and purified by flash column chromatography to afford the
ynone product.
literature procedures.
General Experimental
General Procedure C: Spirocyclisation using Sn(II)/Cu(II)
General Procedure A: Weinreb Amide Synthesis I
2 2
To a solution of ynone (1.00 mmol) in CH Cl (10 mL) was
added an acid catalyst (0.1–5.0 equiv.). The resulting
suspension was stirred at the specified temperature until
completion was observed by TLC, before adding an excess of
To a suspension of acid (1.00 mmol) in DCM (2 mL) at RT was
added CDI (220 mg, 1.20 mmol). A homogeneous solution
quickly formed, and was stirred at RT for 1 h, after which time
MeNH(OMe)·HCl (107 mg, 1.10 mmol) and stirring continued
for a further 2 h. The crude reaction mixture was then poured
into water (10 mL) and basified to ca. pH 10 with 2 M aq.
NaOH extracted with EtOAc (3 × 30 mL) and washed with 10%
solid K
2
CO
3
and stirring for an additional 10 min. The mixture
Cl and concentrated in
was then filtered, rinsed with CH
2
2
vacuo. Purification by flash column chromatography afforded
the spirocyclic product.
aq. HCl (15 mL). The organic extracts were dried over MgSO
4
General Procedure C2: Spirocyclisation using AgNO
To a solution of ynone (1 mmol) in CH Cl (10 mL) was added
AgNO ·SiO (0.01–0.1 equiv., 1 wt. % AgNO on SiO ). The
3 2
·SiO
and concentrated in vacuo, affording the Weinreb amide
product which was used without further purification.
2
2
3
2
3
2
mixture was stirred at the specified temperature until
completion was observed by TLC. The reaction mixture was
filtered, washing the catalyst with EtOAc (10 mL), then
concentrated in vacuo to afford the spirocyclic product.
General Procdure A2: Weinreb Amide Synthesis II
To a stirred solution of acid (1.00 mmol), MeNH(OMe)·HCl (107
2 2
mg, 1.10 mmol) and DIPEA (0.52 mL, 3.00 mmol) in CH Cl (2.5
mL) was added T3P 50% in EtOAc (955 mg, 1.50 mmol). The
solution was stirred at RT until completion was observed by
TLC. The reaction mixture was poured into water (10 mL) and
Compound Synthesis
acidified using 10% aq. HCl (5 mL). The organics were collected 4-(4-Methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione
and the aqueous extracted with EtOAc (3 × 30 mL). The (10d). Synthesised using general procedure C from ynone 9d
organics were combined, washed with aq. 2 M NaOH (10 mL), (25.0 mg, 0.0892 mmol) and copper(II) triflate (32.3 mg,
brine (10 mL), dried over MgSO
4
and concentrated in vacuo to 0.0892 mmol) for 1 h at RT. Purification by flash column
afford the Weinreb amide product which was used without chromatography (2:1 petrol:EtOAc) afforded the title
further purification.
compound 10d as a brown solid (19 mg, 80%); mp. 135–137 °C;
−
1
Rf 0.20 (1:1 petrol:EtOAc); νmax (thin film)/cm 1669, 1639,
579, 1541, 1488, 1234, 1163, 1013, 848, 822; δ (400 MHz,
CDCl ) 2.75 (2 H, s), 3.81 (3 H, s), 6.46 (2 H, d, J = 10.0), 6.62 (1
General Procedure B: Ynone Formation I
1
H
3
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H, s), 6.85 (2 H, d, J = 9.0), 6.95 (2 H, d, J = 10.0), 7.48 (2 H, d, J 1.98–2.10 (1 H, m), 3.14 (3 H, s), 3.49 (3 H, s), 3.76 (3 H, s),
=
9.0); δ
C
(100 MHz, CDCl
3
) 46.8, 51.0, 55.4, 114.3, 125.3, 3.78–3.86 (1 H, m), 6.82 (2 H, d, J = 8.5), 7.23 (2 H, d, J = 8.5);
(100 MHz, CDCl ) 12.2, 27.2, 32.1, 48.3, 55.1, 61.2, 113.8,
3
H14NaO (MH ) Requires 289.0835 129.1, 132.2, 158.4, 175.0; HRMS (ESI ): Found: 238.1438;
1
27.5, 129.4, 130.0, 152.0, 162.3, 173.1, 184.7, 203.0; HRMS
δ
C
3
+
ESI ): Found: 289.0825; C17
+
+
(
+
(
3.5 ppm error). Spectroscopic data matched those previously
1
C
13
H20NO
3
(MH ) Requires 238.1438 (0 ppm error).
6
reported in the literature.
1
,4-Bis(4-methoxyphenyl)hex-1-yn-3-one (9g). Synthesised
4
-(4-(Dimethylamino)phenyl)spiro[4.5]deca-3,6,9-triene-2,8-
dione (10e). Synthesised using general procedure C from 3.17 mmol) and Weinreb amide S1 (500 mg, 2.11 mmol).
ynone 9e (32 mg, 0.109 mmol) and SnCl .2H O (2.5 mg, 0.0109 Purification by flash column chromatography afforded the title
mmol) for 20 at RT. Purification by flash column compound 9g as a yellow oil (482 mg, 74%); R 0.71 (1:1
chromatography (2:1 petrol:EtOAc) afforded the title petrol:EtOAc); νmax (thin film)/cm 2188, 1658, 1601, 1508,
compound 10e as a yellow solid (29 mg, 95%); mp. 199–201 °C; 1248, 1058, 1027, 831, 540; δ (400 MHz, CDCl ) 0.91 (3 H, t, J
0.20 (1:1 petrol:EtOAc); νmax (thin film)/cm 1656, 1636, = 7.5), 1.77–1.89 (1 H, m), 2.16–2.27 (1 H, m), 3.63–3.67 (1 H,
581, 1548, 1500, 1353, 1182, 1156, 719; δ (400 MHz, CDCl m), 3.79 (3 H, s), 3.82 (3 H, s), 6.85 (2 H, d, J = 9.0), 6.89 (2 H, d,
.72 (2 H, s), 3.02 (6 H, s), 6.46 (2 H, d, J = 10.0), 6.55 (1 H, s), J = 9.0), 7.24 (2 H, d, J = 9.0), 7.41 (2 H, d, J = 9.0); δ (100 MHz,
.58 (2 H, d, J = 9.0), 6.98 (2 H, d, J = 10.0), 7.43 (2 H, d, J = 9.0); CDCl ) 12.0, 24.8, 55.2, 55.4, 61.7, 87.5, 93.5, 111.9, 114.1,
(100 MHz, CDCl ) 39.9, 46.7, 50.9, 111.3, 119.9, 124.0, 114.2, 129.7, 130.0, 135.0, 158.9, 161.5, 188.4; HRMS (ESI ):
29.2, 129.5, 152.3, 152.9, 173.3, 185.0, 203.0; HRMS (ESI ): Found: 309.1490; C20
using general procedure B from 4-ethynyl-anisole (0.41 mL,
2
2
h
f
−1
H
3
−1
R
f
1
2
6
H
3
)
C
3
+
δ
1
C
3
+
+
21 3
H O
(MH ) Requires 309.1485 (−1.6
+
Found: 280.1334; C18
2
H18NO (MH ) Requires 280.1332 (0.8 ppm error).
ppm error). Spectroscopic data matched those previously
1
reported in the literature.
0a
1-Ethyl-4-(4-methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-
dione (10g). Synthesised using general procedure C from
1
-(4-Methoxyphenyl)-4-(thiophen-2-yl)but-3-yn-2-one
(9f). ynone 9g (60.0 mg, 0.195 mmol) and copper(II) triflate (70.5
from 2- mg, 0.195 mmol) for 20 h at RT. Purification by flash column
Synthesised using general procedure
B
17
ethynylthiophene (303 mg, 2.80 mmol) and N-methoxy-2-(4- chromatography (2:1 petrol:EtOAc) afforded the title
1
8
methoxyphenyl)-N-methylacetamide (391 mg, 1.87 mmol). compound 10g as a pale brown oil (43 mg, 75%); R
f
0.50 (1:1
Purification by flash column chromatography afforded the title petrol:EtOAc); νmax (thin film)/cm 1696, 1661, 1590, 1509,
compound 9f as a pale yellow oil (310 mg, 65%); R 0.73 (1:1 1257, 1177, 1030, 908, 832, 725; δ (400 MHz, CDCl ) 0.97 (3
petrol:EtOAc); νmax (thin film)/cm 2148, 1636, 1586, 1489, H, t, J = 7.5), 1.25–1.35 (1 H, m), 1.75–1.84 (1 H, m), 2.66 (1 H,
230, 1019, 704; δ (400 MHz, CDCl ) 3.80 (3 H, s), 3.85 (2 H, t, J = 7.0), 3.81 (3 H, s), 6.47 (1 H, dd, J = 10.0, 1.5), 6.56 (1 H,
s), 6.90 (2 H, d, J = 8.5), 7.03 (1 H, dd, J = 5.0, 3.5) 7.22 (2 H, d, J s), 6.56 (1 H, dd, J = 10.0, 1.5), 6.80 (1 H, dd, J = 10.0, 3.0), 6.84
8.5), 7.40 (1 H, d, J = 3.5), 7.47 (1 H, d, J = 5.0); δ (100 MHz, (2 H, d, J = 9.0), 6.96 (1 H, dd, J = 10.0, 3.0), 7.44 (2 H, d, J =
CDCl ) 50.9, 55.2, 86.7, 92.4, 114.1, 119.6, 125.1, 127.6, 130.8, 9.0); δ (100 MHz, CDCl ) 12.6, 20.0, 55.4, 55.8, 58.9, 114.3,
31.8, 136.7, 158.9, 189.1; HRMS (ESI ): Found: 257.0625; 125.6, 126.9, 129.3, 130.0, 131.6, 151.0, 152.2, 162.1, 171.5,
−1
f
H
3
−
1
1
H
3
=
C
3
C
3
+
1
C
+
+
+
15
H
13
O
2
S (MH ) Requires 257.0631 (1.7 ppm error).
185.3, 205.1; HRMS (ESI ): Found: 295.1324; C19
Requires 295.1329 (1.6 ppm error).
19 3
H O (MH )
4-(Thiophen-2-yl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10f).
Synthesised using general procedure C from ynone 9f (40 mg, 2-(2,4-Dimethoxyphenyl)-N-methoxy-N-methylacetamide
0.156 mmol) and copper(II) triflate (56.4 mg, 0.156 mmol) for (S2). Synthesised using general procedure A from 2-(2,4-
20 h at RT. Purification by flash column chromatography (2:1 dimethoxyphenyl)acetic acid (981 mg, 5.00 mmol) affording
petrol:EtOAc) afforded the title compound 10f as a pale yellow the title compound S2 as a pale yellow oil (1.13 g, 91%); νmax
−
1
oil (28 mg, 73%); R
f
0.50 (1:1 petrol:EtOAc); νmax (thin (thin film)/cm 1641, 1590, 1486, 1442, 1273, 1191, 1139,
film)/cm 1691, 1661, 1576, 1246, 1027, 907, 859, 724; δ 1021; δ (400 MHz, CDCl ) 3.19 (3 H, s), 3.67 (3 H, s), 3.69 (2 H,
400 MHz, CDCl ) 2.77 (2 H, s), 6.49 (2 H, d, J = 10.0), 6.58 (1 H, s), 3.78 (6 H, s), 6.42–6.47 (2 H, m), 7.07–7.11 (1 H, m); δ (100
s), 6.92 (2 H, d, J = 10.0), 7.03 (1 H, dd, J = 4.5, 3.5) 7.32 (1 H, d, MHz, CDCl ) 32.4, 32.7, 55.3, 55.4, 61.1, 98.5, 104.1, 116.1,
−1
H
H
3
(
3
C
3
+
J = 3.5), 7.52 (1 H, d, J = 4.5); δ
C
(100 MHz, CDCl
3
) 46.3, 50.9, 131.1, 158.2, 159.8, 173.0; HRMS (ESI ): Found: 240.1232;
+
1
27.3, 128.7, 130.2, 130.5, 131.4, 135.8, 150.9, 166.3, 184.7,
+
12 4
C H18NO (MH ) Requires 240.1230 (1.0 ppm error).
+
02.6; HRMS (ESI ): Found: 243.0480; C14
2
11 2
H O S (MH )
Requires 243.0474 (−2.3 ppm error).
1-(2,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-
one (9h). Synthesised using general procedure B from 4-
N-Methoxy-2-(4-methoxyphenyl)-N-methylbutanamide (S1). ethynyl-anisole (741 mg, 5.61 mmol) and Weinreb amide S2
Synthesised using general procedure from 2-(4- (894 mg, 3.74 mmol). Purification by trituration with ether
methoxyphenyl)butanoic acid (1.07 g, 5.51 mmol) affording afforded the title compound 9h as a pale yellow crystalline
the title compound S1 as a colourless oil (1.31 g, 100%); νmax solid (789 mg, 68%); mp. 102–104 °C; 0.68 (1:1
thin film)/cm 1656, 1510, 1461, 1380, 1247, 1178, 997, 822; petrol:EtOAc); νmax (thin film)/cm 2184, 1664, 1601, 1589,
A
1
9
R
f
−
1
−1
(
δ
H 3 H
(400 MHz, CDCl ) 0.85 (3 H, t, J = 7.5), 1.64–1.75 (1 H, m), 1508, 1256, 1211, 1124, 1071, 1027, 835, 786, 575; δ (400
6
| 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
View Article Online
DOI: 10.1039/C6OB02426B
ARTICLE
2
1
MHz, CDCl
d, J = 8.5), 7.11 (1 H, d, J = 8.5), 7.37 (2 H, d, J = 8.5); δ
MHz, CDCl ) 46.0, 55.3, 55.3, 55.4, 87.7, 92.7, 98.5, 104.2, the title compound 9j as a yellow oil (313 mg, 33%); R
11.9, 114.2, 115.1, 131.7, 135.1, 158.7, 160.4, 161.5, 186.2; (1:1 petrol:EtOAc); νmax (thin film)/cm 2115, 1651, 1510,
3
) 3.77–3.84 (11 H, m), 6.46–6.50 (2 H, m), 6.84 (2 H, 2-(4-methoxyphenyl)-N-methylacetamide
(100 mmol). Purification by flash column chromatography afforded
0.81
(697 mg, 3.33
C
3
f
−1
1
+
+
HRMS (ESI ): Found: 311.1284; C19
11.1278 (2.1 ppm error).
H
19
O
4
(MH ) Requires 1246, 1176, 1120, 738, 686; δ
3.80 (3 H, s), 6.89 (2 H, d, J = 8.5), 7.17–7.35 (7 H, m); δ
MHz, CDCl ) 50.2, 55.2, 87.6, 100.7, 114.2, 125.0, 127.0, 127.8,
129.5, 129.6, 130.9, 158.9, 183.3; HRMS (ESI ): Found:
H
(400 MHz, CDCl
3
) 3.79 (2 H, s),
3
C
(100
3
+
6
-Methoxy-4-(4-methoxyphenyl)spiro[4.5]deca-3,6,9-triene-
,8-dione (10h). Synthesised using general procedure C from 283.0786; C17
O (78 mg, 0.200
at RT. Purification by flash column 4-(Phenylthio)spiro[4.5]deca-3,6,9-triene-2,8-dione
+
2
15 2
H O S (MH ) Requires 283.0787 (0.1 ppm error).
ynone 9h (60.3 mg, 0.200 mmol) and SnCl2·2H
mmol) for 20
2
h
(10j).
chromatography (2:1 petrol:EtOAc, then 1:1 petrol:EtOAc) Synthesised using general procedure C from ynone 9j (70.6
afforded the title compound 10h as a white solid (51 mg, 89%); mg, 0.250 mmol) and copper(II) triflate (90.4 mg, 0.250 mmol)
mp. 169–171 °C; R
f
0.19 (1:1 petrol:EtOAc); νmax (thin for 2 h at RT. Purification by flash column chromatography (2:1
−1
film)/cm 1689, 1652, 1588, 1360, 1244, 1177, 1027, 989, 858, petrol:EtOAc, then 1:1 petrol:EtOAc) afforded the title
8
40; δ
H 3
(400 MHz, CDCl ) 2.61 (1 H, d, J = 18.0), 2.86 (1 H, d, J = compound 10j as a pale orange solid (43 mg, 64%); mp. 113–
−1
1
8.0), 3.65 (3 H, s), 3.79 (3 H, s), 5.76 (1 H, d, J = 1.5), 6.34 (1 H, 115 °C; R
f
0.25 (1:1 petrol:ethyl acetate); νmax (thin film)/cm
(400 MHz, CDCl ) 2.74 (2 H, s),
) 47.7, 52.5, 5.63 (1 H, s), 6.47 (2 H, d, J = 10.0), 6.79 (2 H, d, J = 10.0), 7.42–
5.4, 56.2, 103.4, 114.3, 125.1, 128.3, 128.4, 128.9, 147.4, 7.49 (5 H, m); δ (100 MHz, CDCl ) 46.2, 51.3, 125.8, 128.4,
62.1, 171.6, 175.5, 187.2, 203.6; HRMS (ESI ): Found: 130.2, 130.4, 130.6, 134.5, 149.2, 182.5, 184.5, 199.8; HRMS
dd, J = 10.0, 1.5), 6.61 (1 H, s), 6.64 (1 H, d, J = 10.0), 6.83 (2 H, 1687, 1665, 1548, 860, 752; δ
d, J = 9.0), 7.43 (2 H, d, J = 9.0); δ (100 MHz, CDCl
H
3
C
3
5
1
2
C
3
+
+
+
+
97.1112; C18
H
17
O
4
(MH ) Requires 297.1121 (1.9 ppm error).
(ESI ): Found: 269.0621; C16
3.0 ppm error).
13 2
H O S (MH ) Requires 269.0631
(
4-(2,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)but-3-yn-2-
one (9i). Synthesised using general procedure B from 1- 1,5-Bis(4-methoxyphenyl)pent-1-yn-3-one (9k). Synthesised
2
ethynyl-2,4-dimethoxybenzene (420 mg, 2.59 mmol) and N- using general procedure B from 4-ethynylanisole (488 mg, 3.70
0
2
1
methoxy-2-(4-methoxyphenyl)-N-methylacetamide (361 mg, mmol)
.73 mmol). Purification by flash column chromatography methylpropanamide (550 mg, 2.46 mmol). Purification by
afforded the title compound 9i as a pale yellow oil (340 mg, flash column chromatography afforded the title compound 9k
and
N-methoxy-3-(4-methoxyphenyl)-N-
2
3
1
−
1
6
3%); R
652, 1600, 1505, 1296, 1244, 1210, 1026, 819; δ
) 3.79 (3 H, s), 3.82 (3 H, s), 3.84–3.87 (5 H, m), 6.39 (1 H, 1293, 1245, 117,1084, 1026, 830; δ
d, J = 2.0), 6.45 (1 H, dd, J = 8.5, 2.0), 6.86 (2 H, d, J = 8.5), 7.25 3.02 (4 H, m), 3.78 (3 H, s), 3.83 (3 H, s), 6.83 (2 H, d, J = 8.5),
2 H, d, J = 8.5), 7.34 (1 H, d, J = 8.5); δ (100 MHz, CDCl ) 51.3, 6.89 (2 H, d, J = 8.5), 7.14 (2 H, d, J = 8.5), 7.51 (2 H, d, J = 8.5);
5.2, 55.5, 55.7, 91.3, 91.9, 98.2, 101.5, 105.4, 114.0, 125.6, (100 MHz, CDCl ) 29.2, 47.1, 55.2, 55.4, 87.7, 92.3, 111.6,
30.9, 136.5, 158.7, 163.2, 163.6, 185.5; HRMS (ESI ): Found: 113.9, 114.3, 129.3, 132.4, 135.1, 158.0, 161.6, 187.1; HRMS
f
0.60 (1:1 petrol:EtOAc); νmax (thin film)/cm 2185, as a yellow solid (500 mg, 69%); mp. 58–60 °C; R
f
0.80 (1:1
(400 MHz, petrol:EtOAc); νmax (thin film)/cm 2185, 1659, 1601, 1508,
(400 MHz, CDCl ) 2.92–
−1
1
H
CDCl
3
H
3
(
C
3
5
1
3
δ
C
3
+
+
+
+
11.1272; C19
H
19
O
4
(MH ) Requires 311.1278 (1.9 ppm error).
(ESI ): Found: 295.1317; C19
3.7 ppm error).
19 3
H O (MH ) Requires 295.1329
(
4-(2,4-Dimethoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-
dione (10i). Synthesised using general procedure C from ynone 7-(4-Methoxyphenyl)spiro[5.5]undeca-1,4,7-triene-3,9-dione
(55.0 mg, 0.177 mmol) and SnCl2·2H O (40.0 mg, 0.177 (10k). Synthesised using general procedure C from ynone 9k
mmol) for 20 at RT. Purification by flash column (62.0 mg, 0.204 mmol) and copper(II) triflate (73.7 mg, 0.204
9i
2
h
chromatography (2:1 petrol:EtOAc, then 1:1 petrol:EtOAc) mmol) for 20 h at 50 °C. Purification by flash column
afforded the title compound 10i as a pale brown solid (48 mg, chromatography (1:1 petrol:EtOAc) afforded the title
9
f
1%); mp. 172–174 °C R 0.19 (1:1 petrol:EtOAc); νmax (thin compound 10k as a pale yellow solid (46 mg, 78%); mp. 165–
−1
−1
film)/cm 1688, 1660, 1605, 1551, 1233, 1213, 1026, 859; δ
H
167 °C; R
) 2.67 (2 H, s), 3.80 (3 H, s), 3.84 (3 H, s), 6.37 1623, 1603, 1510, 1243, 1178, 1030, 859, 731; δ
1 H, dd, J = 8.5, 2.5), 6.40 (2 H, d, J = 10.0), 6.46 (1 H, d, J = CDCl ) 2.25 (2 H, t, J = 6.5), 2.68 (2 H, t, J = 6.5), 3.78 (3 H, s),
.5), 6.95 (2 H, d, J = 10.0), 6.97 (1 H, s), 7.26 (1 H, d, J = 8.5); δ 6.30 (1 H, s), 6.42 (2 H, d, J = 10.0), 6.79 (2 H, d, J = 9.0), 7.06 (2
100 MHz, CDCl ) 46.1, 52.4, 55.4, 55.5, 98.9, 104.4, 115.0, H, d, J = 10.0), 7.19 (2 H, d, J = 9.0); δ (100 MHz, CDCl ) 34.0,
29.2, 130.2, 131.6, 152.9, 160.1, 163.2, 168.8, 184.9, 204.7; 37.7, 45.5, 55.3, 114.0, 127.7, 128.1, 130.1, 130.4, 152.6,
f
0.25 (1:1 petrol:EtOAc); νmax (thin film)/cm 1657,
(
400 MHz, CDCl
3
H
(400 MHz,
(
3
2
C
(
3
C
3
1
+
+
+
17 4
HRMS (ESI ): Found: 297.1113; C18H O (MH ) Requires 159.2, 161.0, 184.7, 196.9; HRMS (ESI ): Found: 281.1179;
+
297.1121 (2.6 ppm error).
18 17 3
C H O (MH ) Requires 281.1172 (2.5 ppm error).
1-(4-Methoxyphenyl)-4-(phenylthio)but-3-yn-2-one
(9j). 1-(4'-Methoxybiphenyl-2-yl)-3-(4-methoxyphenyl)prop-2-yn-
Synthesised
using general procedure
B
from 1-one (9l). Synthesised using general procedure B from 4-
2
2
ethynyl(phenyl)sulfane (671 mg, 5.00 mmol) and N-methoxy- ethynylanisole (190 mg, 1.44 mmol) and N,4'-dimethoxy-N-
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Organic & Biomolecular Chemistry
Page 8 of 13
View Article Online
DOI: 10.1039/C6OB02426B
ARTICLE
Journal Name
2
4
+
(MH ) Requires 237.0910
methyl-[1,1'-biphenyl]-2-carboxamide
(260 mg, 0.958). error), Found: 237.0919; C16H
13
O
2
Purification by flash column chromatography (10:1 (−3.8 ppm error).
petrol:EtOAc, then 5:1 petrol:EtOAc) afforded the title
compound 9l as a pale yellow oil (141 mg, 43%); R
f
0.70 (1:1 4-Phenylspiro[4.5]deca-3,6,9-triene-2,8-dione
petrol:EtOAc); νmax (thin film)/cm 2184, 1620, 1599, 1508, Synthesised using general procedure C2 from ynone 11c (100
289, 1248, 1027, 999, 830, 760; δ (400 MHz, CDCl ) 3.77 (3 mg, 0.423 mmol) and AgNO ·SiO (719 mg, 0.0423 mmol) for
H, s), 3.80 (3 H, s), 6.79 (2 H, d, J = 9.0), 6.94 (2 H, d, J = 8.5), 24 h at 40 °C. Afforded the title compound 10c without further
(10c).
−
1
1
H
3
3
2
7
7
5
1
.22 (2 H, d, J = 9.0), 7.35 (2 H, d, J = 8.5), 7.40–7.45 (2 H, m), purification as a pale brown solid (94.0 mg, 94%); mp 124–126
-1
.53–7.58 (1 H, m), 7.92 (1 H, d, J = 7.5); δ
5.3, 55.4, 88.9, 94.9, 112.0, 113.8, 114.0, 127.0, 129.9, 130.7, 1658, 1592, 1251, 859, 764; δ
30.9, 131.9, 132.9, 135.0, 138.1, 142.3, 159.4, 161.4, 180.8; 6.49 (2 H, d, J = 10.0), 6.71 (1 H, s), 6.96 (2 H, d, J = 10.0), 7.34–
C
(100 MHz, CDCl
3
)
°C; R
f
0.31 (1:1 hexane:EtOAc); νmax (thin film)/cm 3068, 1693,
H
(400 MHz, CDCl ) 2.80 (2 H, s),
3
+
+
HRMS (ESI ): Found: 343.1324; C23
H
19
O
3
(MH ) Requires 7.40 (2 H, m), 7.42–7.48 (1 H, m), 7.49–7.54 (2 H, m); δ
C
(100
3
43.1329 (1.0 ppm error).
MHz, CDCl ) 46.9, 51.2, 127.4, 129.0, 129.9, 130.0, 131.6,
3
+
32.9, 151.4, 173.9, 184.7, 203.3; HRMS (ESI ): Found:
1
+
2'-(4-Methoxyphenyl)-4'H-spiro[cyclohexa[2,5]diene-1,1'-
259.0732; C16H12NaO
2
(MNa ) Requires 259.0730 (−0.9 ppm
naphthalene]-4,4'-dione (10l). Synthesised using general error). Spectroscopic data matched those previously reported
2
procedure C from ynone 9l (66.0 mg, 0.193 mmol) and in the literature.
5
copper(II) triflate (69.6 mg, 0.193 mmol) for 48 h at RT.
Purification by flash column chromatography (2:1 1-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-one
petrol:EtOAc) afforded the title compound 10l as a pale yellow (11d). Synthesised using general procedure B from 1-ethynyl-
oil (47 mg, 74%); R
f
0.25 (1:1 petrol:EtOAc); νmax (thin 4-methoxybenzene (983 mg, 7.44 mmol) and Weinreb amide
film)/cm 1655, 1602, 1510, 1331, 1251, 1031, 836; δ (400 S3 (484 mg, 2.48 mmol) stirring at RT for 1 h. Purification by
MHz, CDCl ) 3.797 (3 H, s), 6.44 (2 H, d, J = 9.5), 6.72 (1 H, s), flash column chromatography (9:1 hexane:EtOAc, then 7:3
.74 (2 H, d, J = 9.5), 6.82 (2 H, d, J = 9.0), 7.25–7.29 (3 H, m), hexane:EtOAc) afforded the title compound 11d as a yellow
.48–7.57 (2 H, m), 8.25 (1 H, d, J = 7.0); δ (100 MHz, CDCl solid (502 mg, 76%); mp 86–88 °C; R 0.62 (1:1 hexane:EtOAc);
0.7, 55.3, 113.7, 127.3, 128.2, 128.7, 128.9, 129.6, 130.0, max (thin film)/cm 3353, 2195, 1651, 1600, 1510, 1254, 1170,
30.0, 130.2, 133.2, 138.3, 150.0, 156.0, 160.6, 183.6, 185.2; 1076, 834; δ (400 MHz, CDCl ) 3.83 (3 H, s), 3.85 (2 H, s), 5.52
(MH ) Requires (1 H, br s), 6.86 (4 H, m), 7.17 (2 H, d, J = 8.0), 7.41 (2 H, d, J =
−1
H
3
6
7
5
1
C
3
)
f
-1
ν
H
3
+
+
17 3
HRMS (ESI ): Found: 329.1170; C22H O
3
29.1172 (0.8 ppm error).
8.5); δ
C
(100 MHz, CDCl
3
) 51.1, 55.4, 87.8, 94.7, 111.5, 114.3,
+
15.6, 125.4, 131.1, 135.2, 155.1, 161.7, 186.3; HRMS (ESI ):
1
+
2-(4-)-N-methoxy-N-methylacetamide (S3). Synthesised using Found: 289.0839; C17
H14NaO
3
(MNa ) Requires 289.0835 (−1.4
general procedure A2 from 2-(4-hydroxyphenyl)acetic acid ppm error).
2.40 g, 15.8 mmol) stirring at RT for 1 h. Afforded the title
compound S3 as a white solid (3.00 g, 100%); mp 110–112 °C; 4-(4-Methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione
(
-
1
R
f
0.58 (9:1 EtOAc:hexane); νmax (thin film)/cm 3264, 1631, (10d). Synthesised using general procedure C2 from ynone 11d
614, 1594, 1515, 1446, 1233, 1172, 1002, 798; δ (400 MHz, (100 mg, 0.376 mmol) and AgNO ·SiO (638 mg, 0.0376 mmol)
CDCl ) 3.22 (3 H, s), 3.65 (3 H, s), 3.70 (2 H, s), 6.68 (2 H, d, J = for 3 h at 40 °C. Afforded the title compound 10d without
.5), 7.07 (2 H, d, J = 8.5); δ (100 MHz, CDCl ) 32.3, 38.2, 61.3, further purification as a brown solid (100 mg, 100%). Data for
15.6, 125.9, 130.4, 155.2, 173.3; HRMS (ESI ): Found: this compound is reported above.
1
H
3
2
3
8
1
2
C
3
+
+
18.0788; C10H13NNaO
3
(MNa ) Requires 218.0788 (−0.3 ppm
+
error), Found: 196.0975; C10
H14NO
3
(MH ) Requires 196.0968 2-(4-Hydroxy-3-methoxyphenyl)-N-methoxy-N-
methylacetamide (S4). Synthesised using general procedure
A2 from 2-(4-hydroxy-3-methoxyphenyl)acetic acid (1.15 g,
(
−3.2 ppm error).
1
-(4-Hydroxyphenyl)-4-phenylbut-3-yn-2-one
(11c). 6.34 mmol) stirring at RT for 1 h. Afforded the title compound
0.21 (1:1
0.34 mL, 3.07 mmol) and Weinreb amide S3 (200 mg, 1.02 hexane:EtOAc); νmax (thin film)/cm 3316, 2939, 1639, 1514,
mmol) stirring at RT for 30 min. Purification by flash column 1432, 1271, 1200, 1151, 1033; δ (400 MHz, CDCl ) 3.19 (3 H,
chromatography (9:1 hexane:EtOAc, then 1:1 hexane:EtOAc) s), 3.62 (3 H, s), 3.70 (2 H, s), 3.87 (3 H, s), 5.35 (1 H, br s), 6.75
afforded the title compound 11c as a pale yellow solid (135 mg, (1 H, d, J = 8.0), 6.82–6.86 (2 H, m); δ (100 MHz, CDCl ) 32.2,
6%); mp 96–98 °C; R 0.51 (6:4 hexane:EtOAc); νmax (thin 38.8, 55.8, 61.3, 111.7, 114.2, 122.1, 126.5, 144.5, 146.5,
Synthesised using general procedure B2 from phenylacetylene S4 as a clear and colourless oil (810 mg, 48%); R
f
-1
(
H
3
C
3
5
f
-1
+
+
film)/cm 3368, 2202, 1655, 1514, 1224, 1079, 758, 688; δ
400 MHz, CDCl ) 3.87 (2 H, s), 5.42 (1 H, br s), 6.83–6.88 (2 H, Requires 248.0893 (3.7 ppm error), Found: 226.1070;
m), 7.16–7.21 (2 H, m), 7.33–7.39 (2 H, m), 7.42–7.50 (3 H, m);
H
4
172.7; HRMS (ESI ): Found: 248.0884; C11H15NNaO (MNa )
(
3
+
11 4
C H16NO (MH ) Requires 226.1074 (1.6 ppm error).
δ
1
2
C
(100 MHz, CDCl
3
) 51.3, 87.7, 93.3, 115.7, 119.7, 125.1,
+
28.6, 130.9, 131.1, 133.1, 155.1, 186.1; HRMS (ESI ): Found: 1-(4-Hydroxy-3-methoxyphenyl)-4-(4-methoxyphenyl)but-3-
+
59.0731; C16H12NaO
2
(MNa ) Requires 259.0730 (−0.6 ppm yn-2-one (11m). Synthesised using general procedure B2 from
1
-ethynyl-4-methoxybenzene (880 mg, 6.66 mmol) and
8
| 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
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DOI: 10.1039/C6OB02426B
ARTICLE
Weinreb amide S4 (500 mg, 2.22 mmol) stirring at RT for 1 h. (2.0 ppm error). Spectroscopic data matched those previously
2
Purification by flash column chromatography (9:1 reported in the literature.
6
hexane:EtOAc, then 7:3 hexane:EtOAc) afforded the title
compound 11m as a yellow solid (443 mg, 58%); mp 61–63 °C; tert-Butyl
(6-(4-hydroxyphenyl)-5-oxohex-3-yn-1-
0.20 (7:3 hexane:EtOAc); νmax (thin film)/cm 3437, 2195, yl)(methyl)carbamate (11o) Synthesised using general
655, 1601, 1509, 1254, 1237, 1170; δ (400 MHz, CDCl ) 3.84 procedure B2 from tert-butyl but-3-yn-1-
5 H, s), 3.89 (3 H, s), 5.63 (1 H, br s), 6.78–6.95 (5 H, m), 7.43 yl(methyl)carbamate (568 mg, 3.10 mmol) and Weinreb
2 H, d, J = 8.5); δ (100 MHz, CDCl ) 51.7, 55.4, 55.9, 87.7, amide S3 (202 mg, 1.03 mmol) stirring at RT for 2.5 h.
4.1, 111.6, 112.0, 114.3, 114.5, 122.8, 125.2, 135.1, 144.9, Purification by flash column chromatography (9:1
-1
R
f
.
1
H
3
1
0d
(
(
C
3
9
1
+
46.6, 161.7, 185.7; HRMS (ESI ): Found: 319.0939; C18
H
16NaO
4
hexane:EtOAc, then 1:1 hexane:EtOAc) afforded the title
compound 11o as a yellow oil (241 mg, 74%); R 0.62 (1:1
hexane:EtOAc); νmax (thin film)/cm 3331, 2977, 2212, 1663,
1515, 1395, 1366, 1225, 1145, 730; δ (400 MHz, CDCl ) 1.47
,8-dione (10m). Synthesised using general procedure C2 from (9 H, s), 2.54 (2 H, t, J = 7.0), 2.86 (3 H, s), 3.36 (2 H, t, J = 7.0),
·SiO (338 mg, 3.71 (2 H, s), 6.07 (1 H, br s), 6.81 (2 H, d, J = 8.0), 7.08 (2 H, d, J
.0199 mmol) for 24 h at 40 °C. Purification by flash column = 8.0); δ (100 MHz, CDCl ) 18.6, 28.4, 35.0, 47.2, 51.2, 80.3,
chromatography (8:2 hexane:EtOAc) afforded the title 81.7, 92.9, 115.8, 124.8, 130.9, 155.6, 155.6, 185.4; HRMS
+
(
MNa ) Requires 319.0941 (0.7 ppm error).
f
-1
7-Methoxy-4-(4-methoxyphenyl)spiro[4.5]deca-3,6,9-triene-
H
3
2
ynone 11m (59.0 mg, 0.199 mmol) and AgNO
3
2
0
C
3
+
+
compound 10m an off-white oil (50.9 mg, 86%); R
f
0.14 (1:1 (ESI ): Found: 340.1522;
C
18
H
23NNaO
4
(MNa ) Requires
-1
hexane:EtOAc); νmax (thin film)/cm 1691, 1664, 1636, 1603, 340.1519 (−0.9 ppm error). Note: majority of peaks broadened
1
1
587, 1509, 1258, 1208, 1177, 831; δ
1 H, d, J = 18.5), 2.86 (1 H, d, J = 18.5), 3.66 (3 H, s), 3.83 (3 H,
s), 5.86 (1 H, d, J = 2.5), 6.50 (1 H, d, J = 9.5), 6.61 (1 H, s), 6.85 tert-Butyl
2 H, d, J = 8.5), 6.97 (1 H, dd, J = 9.5, 2.5), 7.48 (2 H, d, J = 8.5); yl)ethyl)(methyl)carbamate (10o). Synthesised using general
H 3
(400 MHz, CDCl ) 2.78 in H NMR spectrum due to presence of rotamers.
(
(2-(3,8-dioxospiro[4.5]deca-1,6,9-trien-1-
(
δ
C
(100 MHz, CDCl
3
) 48.0, 51.6, 55.2, 55.4, 114.3, 119.4, 125.3, procedure C2 from ynone 11o (73.5 mg, 0.232 mmol) and
·SiO (394 mg, 0.0232 mmol) for 10 h at RT. Afforded
(MNa ) Requires the title compound 10o without further purification as a pale
yellow oil (68.5 mg, 93%); R 0.22 (1:1 hexane:EtOAc); νmax
thin film)/cm 2975, 1720, 1688, 1662, 1624, 1615, 1392,
-(4-Hydroxyphenyl)oct-3-yn-2-one(11n). Synthesised using 1365, 1165, 1144, 860; δ (400 MHz, CDCl ) 1.43 (9 H, s), 2.31
127.1, 129.0, 129.4, 151.7, 152.4, 162.2, 173.7, 180.1, 203.4; AgNO
3
2
+
+
HRMS (ESI ): Found: 319.0947; C18H16NaO
4
3
19.0941 (−2.0 ppm error).
f
-1
(
1
H
3
general procedure B2 from hex-1-yne (0.35 mL, 3.07 mmol) (2 H, t, J = 7.0), 2.62 (2 H, s), 2.81 (3 H, s), 3.39 (2 H, t, J = 7.0),
and Weinreb amide S3 (200 mg, 1.02 mmol) stirring at RT for 1 6.20 (1 H, s), 6.43 (2 H, d, J = 9.5), 6.65–6.73 (2 H, br m); δ
h. Purification by flash column chromatography (9:1 (100 MHz, CDCl ) 27.2, 28.4, 34.2, 45.1, 47.1, 52.8, 80.0, 130.9,
hexane:EtOAc, then 7:3 hexane:EtOAc) afforded the title 132.0, 149.4, 155.5, 176.9, 184.5, 203.8; HRMS (ESI ): Found:
C
3
+
+
compound 11n as a yellow oil (181 mg, 82%); R
f
0.76 (1:1 340.1522; C18
H23NNaO
4
(MNa ) Requires 340.1519 (−0.8 ppm
-1
1
hexane:EtOAc); νmax (thin film)/cm 3373, 2959, 2933, 2209, error). Note: majority of peaks broadened in H NMR spectrum
1652, 1514, 1224, 796; δ
H 3
(400 MHz, CDCl ) 0.89 (3 H, t, J = due to presence of rotamers.
7.5), 1.35 (2 H, qt, J = 7.5, 7.5), 1.48 (2 H, tt, J = 7.5, 7.0), 2.32
(2 H, t, J = 7.0), 3.74 (2 H, s), 5.93 (1 H, br s), 6.80 (2 H, d, J = 6-((tert-Butyldimethylsilyl)oxy)-1-(4-hydroxyphenyl)hex-3-yn-
8
C 3
.0), 7.09 (2 H, d, J = 8.0); δ (100 MHz, CDCl ) 13.4, 18.6, 21.8, 2-one (11p). To an oven-dried 100 mL round-bottom flask
2
9.5, 51.3, 80.7, 97.3, 115.6, 124.9, 130.9, 155.1, 186.7; HRMS containing (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (753
7
2
+
+
(MNa ) Requires 239.1043 mg, 4.09 mmol) and freshly distilled THF (15 mL) at –78 °C
(
ESI ): Found: 239.1050; C14
−3.2 ppm error).
H16NaO
2
(
under argon was added n-BuLi (1.3 mL, 4.3mmol, 2.5 M in
hexanes) drop-wise over 10 min. After stirring at –78 °C for 60
4
-Butylspiro[4.5]deca-3,6,9-triene-2,8-dione(10n).
Synthesised using general procedure C2 from ynone 11n (85.4 oven-dried round-bottom flask containing Weinreb amide S3
mg, 0.395 mmol) and AgNO ·SiO (671 mg, 0.0395 mmol) for (266 mg, 1.36 mmol) in THF (15 mL) and stirred at –78 °C for
4 h at RT. Afforded the title compound 10n without further 10 min. The resulting suspension was warmed to RT, quenched
purification as a pale yellow solid (80.3 mg, 94%); mp 100–102 with saturated aqueous NH Cl (20 mL), extracted successively
0.35 (1:1 hexane:EtOAc); νmax (thin film)/cm 2959, 2929, with EtOAc (3 x 15 mL), and the combined organics washed
875, 2857, 1720, 1696, 1657, 1614, 1599, 1255, 1232, 862; δ with brine (20 mL), dried (MgSO ), and concentrated under
400 MHz, CDCl ) 0.90 (3 H, t, J = 7.5), 1.33 (2 H, qt, J = 7.5, vacuum to yield a crude product. The crude product was
.5), 1.52 (2 H, tt, J = 7.5, 7.5), 2.10 (2 H, t, J = 7.5), 2.65 (2 H, purified by flash column chromatography (9:1 hexane:EtOAc,
s), 6.22 (1 H, s), 6.45 (2 H, d, J = 9.0), 6.66 (2 H, d, J = 9.0); δ then 6:4 hexane:EtOAc) to afford the title compound 11p as a
100 MHz, CDCl ) 13.7, 22.2, 28.8, 29.5, 45.0, 52.6, 130.58, yellow oil (367 mg, 84%); R 0.56 (1:1 hexane:EtOAc); νmax (thin
min, the alkyne solution was transferred via cannula into an
3
2
2
4
-1
°
C; R
f
2
H
4
(
3
7
C
(
3
f
+
-
1
30.61, 150.0, 181.6, 184.9, 204.6; HRMS (ESI ): Found: film)/cm 3379, 2953, 2929, 2857, 2213, 1670, 1514, 1253,
+
(MNa ) Requires 239.1043 (−0.3 ppm 1106, 836, 795, 778; δ
239.1043; C14
H16NaO
2
H
(400 MHz, CDCl
3
) 0.06 (6 H, s), 0.88 (9
+
(MH ) Requires 217.1223 H, s), 2.53 (2 H, t, J = 7.0), 3.71 (2 H, t, J = 7.0), 3.73 (2 H, s),
error), Found: 217.1219; C14
H
17
O
2
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB02426B
ARTICLE
Journal Name
6
.77 (2 H, app. d, J = 8.5), 7.06 (2 H, app. d, J = 8.5); δ
C
(100 yellow oil (207 mg, 89%); R
f
0.74 (1:1 hexane:EtOAc); νmax (thin
-
1
) -5.2, 18.4, 23.5, 25.9 , 51.3, 60.8, 81.5, 93.7, film)/cm 3376, 2961, 2871, 2205, 1650, 1514, 1224, 1172; δ
MHz, CDCl
3
H
+
15.7, 124.8, 131.0, 155.2, 186.3; HRMS (ESI ): Found: (400 MHz, CDCl
1
3
) 1.50–1.76 (6 H, m), 1.83–1.97 (2 H, m), 2.73
+
341.1536; C18
H26NaO
3
Si (MNa ) Requires 341.1543 (2.3 ppm (1 H, tt, J = 7.5, 7.5), 3.74 (2 H, s), 5.49 (1 H, br s), 6.80 (2 H, d, J
= 8.0), 7.10 (2 H, d, J = 8.0); δ (100 MHz, CDCl ) 25.1, 30.0,
3.0, 51.3, 80.2, 101.3, 115.5, 125.2, 130.9, 154.9, 186.6;
error).
C
3
3
+
+
4
-(2-((tert-Butyldimethylsilyl)oxy)ethyl)spiro[4.5]deca-3,6,9-
triene-2,8-dione (10p). Synthesised using general procedure 251.1043 (0.7 ppm error).
C2 from ynone 11p (55.0 mg, 0.170 mmol) and AgNO ·SiO
293 mg, 0.0170 mmol) 16 h at RT. Purification by flash column 4-Cyclopentylspiro[4.5]deca-3,6,9-triene-2,8-dione
chromatography (8:2 hexane:EtOAc, then 1:1 hexane:EtOAc) Synthesised using general procedure C2 from ynone 11r (60.2
afforded the title compound 10p as an orange solid (49.0 mg, mg, 0.264 mmol) and AgNO ·SiO (448 mg, 0.0264 mmol) for 6
9%); R 0.42 (1:1 hexane:EtOAc); mp 76–80 °C ; νmax (thin h at RT. Afforded the title compound 10r without further
2
HRMS (ESI ): Found: 251.1041; C15H16NaO (MNa ) Requires
3
2
(
(10r).
3
2
8
f
-
1
film)/cm 2928, 2857, 1721, 1698, 1657, 1621, 1254, 1102, purification as a white solid (60.0 mg, 100%); mp 129–131 °C;
-1
864, 834, 775; δ
2.28 (2 H, dt, J = 6.0, 1.5), 2.26 (2 H, s), 3.75 (2 H, t, J = 6.0), 1657, 1621, 1609, 1403, 1249, 864; δ
6
.31 (1 H, t, J = 1.5), 6.42 (2 H, app. d, J = 10.0), 6.64 (2 H, app. 1.50 (2 H, m), 1.52−1.67 (2 H, m), 1.68–1.82 (2 H, m),
H
(400 MHz, CDCl
3
) 0.01 (6 H, s), 0.85 (9 H, s),
R
f
0.43 (1:1 hexane:EtOAc); νmax (thin film)/cm 2958, 1697,
H
(400 MHz, CDCl ) 1.37–
3
d, J = 10.0); δ
C
(100 MHz, CDCl
3
) -5.35, 18.3, 25.9, 32.3, 44.9, 1.83−1.95 (2 H, m), 2.30 (1 H, ꢁ, J = 8.0, 8.0), 2.64 (2 H, s), 6.22
(100
) 25.5, 34.8, 40.2, 45.0, 53.0, 129.0, 130.5, 150.0,
5
2.7, 60.6, 130.8, 132.0, 149.8, 178.0, 184.9, 204.8; HRMS (1 H, s), 6.44 (2 H, d, J = 10.0), 6.69 (2 H, d, J = 10.0); δ
C
+
ESI ): Found: 341.1541;
+
(
C
18
H
26NaO
3
Si (MNa ) Requires MHz, CDCl
185.0, 186.8, 204.7; HRMS (ESI ): Found: 251.1033; C15H16NaO
2
3
+
341.1543 (0.7 ppm error).
+
MNa ) Requires 251.1043 (3.9 ppm error), Found: 229.1215;
(
+
4
-Cyclopropyl-1-(4-hydroxyphenyl)but-3-yn-2-one
(11q).
C
15 17 2
H O (MH ) Requires 229.1223 (3.7 ppm error).
Synthesised
using general procedure
B2
from
ethynylcyclopropane (0.40 mL, 4.61 mmol) and Weinreb amide 2-(2-Hydroxyphenyl)-N-methoxy-N-methylacetamide
(S5).
S3 (300 mg, 1.54 mmol) stirring at RT for 1 h. Purification by Synthesised using general procedure A2 from 2-(2-
flash column chromatography (1:1 hexane:EtOAc) afforded the hydroxyphenyl)acetic acid (2.00 g, 13.1 mmol) stirring at RT for
title compound 11q as a white solid (276 mg, 90%); mp 81–83 1.5 h. Purification by flash column chromatography (9:1
-
1
°
C; R
f
0.59 (1:1 hexane:EtOAc); νmax (thin film)/cm 3367, 2201, hexane:EtOAc, then 1:1 hexane:EtOAc) afforded the title
647, 1514, 1222; δ (400 MHz, CDCl ) 0.80–0.85 (2 H, m), compound S5 as a white solid (788 mg, 31%); mp 63–65 °C; R
.92–0.98 (2 H, m), 1.31–1.39 (1 H, m), 3.71 (2 H, ), 5.30 (1 H, 0.39 (1:1 hexane:EtOAc); νmax (thin film)/cm 3260, 1628,
1
0
H
3
f
-1
br s), 6.80 (2 H, d, J = 8.0), 7.09 (2 H, d, J = 8.0); δ
CDCl
86.0; HRMS (ESI ): Found: 223.0734; C13
C
H 3
(100 MHz, 1596, 1456, 1246, 1000, 753; δ (400 MHz, CDCl ) 3.24 (3 H, s),
) −0.3, 9.9, 51.1, 76.5, 101.6, 115.5, 125.3, 130.9, 154.9, 3.80 (3 H, s), 3.87 (2 H, s), 6.85 (1 H, dd, J = 8.0, 7.5), 6.99 (1 H,
3
+
+
1
H
12NaO
2
(MNa ) d, J = 8.0), 7.09 (1 H, d, J = 7.5), 7.19 (1 H, dd, J = 8.0, 8.0), 9.50
(100 MHz, CDCl ) 32.0, 35.1, 62.0, 118.2, 120.2,
120.9, 129.1, 130.9, 156.8, 173.5; HRMS (ESI ): Found:
Requires 223.0730 (−2.1 ppm error), Found: 201.0906; (1 H, s); δ
C
3
+
+
13 13 2
C H O (MH ) Requires 201.0910 (1.9 ppm error).
+
2
18.0794; C10
error), Found: 196.0967; C10
Synthesised using general procedure C2 from ynone 11q (101 (−0.8 ppm error).
mg, 0.504 mmol) and AgNO ·SiO (857 mg, 0.0504 mmol) for 2
h at RT. Afforded the title compound 10q without further 4-Cyclopropyl-1-(2-hydroxyphenyl)but-3-yn-2-one
purification as a white solid (100 mg, 99%); mp 109–111 °C; R Synthesised using general procedure
H13NNaO
3
(MNa ) Requires 218.0788 (−3.0 ppm
+
4-Cyclopropylspiro[4.5]deca-3,6,9-triene-2,8-dione
(10q)
.
3
H14NO (MH ) Requires 196.0968
3
2
(11s).
f
B2
from
-
1
0
.45 (1:1 hexane:EtOAc); νmax (thin film)/cm 1689, 1666, ethynylcyclopropane (0.65 mL, 7.68 mmol) and Weinreb amide
624, 1605, 1401, 1252, 860; δ (400 MHz, CDCl ) 0.77–0.82 (2 S5 (500 mg, 2.56 mmol) stirring at RT for 45 min. Purification
1
H
3
H, m), 1.11−1.17 (2 H, m), 1.18−1.24 (1 H, m), 2.64 (2 H, s), by flash column chromatography (1:1 hexane:EtOAc) afforded
.75 (1 H, s), 6.45 (2 H, d, J = 10.0), 6.72 (2 H, d, J = 10.0); δ the title compound 11s as an off-white solid (452 mg, 88%); mp
100 MHz, CDCl ) 11.0, 13.8, 45.0, 52.8, 123.5, 130.6, 150.0, 98–100 °C; R
5
C
-
1
(
3
f
0.78 (1:1 hexane:EtOAc); νmax (thin film)/cm
3369, 2202, 1649, 1458, 1269, 755; δ (400 MHz, CDCl ) 0.87–
+
1
84.9, 185.6, 204.2; HRMS (ESI ): Found: 223.0733; C13
H
12NaO
2
H
3
+
MNa ) Requires 223.0730 (−1.7 ppm error), Found: 201.0906; 0.92 (2 H, m), 0.97–1.04 (2 H, m), 1.37–1.45 (1 H, m), 3.85 (2 H,
(
+
(MH ) Requires 201.0910 (2.2 ppm error.
C
13
H
13
O
2
s), 6.70 (1 H, br s), 6.88–6.93 (2 H, m), 7.11 (1 H, app. d, J =
.5), 7.19 (1 H, app. dd, J = 8.0, 8.0); δ (100 MHz, CDCl
) −0.1,
(11r). 10.2, 47.5, 76.8, 103.2, 117.1, 120.6, 120.9, 129.2, 131.3,
7
C
3
4
-Cyclopentyl-1-(4-hydroxyphenyl)but-3-yn-2-one
Synthesised using general procedure
ethynylcyclopentane (0.36 mL, 3.07 mmol) and Weinreb amide (MNa ) Requires 223.0730 (−3.6 ppm error), Found: 201.0918;
+
B2
from 154.9, 187.2; HRMS (ESI ): Found: 223.0738; C13H12NaO
2
+
+
S3 (200 mg, 1.02 mmol) stirring at RT for 1 h. Purification by
flash column chromatography (9:1 hexane:EtOAc, then 7:3
hexane:EtOAc) afforded the title compound 11r as a pale
C
13
H
13
O
2
(MH ) Requires 201.0910 (−3.8 ppm error).
1
0 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB02426B
ARTICLE
4
-Cyclopropylspiro[4.5]deca-3,7,9-triene-2,6-dione
Synthesised using general procedure C2 from ynone 11s (108 hexane:EtOAc); νmax (thin film)/cm 3364, 2193, 1645, 1599,
mg, 0.538 mmol) and AgNO ·SiO (915 mg, 0.0538 mmol) for 2 1508, 1254, 1080, 834; δ (400 MHz, CDCl ) 3.85 (3 H, s), 3.99
h at RT. Afforded the title compound 12s without further (2 H, s), 6.64 (1 H, s), 6.87–6.96 (4 H, m), 7.17–7.24 (2 H, m),
purification as a yellow oil (104 mg, 96%); R 0.34 (1:1 7.49 (2 H, d, J = 8.0); δ (100 MHz, CDCl ) 47.6, 55.4, 87.0, 95.8,
hexane:EtOAc); νmax (thin film)/cm 1694, 1660, 1632, 1607, 111.2, 114.4, 117.1, 120.7, 121., 129.2, 131.5, 135.5, 154.9,
(12s)
.
solid (478 mg, 70%); mp 108–110 °C;
R
f
0.29 (7:3
-1
3
2
H
3
f
C
3
-1
+
1
0
2
H 3 3
557, 1200, 862; δ (400 MHz, CDCl ) 0.68–0.79 (2 H, m), 162.0, 187.2; HRMS (ESI ): Found: 289.0833; C17H14NaO
+
.97−1.09 (2 H, m), 1.20−1.28 (1 H, m), 2.39 (1 H, d, J = 18.0), (MNa ) Requires 289.0835 (0.6 ppm error).
.77 (1 H, d, J = 18.0), 5.72 (1 H, s), 6.23 (1 H, d, J = 9.5), 6.28 (1
H, d, J = 9.0), 6.47 (1 H, dd, J = 9.0, 5.5), 7.19 (1 H, ddd, J = 9.5, 4-(4-Methoxyphenyl)spiro[4.5]deca-3,7,9-triene-2,6-dione
5
.5, 1.5); δ
C
(100 MHz, CDCl
3
) 11.0, 11.9, 13.2, 46.8, 62.7, (12u). Synthesised using general procedure C2 from ynone 11u
·SiO (319 mg, 0.0188 mmol)
2
H12NaO (MNa ) Requires 223.0730 for 24 h at RT. Afforded the title compound 12u without
122.8, 123.9, 126.7, 142.5, 142.8, 184.5, 200.3, 206.2; HRMS (50 mg, 0.188 mmol) and AgNO
3
2
+
+
(
ESI ): Found: 223.0732; C13
−1.3 ppm error), Found: 201.0907; C13
+
(
H
13
O
2
(MH ) Requires further purification as a yellow oil (49.5 mg, 99%); R
f
0.25 (1:1
hexane:EtOAc); νmax (thin film)/cm 1689, 1659, 1602, 1587,
510, 1262, 1179, 1026, 833, 731; δ (400 MHz, CDCl ) 2.51 (1
H, d, J = 18.0), 2.75 (1 H, d, J = 18.0), 3.81 (3 H, s), 6.34 (1 H, d, J
-1
201.0910 (1.3 ppm error).
1
H
3
1-(2-Hydroxyphenyl)-4-phenylbut-3-yn-2-one
(11t).
Synthesised using general procedure B2 from phenylacetylene = 9.5), 6.45–6.47 (2 H, m), 6.68 (1 H, s), 6.85 (2 H, d, J = 8.5),
2.0 mL, 18.1 mmol) and Weinreb amide S5 (1.18 g, 6.04 7.25–7.31 (3 H, m); δ (100 MHz, CDCl ) 48.3, 55.4, 60.4, 114.4,
mmol) stirring at RT for 1 h. Purification by flash column 121.5, 124.8, 126.5, 127.2, 129.2, 142.3, 145.0, 162.2, 173.4,
(
C
3
+
chromatography (9:1 hexane:EtOAc, then 7:3 hexane:EtOAc) 200.5, 204.5; HRMS (ESI ): Found: 289.0834; C17H14NaO
3
+
afforded the title compound 11t as a yellow solid (1.33 g, 93%); (MNa ) Requires 289.0835 (0.4 ppm error), Found: 267.1004;
-
+
mp 106–108 °C; R
f
0.67 (6:4 hexane:EtOAc); νmax (thin film)/cm
333, 2982, 2202, 1661, 1489, 1458, 1156,753; δ (400 MHz,
CDCl ) 4.01 (2 H, s), 6.27 (1 H, br s), 6.94–6.98 (2 H, m), 7.19– 4-(4-Fluorophenyl)-1-(2-hydroxyphenyl)but-3-yn-2-one (11v).
.26 (2 H, m), 7.39 (2 H, m), 7.45–7.50 (1 H, m), 7.51–7.55 (2 H, Synthesised using general procedure B2 from 1-ethynyl-4-
m); δ (100 MHz, CDCl ) 47.5, 87.8, 94.0, 116.8, 119.6, 120.4, fluorobenzene (923 mg, 7.68 mmol) and Weinreb amide S5
17 15 3
C H O (MH ) Requires 267.1016 (4.2 ppm error).
1
3
H
3
7
C
3
1
21.0, 128.6, 129.3, 131.1, 131.5, 133.3, 154.8, 187.0; HRMS (500 mg, 2.56 mmol) stirring at RT for 1 h. Purification by flash
+
(MNa ) Requires 259.0730 column chromatography (9:1 hexane:EtOAc, then 7:3
+
ESI ): Found: 259.0722; C16
(
H
12NaO
2
+
(MH ) Requires hexane:EtOAc) afforded the title compound 11v as a yellow
(3.1 ppm error), Found: 237.0914; C16
H
13
O
2
2
37.0910 (−1.5 ppm error).
solid (430 mg, 66%); mp 115–117 °C;
R
f
0.46 (7:3
hexane:EtOAc); νmax (thin film)/cm 3357, 2203, 1651, 1598,
1505, 1458, 1234, 1082, 838, 754; δ (400 MHz, CDCl ) 3.99 (2
-1
4-Phenylspiro[4.5]deca-3,7,9-triene-2,6-dione
(12t)
.
H
3
3
Synthesised using general procedure C2 from ynone 11t (115 H, s), 6.25 (1 H, s), 6.89–6.97 (2 H, m), 7.08 (2 H, dd, JHH = 8.5,
3
3
4
mg, 0.487 mmol) and AgNO
4 h at RT. Purification by flash column chromatography (9:1
hexane:EtOAc, then 1:1 hexane:EtOAc) afforded the title (d, JCF = 22.0), 116.8, 120.4, 121.1, 129.3, 131.5, 135.6 (d, JCF
3
·SiO
2
(826 mg, 0.0487 mmol) for
JHF 8.5), 7.18–7.25 (2 H, m), 7.51 (2 H, dd, JHH = 8.5, JHF = 5.5);
4
2
C 3
δ (100 MHz, CDCl ) 47.4, 87.7, 92.8, 115.7 (d, JCF = 4.0), 116.2
2
3
1
+
f
compound 12t a pale yellow oil (103 mg, 90%); R 0.22 (7:3 = 8.5), 154.7, 164.1 (d, JCF = 255), 186.8; HRMS (ESI ): Found:
-1
+
2
hexane:EtOAc); νmax (thin film)/cm 1694, 1659, 1595, 1195, 277.0628; C16H11FNaO (MNa ) Requires 277.0635 (2.5 ppm
7
1
7
60; δ
8.0), 6.34 (1 H, d, J = 10.0), 6.44–6.49 (2 H, m), 6.77 (1 H, s),
.24–7.30 (1 H, m), 7.30–7.38 (4 H, m), 7.38–7.44 (1 H, m); δ
) 48.3, 60.5, 121.8, 126.5, 127.3, 129.0, 129.5, (12v). Synthesised using general procedure C2 from ynone 11v
H 3
(400 MHz, CDCl ) 2.54 (1 H, d, J = 18.0), 2.78 (1 H, d, J = error).
C
4-(4-Fluorophenyl)spiro[4.5]deca-3,7,9-triene-2,6-dione
(100 MHz, CDCl
3
+
131.5, 132.3, 142.3, 144.6, 173.7, 200.2, 204.6; HRMS (ESI ): (98.8 mg, 0.389 mmol) and AgNO
3
·SiO
2
(661 mg, 0.0389 mmol)
+
Found: 259.0723; C16
ppm error), Found: 237.0906; C16
37.0910 (1.9 ppm error).
The title compound was also prepared in an enantioenriched film)/cm 1694, 1659, 1601, 1582, 1508, 1238, 1193, 1163,
H12NaO (MNa ) Requires 259.0730 (2.5 for 48 h at RT. Purification by flash column chromatography
2
+
H
13
O
2
(MH ) Requires (8:2 EtOAc:hexane) afforded the title compound 12v a yellow
oil (88.7 mg, 90%); R 0.36 (1:1 hexane:EtOAc); νmax (thin
2
f
-
1
1
5
21
D
form using CPA 16 (56% conv., 23% ee, see Scheme 4); [α]
836; δ
H 3
(400 MHz, CDCl ) 2.53 (1 H, d, J = 18.0), 2.76 (1 H, d, J =
=
+5.6 (c = 0.2, CHCl
3
).
18.0), 6.33 (1 H, d, J = 9.5), 6.42–6.50 (2 H, m), 6.70 (1 H, s),
3
.03 (2 H, dd, JHH = 8.5, JHF 8.5), 7.25–7.29 (1 H, m), 7.29–7.34
3
7
2
1
-(2-Hydroxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-one
C 3
(2 H, m); δ (100 MHz, CDCl ) 48.4, 60.5, 116.2 (d, JCF = 22.0),
4
3
11u). Synthesised using general procedure B2 from 1-ethynyl- 121.9, 126.5, 128.6 (d, JCF = 3.0), 129.2, 129.5 (d, JCF = 8.5),
(
1
-methoxybenzene (1.01 g, 7.68 mmol) and Weinreb amide S5 142.4, 144.3, 164.3 (d, JCF = 254), 172.3, 200.1, 204.3; HRMS
4
+
500 mg, 2.56 mmol) stirring at RT for 1 h. Purification by flash (ESI ): Found: 277.0642;
+
(MNa ) Requires
(
C
16
H
11FNaO
2
+
(MH )
column chromatography (9:1 hexane:EtOAc, then 7:3 277.0635 (−2.4 ppm error), Found: 255.0818; C16
H12FO
2
hexane:EtOAc) afforded the title compound 11u as a yellow Requires 255.0816 (−0.7 ppm error).
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB02426B
ARTICLE
Journal Name
+
2
Found: 218.1170; C13H16NO (MH ) Requires 218.1176 (2.5
tert-Butyl
3-(4-(4-hydroxyphenyl)-3-oxobut-1-yn-1-yl)-1H- ppm error).
indole-1-carboxylate (13). Synthesised using general
procedure B2 from tert-butyl 3-ethynyl-1H-indole-1- 4,4a,6,7-Tetrahydro-3H-cyclopenta[d]chromene-3,9(10H)-
5
carboxylate (738 mg, 3.06 mmol) and Weinreb amide S3 (199 dione (15). To a 10 mL reaction vial containing 4-(2-((tert-
mg, 1.02 mmol) stirring at RT for 1 h. Purification by flash butyldimethylsilyl)oxy)ethyl)spiro[4.5]deca-3,6,9-triene-2,8-
column chromatography (9:1 hexane:EtOAc, then 8:2 dione 10p (31.0 mg, 0.097 mmol) in THF (3 mL) was added 10%
hexane:EtOAc) afforded the title compound 13 as a yellow oil aqueous HCl (0.1 mL) and the reaction stirred under argon at
-
1
(
306 mg, 80%); R
374, 2980, 2188, 1743, 1369, 1232, 1150, 1072; δ
CDCl ) 1.70 (9 H, s), 3.89 (2 H, s), 4.98 (1 H, br s), 6.87 (2 H, d, J x 10 mL), the combined organics washed with brine (10 mL),
8.0), 7.23 (2 H, d, J = 8.0), 7.32 (1 H, dd, J = 8.0, 7.5), 7.38 (1 dried over Na SO and concentrated to yield a crude product.
H, dd, J = 8.0, 7.5), 7.51 (1 H, d, J = 8.0), 7.91 (1 H, s), 8.14 (1 H, The product was purified by flash column chromatography (8:2
d, J = 8.0); δ (100 MHz, CDCl ) 28.2, 51.2, 85.3, 86.8, 92.4, hexane:EtOAc, then 8:2 EtOAc:hexane) to afford the title
00.5, 115.5, 115.8, 120.1, 123.8, 125.7, 125.8, 129.9, 131.2, compound 15 as an off-white solid (15.0 mg, 75%); R 0.47
33.1, 134.8, 148.6, 155.2, 185.3; HRMS (ESI ): Found: (EtOAc); mp 115–120 °C; νmax (thin film)/cm 3564, 2961,
f
0.37 (7:3 hexane:EtOAc); νmax (thin film)/cm
RT. After 1.5 h, the reaction was quenched with saturated
3
H
(400 MHz, aqueous NaHCO
3
(10 mL), extracted successively with EtOAc (3
3
=
2
4
C
3
1
1
3
f
+
-1
+
4
98.1357; C23H21NNaO (MNa ) Requires 398.1363 (1.5 ppm 2925, 2856, 1706, 1682, 1629, 1404, 1234, 1204, 1060, 1009,
1
3
error). Note: some peaks broadened in C NMR spectrum due 781, 701; δ
to presence of rotamers. d, J = 18.5), 2.60–2.75 (4 H, m), 3.50 (1 H, dt, J = 11.5, 3.0),
.81–3.83 (1 H, m), 4.22 (1 H, ddd, J = 11.5, 5.5, 2.5), 6.08 (1 H,
3-(3-oxo-5-(4-oxocyclohexa-2,5-dien-1- d, J = 1.5), 6.13 (1 H, d, J = 10.0), 6.42 (1 H, dd, J = 10.0, 3.0); δ
yl)cyclopent-1-en-1-yl)-1H-indole-1-carboxylate (8). (100 MHz, CDCl ) 30.1, 41.5, 44.3, 48.9, 68.1, 81.5, 128.8,
Synthesised using general procedure C2 from ynone 13 (68.4 129.7, 148.2, 179.5, 195.1, 204.3; HRMS (ESI ): Found:
H 3
(400 MHz, CDCl ) 2.40 (1 H, d, J = 18.5), 2.55 (1 H,
3
tert-Butyl
C
3
+
+
mg, 0.182 mmol) and AgNO
h at RT. Afforded the title compound
purification as a pale brown solid (67.9 mg, 99%); mp 190–192
3
·SiO
2
(310 mg, 0.0182 mmol) for 7 227.0680; C12
3
H12NaO (MNa ) Requires 227.0679 (-0.6 ppm
8
without further error).
-1
°
C; R
662, 1595, 1370, 1351, 1228, 1148, 1109, 861, 732; δ
MHz, CDCl ) 1.63 (9 H, s), 2.76 (2 H, s), 6.50 (2 H, d, J = 9.5),
.91 (1 H, s), 6.97 (2 H, d, J = 9.5), 7.34–7.45 (2 H, m), 7.78 (1 H,
d, J = 8.0), 7.93 (1 H, s), 8.25 (1 H, d, J = 8.0); δ (100 MHz,
CDCl ) 28.0, 45.6, 51.9, 85.4, 114., 115.7, 120.3, 124.2, 125.7,
27.8, 128.2, 128.4, 129.7, 135.8, 148.4, 151.9, 165.9, 184.3,
f
0.46 (1:1 hexane:EtOAc); νmax (thin film)/cm 1742, 1694,
Acknowledgements
1
H
(400
3
The authors would like to thank the University of York (A.K.C.,
J.D.C., W.P.U.), the EPSRC (J.T.R.L. EP/M018601/01) and the
Leverhulme Trust (for an Early Career Fellowship, ECF-2015-
6
C
3
0
13, W.P.U.) for financial support. We would also like to thank
1
2
Jack Partington, Harry Kirby, Jamie Rose and Richard Bickford-
Smith (University of York undergraduate students) for
assistance during preliminary studies.
13
03.4. Note: some peaks broadened in C NMR spectrum due
to presence of rotamers. Spectroscopic data matched those
5
previously reported in the literature.
5
-methyl-4a,5,6,7-tetrahydrocyclopenta[d]quinoline-
Notes and references
3,9(4H,10H)-dione(14). To a stirred solution of tert-butyl (2-
1
(a) R. A. Edrada, C. C. Stessman and P. Crews, J. Nat. Prod.,
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(
3,8-dioxospiro[4.5]deca-1,6,9-trien-1-
yl)ethyl)(methyl)carbamate 10o (64.2 mg, 0.202 mmol) in
CH Cl (2 mL) at 0 °C was added TFA (0.2 mL) dropwise. The
mixture was warmed to RT and stirred for 2 h. The reaction
was quenched by the addition of sat. aq. NaHCO (5 mL). The
organic layer was separated and the aqueous layer extracted
with CH Cl (2 × 5 mL). The organics were combined, washed
with brine, dried over MgSO and concentrated in vacuo. The
crude material was purified by flash column chromatography
9:1 EtOAc:MeOH) to afford the title compound 14 as a
colourless oil (29.2 mg, 66%); R 0.47 (9:1 EtOAc:MeOH); νmax
thin film)/cm 2790, 1709, 1684, 1632, 1209; δ (400 MHz,
CDCl ) 2.23–2.32 (4 H, m), 2.45–2.54 (2 H, m), 2.58–2.75 (4 H,
m), 2.87 (1 H, dd, J = 16.0, 2.5), 3.10 (1 H, ddd, J = 11.0, 5.5,
2
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2.5), 6.00 (1 H, s), 6.09 (1 H, d, J = 10.0), 6.41 (1 H, dd, J = 10.0,
2.5); δ (100 MHz, CDCl ) 29.7, 40.0, 42.1, 45.9, 49.4, 56.7,
70.2, 127.7, 129.2, 149.8, 181.3, 196.1, 204.9; HRMS (ESI ):
C
3
+
1
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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3
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DOI: 10.1039/C6OB02426B
ARTICLE
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2
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25 R. A. Haack and K. R. Beck, Tetrahedron Lett., 1989, 30, 1605.
5
6
For the synthesis of other spirocyclic natural products 26 F. T. Boyle, O. Hares, Z. S. Matusiak, W. Li and D. A. Whiting,
developed by our group, see: (a) W. P. Unsworth, K. A. J. Chem. Soc., Perkins Trans. 1, 1997, 2707.
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,
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1147.
7
2 2
For synthetic applications of SnCl .2H O, see: A. N. Cayley, K.
A. Gallagher, C. Ménard-Moyon, J. P. Schmidt, L. J. Diorazio
and R. J. K. Taylor, Synthesis, 2008, 3846.
8
9
For another synthesis of spirobacillene A, see: H. Yang, J.
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For recent reviews on dearomatising spirocyclisation
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2
016, 22, 2856.
1
0 For examples based on alkyne activation, see: (a) M. J.
James, J. D. Cuthbertson, P. O’Brien, R. J. K. Taylor and W. P.
Unsworth, Angew. Chem. Int. Ed., 2015, 54, 7640; (b) M. J.
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1
R. J. K. Taylor and W. P. Unsworth, Chem. Eur. J., 2016, 22
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8
777.
1
1 For examples based on other activation modes, see: M. J.
James, P. O’Brien, R. J. K. Taylor and W. P. Unsworth, Angew.
Chem. Int. Ed., 2016, 55, 9671.
1
1
2 This refers to the direct conversion of an anisole-tethered
ynone into a spirocyclic dienone.
3 AgNO
on this reaction system, with no reaction observed when
ynone 11c was treated with 10 mol% Cu(OTf) at RT for 3 d.
3 2 2
·SiO is also a far more effecient catalyst than Cu(OTf)
2
The reactions were not performed in the dark and to the
best of our knowledge, are insensitive to light.
1
4 For
dearomatisation
using
ortho-substituted
phenols/napthols, see: (a) J. C. Green and T. R. R. Pettus, J.
Am. Chem. Soc., 2011, 133, 1603; (b) A. Rudolph, P. H. Bos,
A. Meetsma, A. J. Minnaaed and B. L. Feringa, Angew. Chem.
Int. Ed., 2011, 50, 5834; (c) A. Seoane, N. Casanova, N.
Quiñones, J. L. Mascareñas and M. Gulías, J. Am. Chem. Soc.,
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