Double gold-catalysed annulation of indoles by enynones

Article abstract of DOI:10.1002/adsc.201300018

The gold-catalysed double functionalisation of indoles is presented. Enynones are used to annulate indoles via a double sodium tetrachloroaurate- catalysed process involving a mixture of C-H activation and alkyne activation modes of promotion. Good yields

Full text of DOI:10.1002/adsc.201300018

FULL PAPERS
DOI: 10.1002/adsc.201300018
Double Gold-Catalysed Annulation of Indoles by Enynones
Stephen J. Heffernan,a James P. Tellam,a Marine E. Queru,a Andrew C. Silvanus,a
David Benito,a Mary F. Mahon,a Alan J. Hennessy,b Benjamin I. Andrews,b
and David R. Carberya,*
a
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
Fax : (+44)-1225-386-231; phone: (+44)-1225-386-144; e-mail: d.carbery@bath.ac.uk
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
b
Received: January 3, 2013; Published online: April 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300018.
Abstract: The gold-catalysed double functionalisa- tion. Good yields for the formation of medicinally
tion of indoles is presented. Enynones are used to relevant [6,5,7]-tricyclic indoles are realised.
annulate indoles via a double sodium tetrachloroau-
ꢀ
rate-catalysed process involving a mixture of C H Keywords: cascade reactions; catalysis; diversity;
activation and alkyne activation modes of promo- gold; indoles
Introduction
indole 3 has been reported as a potent and selective
fatty-acid binding protein (FABP) inhibitor.[11] In
Indoles are an extensive and important family of bio- each instance, the specified [6,5,7]-core offered maxi-
logically active molecules.[1] The indole nucleus plays mum biological activity in their respective assays in
a key role in mammalian neurochemistry in the form comparison with the [6,5,6]- and [6,5,5]-fused tricyclic
of the neurotransmitter serotonin and is therefore piv- homologues.
otal to a large number of physiological functions. Ad-
Accordingly, it is reasonable to suggest that this
ditionally, indoles and indole-derived compounds are [6,5,7] indole core displays significant promise in me-
found in an extraordinary range of secondary natural dicinal drug-discovery contexts and would benefit
product metabolites with wide-ranging associated bio- from future exploration. It is noteworthy that the
logical activities.[2,3] Thirdly, the indole skeleton has [6,5,7]-indole core in 1–3 was constructed through
been incorporated into a large number of medicinal a classical Fischer indole synthesis and therefore ac-
chemistry designs and clinical products and as such cessed from restricted chemical space. With a clear
has been viewed as a privileged structure.[4,5] When medicinal rationale, we reasoned that novel and flexi-
considered together, it is therefore understandable ble approaches to such [6,5,7]-tricyclic indoles might
why indoles remain an area of intense synthetic ex- open new areas of chemical space for exploration in
ploration,[6] both in terms of de novo syntheses[7] but a small-molecule discovery context. In addition,
also in the elaboration of pre-existing indole frame- a number of natural products with impressive biologi-
works.[8]
cal activity exist which feature this [6,5,7]-tricyclic
Three structurally related indoles (1–3, Figure 1), core. For example, actinophyllic acid,[12] the ambi-
recently reported in the medicinal chemistry literature guines[13] and the ervatamine-silicine alkaloids[14] all
with potent biological activity, have attracted our in- feature this key indole structural unit.
terest due to the presence of a shared [6,5,7]-fused tri-
cyclic indole core. Indole 1 displays high potency and
excellent oral bioavailability in mouse model tumour Results and Discussion
xenografts, acting as an aurora kinase inhibitor.[9]
Carboxamide 2 acts as a potent and selective inhibi- Building on our Brønsted acid-catalysed annulation of
tor of the deacetylase, SIRT1 2.[10] This amide repre- indoles[15] by divinyl ketones we have sought to
sents the most active SIRT1 inhibitor reported to date expand the scope of such indole-focussed annulations.
and with a favourable ADME profile, has been sug- With this in mind, we chose to consider structurally
gested as a lead towards therapeutics. Additionally, related ketonic double electrophiles, such as enyn-
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were successful in forming tricycle 7a (Table 1).
Metals studied included Fe
and Au(I) catalyst systems (Table 1, entries 2–8). The
sole exception was the readily available Au(III) cata-
ACHTUNGTNER(NUNG III), Pt(II), Cu(I), Pd(II)
AHCTUNGTRENNUNG
lyst, NaAuCl4·2H2O (entry 9) offering 22% conver-
sion after 24 h.[18] Subsequent solvent optimisation re-
vealed a marked improvement in reaction efficiency
on choosing acetonitrile (entries 9–14). In this initial
system, 2 mol% loading was found to be adequate
with full conversion observed after 4 h (entry 16). The
intermediacy of indole 6a in this cascade was further
1
supported by in situ reaction monitoring by H NMR
(Figure 2).[19] This experiment confirms the presence
of 6a (20%) before the observable formation of tricy-
cle 7a. Additionally, isolated 6a cleanly and quantita-
tively converts to 7a under identical reaction condi-
Figure 1. Medicinally active indoles containing a [6,5,7]-
fused tricyclic unit.
ACHTUNGTRENNUNGones, with a view to rapidly forming new functional- tions.
ised tricyclic indole structures.[16,17] An initial examina-
The majority of Au-catalysed indole cascades are
tion was conducted with ketone 4a which was reacted performed in a non-convergent fashion, with reactive
with indole in dichloromethane in the presence of the functionality attached to the indole core prior to an
previously successful strong Brønsted acid promoter, Au-promoted cascade or cyclisation. We reasoned
2,4-dinitrobenzenesulfonic acid (Table 1).
that suitable discovery reactions for the synthesis of
A clean intermolecular enone Friedel–Crafts reac- new indoles comprising medium-sized rings should
tion occurred, however, no annulation was observed. maximise molecular divergency, synthetic convergen-
ꢀ
A range of Lewis acid catalysts, including typical p- cy and seek to form two C C bonds as part of a one-
acidic metals were subsequently examined yet none pot cascade. An inspection of the literature reveals
Table 1. Metal catalyst screen.
Entry
Catalyst
Solvent
4a:6a:7a [%][a]
Yield 7a [%]
1
2
3
4
5
6
7
8
DNsOH[b]
FeCl3·6H2O
PtCl2
CuOTf
PdCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
Et2O
DMF
EtOH
MeCN
MeCN
MeCN[e]
0:100:0
25:75:0
90:10:0
30:70:0
83:17:0
12:88:0
100:0:0
100:0:0
33:45:22
50:49:1
40:30:30
35:65:0
0:38:62
0:0:100
0:0:100
0:0:100
–
–
–
–
–
–
–
–
–
–
–
–
Pd
N
AuPPh3Cl
AuPPh3Cl[c]
9
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O[d]
NaAuCl4·2H2O[d]
10
11
12
13
14
15
16
–
96
99
98
[a]
1
Determined by H NMR analysis of crude reaction mixture.
DNsOH=2,4-dinitrobenzenesulfonic acid.
5 mol% AgSbF6 additive used.
[b]
[c]
[d]
[e]
2 mol% catalyst used.
Reaction conducted for 4 h.
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Double Gold-Catalysed Annulation of Indoles by Enynones
by Hashmi when an enynone was reacted with
a furan.[16a]
A range of indoles has been examined with a view
to demonstrating flexibility and diversity (Scheme 3).
The system is compatible with electron-rich (7b and
7k) and electron-deficient (7c–e) indoles. The indole
annulation is unaffected by substitution on the
benzenACTHNUTRGENUGoN id fragment (7f–i) as gauged by a range of
methylindole regioisomers. In particular, the boronate
ester and iodide systems (7j and 7k) are expected to
offer flexibility for subsequent synthetic elaboration
by employing late-stage diversity strategies. The for-
mation of 7l is also noteworthy in a context of pro-
Figure 2. 1H NMR monitoring of the tandem cascade reac-
tion (CD3CN at 208C; 500 MHz). & =4a, =6a, =7a.
ꢀ
tecting group-free synthesis as neither the indole N
~
&
ꢀ
H or O H bonds require protection for a clean annu-
lation reaction to occur.[21]
The modularity and ease of substrate synthesis has
that this strategy is uncommon.[20] The clean reaction allowed for the ready examination of substrate scope
of these enynone double electrophiles with indoles (Table 2). Accordingly, this annulation shows a good
contrasts to the complex synthetic outcomes reported level of structural scope with respect to the enynone.
Scheme 1. Indole scope.
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Table 2. Scope of the enynone in cascade reactions.
Entry
R1
R2
R3
R4
Time [h]
Temperature [8C]
Yield [%]
1
2
3
4
5
6
7
8
Me
Me
Me
Ph
Ph
Me
Ph
Ph
Ph
Me
Me
H
H
i-Pr
H
Me
Me
Ph
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
4-MeC6H4 (4b)
4-OMeC6H4 (4c)
4-CF3C6H4 (4d)
Ph (4e)
H (5a)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6
23
23
23
82
82
23
23
82
82
82
82
82
23
23
23
82
23
82
23
98 (7m)
82 (7n)
73 (7o)
77 (7p)
100[b]
81 (7q)
97 (7r)
47 (7s)
69[b,c]
24
16
24
3
Ph
2-naphthyl (4f)
2-naphthyl (4g)
n-Bu (4h)
n-Bu
n-Bu (4i)
n-Bu
n-Bu (4j)
Ph (4k)
Ph (4l)
Ph (4m)
Ph(4n)
Ph
H (4o)
8
24
72
18
24
4
96
12
18
8
9
10
11
12
13
14
15
16
17
18
19
79 (7t)
82[b]
60 (7u)
99 (7v)
72 (7w)
76 (7x)
15 (7y)[a]
73[a,b]
8
H
H
18
18
20
0
H
Ph (4a)
Me (5b)
71 (7z)
[a]
1
4:1 syn/anti based on H NMR analysis of crude reaction mixture.
2 equiv. of H2O added.
[b]
[c]
Based on recovery of starting material.
The cascade is general with respect to the enynone reoselectivity was confirmed by single crystal X-ray
double electrophile, accommodating both electron- diffraction analysis of the major isomer (Figure 3).
rich and electron-deficient arylacetylene moieties (en- The annulation under discussion was initially devel-
tries 1–3). It is possible to construct substrates bearing oped using NaAuCl4·2H2O for pragmatic reasons as
alkyl or aryl groups on both the enone or ynone frag- this catalyst is a bench-stable, robust catalyst. Howev-
ments, revealing some reactivity trends (entries 1, 4, er, we felt this salt was acting as a pre-catalyst for
8, 10). Alkyl substitution upon the enone and aryl AuCl3.[18] To probe this, the annulation reaction be-
substitution upon the ynone fragment appear to offer tween 4a and 5a was repeated with AuCl3 and found
optimal substrate reactivity. Monosubstituted enones to promote the reaction with improved reaction effi-
can be accommodated without incidence (Entry 12), ciency (Scheme 2).
however, terminal alkynes would appear incompatible
The diastereoselectivity observed in the formation
in this reaction (entry 18), possibly due to the forma- of 7y is important for two key reasons. Firstly, we be-
tion of a catalytically inactive Au-acetylide.[22] In con- lieve this diastereoselectivity is kinetic in origin, as
trast, substitution at the indole N-centre is compatible judged by attempts to epimerise diastereomerically
(entry 19). It is worth mentioning that reaction moni- pure cis-7y (Scheme 3). Exposure of cis-7y to acidic
toring studies have led us to the observation that (2,4-dinitrobenzenesulfonic acid) or basic (DBU) con-
small quantites of H2O (2 equivalents) as an additive ditions led to an observed erosion in diastereomeric
can have a pronounced beneficial effect (entries 5, 9, ratio to 4:1 and 20:1, respectively. However, re-expo-
11, 17). Whilst the reason for this improvement is not sure of cis-7y to 5 mol% NaAuCl4·2H2O resulted in
entirely clear, we feel that this observation may be no loss of diastereomeric purity.
linked to an indole auration processes during this cas-
Secondly, the final level of annulation diastereose-
cade (vide infra). Finally, the cascade sequence pro- lectivity is controlled by the diastereoselectivity of the
ceeds with substrates containing a trisubstituted initial intermolecular Au-catalysed Friedel–Crafts re-
enone with tricycle 7y being formed in good yield action as isolated mono-addition product 6b is formed
with 4:1 cis-diastereoselectivity (entry 16). This diaste- with the same level of diastereoselectivity [Eq. (1),
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Double Gold-Catalysed Annulation of Indoles by Enynones
reoselective protonation of an oxygen-bound copper
enolate.
Friedel–Crafts reactions are highly atom efficient
reactions. In this instance, it may be expected that the
indolyl C-2 and C-3 protons ultimately become incor-
porated at the ketonic a-methylene positions. To
probe this matter, C-2 and C-3 deuterated analogues
of N-methylindole have been synthesised and exam-
ined (Scheme 5). The N-methyl group was chosen to
obviate facile H!D exchange during these studies.
Unexpectedly, no deuterium incorporation was ob-
served when either labelled indole was reacted with
1
4a, as gauged by H NMR analysis of the reaction
products. In both instances, the reaction was found to
proceed without incidence, when compared to the
original reaction (Table 2, entry 19).
A possible explanation for the disappearance of the
deuterium from the product would be a scrambling of
the single deuterium through all positions of 7z and
therefore unidentifiable by 1H NMR integration.
However, this was ruled out by HR-MS analysis
which was identical to that of product 7z obtained
from the original reaction. We have gone to consider-
able efforts to try and determine the whereabouts of
the indolyl deuterium. We hypothesised that a facile
D!H exchange process was occurring. In an attempt
to remove adventitious sources of protons, this reac-
tion has been attempted in dried CD3CN (Table 3,
entry 1), however, no deuterium incorporation into 7z
is observed. In the presence of 4 ꢁ molecular sieves,
either with (entry 3) or without (entry 2) deuterated
solvent one sees no transfer of the indolyl deuterium.
Similarly, utilisation of silylated glassware[24,25] (en-
tries 4 and 5) or Teflon reaction vessels (entry 6) re-
sults in no D-incorporation into 7z. Indeed, all scenar-
ios result in a reaction outcome which is relatively in-
variable with respect to final yield (28–44%) over ex-
tended reaction times.
Figure 3. ORTEP Plot of XRD analysis of 7y (25% proba-
bility). Structure is deposited with the CCDC (CCDC
834635; these data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif).
Scheme 2. AuCl3 catalysis of the annulation reaction.
With no transfer of deuterium from indole nucleo-
phile, either from the C-3 or C-2 positions to the an-
nulated product, at any position, we wished to exam-
ine the behaviour of these labelled indoles in the
presence of gold catalyst in the absence of an external
electrophile. The contrast between the C-3 and C-2 la-
belled indoles was strong with the C-3 labelled indole
immediately losing a significant level of deuterium
Scheme 3. Probing the possibility of product equilibration.
after 13 min. In the time it took to add the catalyst
1
Scheme 4]. We believe that this stereoselectivity is and record a H NMR spectrum, the amount of ob-
governed by kinetic protonation of an enolate formed servable adventitious H2O present in the NMR sol-
from the addition of the indole nucleophile to 4n [Eq. vent had exchanged both available protons at the C-3
(2), Scheme 4). This scenario mirrors that understood indole position [Eq. (1), Scheme 6]. In contrast, the
for cuprate addition to a,b-unsaturated carbonyl elec- C-2 position was found to be robust under the same
trophiles. Significantly, a similar outcome has been re- NMR conditions for an extended period [Eq. (2)]. In
ported by Yamamoto where the addition of organo- an attempt to prepare a labelled indole model which
copper reagents to methyl tiglate forms ester 9 in more closely resembled an intermediate ynone, C-
a
2:1 anti/syn diastereomeric mixture [Eq. (3), 2-2H-5b was reacted, under comparable AuCl3 cataly-
Scheme 4].[23] Key to this understanding was the ste- sis in CD3CN, with enone 10 to afford the Friedel–
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Scheme 4. Significance of diastereoselectivity from an initial intermolecular Friedel–Crafts reaction.
Crafts product in 66% yield [Eq. (3), Scheme 6]. Table 3. Attempted deuterium incorporation.
However, C-2-2H-11 was now isolated with a dimin-
2
1
ished level of H-labelling (72% by H NMR integra-
tion). When C-2-2H-11 was resubjected to only the
AuCl3 catalyst in CD3CN, a continual erosion of label-
ling was observed [Scheme 6, Eq. (4)].
These observations demonstrate the rapid AuACTHNUGRTNEUNG(III)-
catalysed scrambling of these indole nucleophiles. The
catalyst aurates the more nucleophilic C-3 indole po-
sition and must readily react with electrophiles pres-
ent in the reaction system, such as protons from ad-
ventitious H2O or an enone. This is further highlight-
ed by the robust nature of the label in the C-2-2H-5b,
however, when auration is precluded at the C-3 posi-
tion by substitution, then C-2 auration becomes ap-
parent. This therefore suggests the presence of both
C-3 and C-2 auration processes that are operative
during this transformation.
Entry Solvent Deuterium Incoporation
[%][a]
Yield of 7z
[%]
1
2
3
4
5
6
CD3CN 0
CH3CN 0
CD3CN 0
CH3CN 0
CD3CN 0
CD3CN 0
44
36[b]
26[b]
30[c]
28[c]
34[d]
[a]
[b]
[c]
[d]
[e]
1
Assayed by integration of H NMR.
Reaction conducted for 24 h.
Reaction conducted with 4 ꢁ molecular sieves.
Reaction conducted in a silylated reaction vessel.
Reaction conducted in a Teflon vessel
With deuterated N-methylindoles offering interest-
ing data but ultimately limited for reaction monitor-
1
ing by H NMR, a substrate was sought which would
still offer some real-time information regarding the
ꢀ
cyclisation step. We chose to return to an N H
indole, the structural moiety which had been demon-
strated to be compatible with NMR monitoring (i.e.,
Figure 2). It was anticipated that a slow cyclisation
may allow an observable population of a C-2 auration
complex to form in solution. Enynone 4i had been
a demonstrably difficult substrate, therefore, ynone 6d
was synthesised [Eq. (1), Scheme 7]. Subjection of
ynone 6d to an equivalent of NaAuCl4·2H2O led to
1
Scheme 5. Reactivity of deuterated indoles.
no observable change in the H NMR spectrum at
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Double Gold-Catalysed Annulation of Indoles by Enynones
Scheme 6. Deuterium-scrambling studies.
room temperature. However, heating at 708C resulted derived from the hydrated gold catalyst. Having al-
in the rapid formation of 7i with complete conversion. ready observed a distinct stalling of reaction efficien-
Unfortunately, limited resolution of peaks, specifi- cy when dried solvent was used, we hypothesised that
cally the indole C-2 proton, has not allowed an un- water is in fact crucial to this process and that the in-
equivocal observation of C-2 auration, although an creased water loading was actually the key. Accord-
improvement in reaction efficiency is strong when ingly, we chose to re-examine difficult substrates, now
compared with the case in which a 5% catalyst load- with the addition of 2 equivalents of water in conjunc-
ing is used. The improvement in reaction efficiency is tion with catalytic loadings of NaAuCl4·2H2O. A sig-
expected to be assisted by an increased loading of the nificant improvement in reaction efficiency is ob-
NaAuCl4·2H2O catalyst. However, a more subtle served when comparing reactions with and without
issue is the concurrent increase in the loading of H2O,
1
Scheme 7. Attempted H NMR observation of C-2 auration.
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Scheme 8. Proposed catalytic cycle.
the water additive (Table 2 cf. entries 4+5, cf. en- nal propiolate electrophiles.[26] We believe that the
tries 8+9, cf. 10+11, entries 16+17).
ring-closure reaction proceeds through an initial
We have therefore incorporated the observations spiro-cyclisation, as precedented by Echavarren.[19b]
into the proposed mechanism by adapting the mecha- The possibility that this annulation could proceed via
nism proposed by Arcadi for Au-catalysed enone a spiroindolene intermediate is supported by an ob-
ꢀ
Friedel–Crafts reactions, namely the C H activation servation made in our laboratory early in our studies
of the indole nucleus (exemplified using 4n and 5b, of indole cascade chemistry, initially overlooked,
Scheme 8). Initial indole C-3 auration and subsequent whereby annulated and spiro-indolene were isolated
reaction with the enone moiety, generates indole (7aa and 13, respectively, Scheme 9). This reaction
6a.[25] The diastereoselectivity is dictated by a kinetic had been conducted in CH2Cl2 solvent and using
enolate protonation.
a substrate bearing a propyne fragment. With the
A second indole auration, now at C-2, initiates an hindsight of the extensive studies presented in this
intramolecular addition of the indole to the alkyne, report, the combination of an alkyl-substituted ynone
leading to 7z and the regeneration of the AuACTHNUGRTENUNG(III) cat- moiety and a solvent other than MeCN would com-
alyst (Scheme 8). In addition, the intramolecular bine to retard the overall annulation sequence and in
attack of indole upon the activated alkyne requires an turn lead to a recoverable population of a spiro inter-
entropically favoured intramolecular scenario as mediate.
Reetz has demonstrated that Au
G
The ability to execute subsequent late-stage diversi-
promote the addition of nucleophilic arenes to inter- ty transformations is demonstrated by the coupling of
boronate 7j and iodide 7k in a Pd-catalyzed Suzuki
reaction to form dimer 14 (Scheme 10).
Conclusions
In conclusion, a highly efficient Au-catalysed cascade
process is presented offering access to medicinally rel-
evant [6,5,7]-tricyclic indoles. The reaction is opera-
tionally simple, structurally modular and open to sub-
sequent late stage diversity operations. Studies to-
wards absolute stereocontrol and application to
target-orientated synthesis are currently ongoing in
Scheme 9. Observation of spiro-products.
our laboratory.
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Double Gold-Catalysed Annulation of Indoles by Enynones
Scheme 10. Demonstration of late-stage diversity through Suzuki couplings.
48.2, 25.0, 17.1; HR-MS (ESI, +ve): m/z=310.1606 (M+
Experimental Section
Na)+, calcd. for C20H17ONNa: 310.1208.
Synthesis of 4b
Synthesis of 7p
To
a
stirred solution of 1-ethynyl-4-methylbenzene
To solid indole 5a (42.9 mg, 0.42 mmol, 1.05 equiv.) in
a round-bottom flask was added an acetonitrile solution
(1 mL) of (E)-1,5-diphenylpent-1-en-4-yn-3-one 4e (94 mg,
(1.02 mL, 8.0 mmol, 1 equiv.) was added n-BuLi (1.6M in
hexane, 5.50 mL, 8.8 mmol, 1.1 equiv.) dropwise and stirred
for a further 10 min. Crotonaldehyde (663 mL, 8.0 mmol,
1 equiv.) in THF (5 mL) was added and the reaction stirred
for 4 h. Saturated NH4Cl solution (100 mL) was added and
subsequently extracted with EtOAc (3ꢂ100 mL), washed
with brine (100 mL), dried over Na2SO4, filtered and con-
centrated under vacuum to afford the crude residue. This
crude reaction product was dissolved in CH2Cl2 (150 mL)
before the addition of MnO2 (17.39 g, 200 mmol, 25 equiv.),
stirred for a further 24 h before filtering through a pad of
Celite and solvent removed under vacuum. Enynone 4b was
purified by flash chromatography (8:1 petroleum ether/
EtOAc) to afford a yellow oil; yield: 893 mg (60%). FT-IR
(thin film): nmax =3035.4, 2964.5, 2909.0, 2203.0, 1641.1,
0.4 mmol, 1 equiv.) followed by
a
solution sodium
tetrachloroaurate(III) hydrate (8 mg, 0.02 mmol, 0.05 equiv.)
AHCTUNGTRENNUNG
in acetonitrile (1 mL). Water (0.84 mmol, 2 equiv.) was final-
ly added before heating the reaction mixture to reflux for
3 h. The reaction was cooled before filtering through Celite
and concentration under vacuum. Purification was achieved
by flash chromatography (8:1 petroleum ether/EtOAc)
which afforded 7p as a yellow oil; yield: 140 mg (100%).
FTI-R (thin film): nmax =3057.5, 2952.2, 1624.3, 1536.6 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.90 (1H, br), 7.53–7.46
(6H, m), 7.32–7.11 (8H, m), 6.12 (1H, d, J=1.3 Hz), 4.86–
4.84 (1H, m), 3.52 (1H, dd, J=14.9, 6.0 Hz), 3.43 (1H, dd,
J=14.9, 3.4 Hz). 13C NMR (125 MHz, CDCl3) d: 198.9,
145.0, 139.8, 139.6, 135.6, 131.2, 129.4 (ꢂ2), 129.0, 128.6 (ꢂ
2), 127.4 (ꢂ2), 126.8, 124.8, 122.9, 120.7, 119.8, 111.4, 48.7,
35.3; HR-MS (ESI, +ve): m/z=350.1554 (M+H)+. calcd.
for C25H20NO: 350.1544.
1615.5, 1603.5, 1509.2 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d=7.41 (2H, app d, J=8.2 Hz), 7.28–7.14 (1H, m), 7.11
(2H, app d, J=8.2 Hz), 6.18 (1H, dq, J=15.7, 1.6 Hz), 2.31
(3H, s), 1.94 (3H, dd, J=6.9, 1.6 Hz); 13C NMR (75 MHz):
d=178.5, 149.2, 141.2, 134.0, 132.9, 129.4, 117.1, 91.7, 86.1,
21.7, 18.5. HR-MS (ESI, +ve): m/z=207.0782 (M+Na)+,
calcd. for C13H12ONa: 207.0786.
Synthesis of 14
To a microwave vial was added 7j (62 mg, 0.15 mmol,
1 equiv.), 7k (62 mg, 0.15 mmol, 1 equiv.), K2CO3 (31 mg,
0.225 mmol, 1.5 equiv.) and PdACHTUNTRGNEUNG(PPh3)4 (7 mg, 0.006 mmol,
Synthesis of 7a
To solid indole 5a (24.6 mg, 0.21 mmol, 1.05 equiv.) in
a round-bottomed flask was added an acetonitrile (1 mL)
solution of enynone 4a (24.6 mg, 0.21 mmol, 1.05 equiv.) fol-
0.04 equiv.). Acetonitrile (3 mL) and water (1 mL) were
added and the vessel was sealed, followed by sonication and
purging with nitrogen concurrently for 10 min. The reaction
mixture was then subjected to microwave irradiation at
1208C for 30 min. The reaction mixture was then passed
through a plug of silica gel before concentration under
vacuum. Purification was achieved by flash chromatography
(8:1 petroleum ether /EtOAc) which afforded 14 as a yellow
oil; yield: 75 mg (87%). FT-IR (thin film): nmax =3353.4,
lowed by a solution of sodium tetrachloroaurateACTHNUTRGNEUG(N III) hy-
drate (0.05 equiv.) in acetonitrile (1 mL). This mixture was
stirred at room temperature for 4 h, before filtering through
celite and was then concentrated under vacuum. Subsequent
purification by flash column chromatography (8:1 Pet/
EtOAc) afforded tricycle 7a as a yellow solid; yield: 57 mg
(100%); mp 170–1718C. FT-IR (thin film): nmax =3057.3,
2960.1, 1630.0, 1583.4, 1565.5, 1531.6 cmꢀ1
;
1H NMR
2956.7, 2924.5, 1707.5, 1623.3 cmꢀ1
;
1H NMR (500 MHz,
(500 MHz, CDCl3): d=7.93–7.87 (2H, m), 7.79 (2H, s),
7.63–7.57 (10H, m), 7.36 (2H, app. d, J=8.5 Hz), 6.22 (2H,
d, J=1.5 Hz), 3.80 (2H, m), 3.23 (2H, dt, J=14.5, 2.9 Hz),
3.00 (2H, ddd, J=14.5, 6.5, 1.1 Hz), 1.41 (3H, d, J=7.3 Hz),
1.40 (3H, d, J=7.3 Hz); 13C NMR (125 MHz, CDCl3): d=
199.8, 145.0, 139.7, 134.9, 134.8, 130.6, 129.3, 129.0 (ꢂ2),
CDCl3): d=7.73 (1H, br), 7.70–7.17 (8H, m), 6.20 (1H, s),
3.61–3.38 (1H, m), 3.19 (1H, dd, J=14.4, 3.1 Hz), 2.97 (1H,
dd, J=14.4, 1.8 Hz), 1.37 (3H, d, J=7.2 Hz); 13C NMR
(75 MHz, CDCl3): d=199.9, 145.2, 139.7, 135.5, 129.9, 129.3,
129.0, 128.9, 128.5, 126.8, 126.2, 124.7, 120.4, 119.5, 111.4,
Adv. Synth. Catal. 2013, 355, 1149 – 1159
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Stephen J. Heffernan et al.
FULL PAPERS
128.5, 127.4, 126.4, 125.1, 117.6, 111.7, 48.2, 25.0, 17.1; HR-
MS (ESI, +ve): m/z=573.2535 (M+H)+, calcd. for
C40H33N2O2: 573.2542.
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Acknowledgements
The authors are grateful to ESCOM (MEQ), GSK (SJH,
ACS) and EPSRC and University of Bath for studentship
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