A Palladium(II)-Catalyzed C-H Activation Cascade Sequence for Polyheterocycle Formation

Article abstract of DOI:10.1002/anie.201501037

Polyheterocycles are found in many natural products and are useful moieties in functional materials and drug design. As part of a program towards the synthesis of Stemona alkaloids, a novel palladium(II)-catalyzed C-H activation strategy for the construction of such systems has been developed. Starting from simple 1,3-dienyl-substituted heterocycles, a large range of polycyclic systems containing pyrrole, indole, furan and thiophene moieties can be synthesized in a single step. Don't overdo it: A palladium(II)-catalyzed C-H activation cascade sequence for the synthesis of polyheterocycles is reported. Aromatization of the initially formed dihydro species occurred with a quinone oxidant. In some cases the use of one equivalent of the oxidant enabled isolation of the dihydro species as a single isomer (see scheme; X=NMe, O, S).

Full text of DOI:10.1002/anie.201501037

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501037
German Edition: DOI: 10.1002/ange.201501037
Domino Cyclization
À
A Palladium(II)-Catalyzed C H Activation Cascade Sequence for
Polyheterocycle Formation**
Stephen P. Cooper and Kevin I. Booker-Milburn*
Abstract: Polyheterocycles are found in many natural prod-
ucts and are useful moieties in functional materials and drug
design. As part of a program towards the synthesis of Stemona
cycle-containing substrates bearing a pendant diene, such as 8,
we identified a plausible and efficient route to the stenine
group of Stemona alkaloids (Scheme 1B).[8] In this envisioned
À
À
alkaloids, a novel palladium(II)-catalyzed C H activation
route, palladium(II)-catalyzed C H activation of the pyrrole
strategy for the construction of such systems has been
developed. Starting from simple 1,3-dienyl-substituted hetero-
cycles, a large range of polycyclic systems containing pyrrole,
indole, furan and thiophene moieties can be synthesized in
a single step.
ring in 8, followed by diene cyclization to the p-allyl system 7
and subsequent nucleophilic capture by the internal siloxy-
furan, would give access to the stenine ring system 6 in a single
reaction from 8. As the methodology required for such an
efficient transformation is not currently available, we herein
describe significant progress towards the synthesis of the
stenine ring system through this cascade sequence by
demonstrating a general and effective method for the syn-
thesis of polyheterocycles.
P
olyheterocycles are frequently found as the cores of both
natural products[1] and drug molecules.[2] Furthermore, the
extended heteroaromatic conjugated systems that these
compounds can contain make them of interest as functional
materials.[3] It is important therefore that new, efficient
methodologies for their construction are developed. In
We began our investigations by examining the cyclizations
of the furyl–pyrrole systems 9a and 9b (Table 1). With
a stoichiometric amount of [Pd(MeCN)2Cl2], the desired
cyclization did indeed take place in both cases to give the fully
aromatic congeners 11a,b in low yield (probably by the
À
recent decades, the selective coupling of unactivated C H
bonds under metal catalysis has been studied extensively
owing to its potential to decrease the step
count in syntheses and reduce the cost
and waste of a process.[4] There has been
great progress in the selective metal-
À
catalyzed C H activation of heterocycles
and their subsequent use in arylation[5]
and alkenylation[6] reactions. Alkenyla-
tion has mostly been carried out with
simple alkenes in intermolecular reac-
tions or through cyclizations. The poten-
tial for the heteroarylation of 1,3-dienes
through novel difunctionalization reac-
tions, however, remains relatively under-
exploited.
We previously reported the 1,2-car-
boamination of electron-deficient dienes
with aryl ureas as both a directing group
À
for ortho C H activation and an internal
nucleophile to trap the p-allyl system
Scheme 1. A) Palladium(II)-catalyzed 1,2-carboamination of dienes via a p-allyl intermediate.[7]
formed after carbopalladation (Sche-
À
B) Retrosynthetic analysis of 9a-bisdehydrotuberostemonine A on the basis of a C H activation
me 1A).[7] Extending this idea to hetero- cascade sequence. BQ=benzoquinone, MS=molecular sieves, Ts=p-toluenesulfonyl.
dehydrogenation of 10a,b by PdII). The formation of the
seven-membered ring in 11b (n = 4) was significantly less
effective than the formation of the six-membered ring in 11a
(n = 3; Table 1, entries 1 and 2). When 1,4-dioxane was used
[*] S. P. Cooper, Prof. Dr. K. I. Booker-Milburn
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: k.booker-milburn@bristol.ac.uk
Homepage: http://www.chm.bris.ac.uk/org/bmilburn/index2.htm
instead of THF as the solvent, the reaction could be carried
[**] We thank the EPSRC Bristol Chemical Synthesis Doctoral Training
out at the higher temperature of 908C, which led to
a significant increase in the yield of 10a and 11a (Table 1,
entry 3).
Centre (EP/G036764/1) for a PhD studentship (S.P.C.) and Argenta
for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501037.
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Table 1: Initial studies with stoichiometric [Pd(MeCN)2Cl2].[a]
Table 2: Optimization studies.[a]
Entry
n
Solvent
T [8C]
t [h]
10 [%]
11 [%]
1[b]
2[b]
3[c]
3
4
3
THF
THF
1,4-dioxane
60
60
90
20
20
2.5
12
0
32
14
6
19
[a] Reaction conditions: 9 (210–250 mmol), [Pd(MeCN)2Cl2], anhydrous
solvent (2.5 mL), N2 atmosphere. [b] [Pd(MeCN)2Cl2] (1.1 equiv).
[c] [Pd(MeCN)2Cl2] (1.0 equiv).
Entry
Catalyst
[mol%]
Oxidant
(equiv)
Solvent
T
[8C]
t
13
[%]
1
2
3
4
5
10
10
10
10
10
10
10
10
1
14 (1)
15 (1)
15 (2)
15 (4)
15 (2)
15 (2)
15 (2)
16 (2)
15 (2)
15 (2)
15 (2)
dioxane
dioxane
dioxane
dioxane
DMF
DMF
DMF
DMF
DMF
90
90
90
90
80
5 h
25 h
18 h
22 h
16
17
27
23
46
60
54
61
60
82
81
Initial attempts to render this reaction catalytic with
respect to palladium suffered from the susceptibility of the
furan moiety to undergo conjugate addition to the benzoqui-
none (BQ) oxidant used. The use of non-quinone-based
oxidants unfortunately did not lead to substantial product
formation. A solution was found in the use of oxidants 14–16
featuring increased steric bulk around a quinone core.[9]
As the use of furylpyrrole-based starting materials led to
mixtures of products, an alternative cyclization substrate was
sought. In preliminary studies with the indole 12 (Table 2),
only the fully oxidized product 13 was ever observed, thus
indicating that the oxidation of the intermediate dihydro ring
system (analogous to 10) was more facile than in the case of
pyrroles. 2,6-Dimethylbenzoquinone (14) and 3,5-di-tert-
butyl-o-benzoquinone (15) were both found to effect catalytic
turnover of palladium (Table 2, entries 1 and 2); however,
during reactions with 14 a side product was observed that
indicated addition of the furan moiety to the quinone was still
taking place. As the initial cyclized product (analogous to 10)
was undergoing oxidation, it followed that two equivalents of
15 would be required for complete conversion. An increase in
the amount of oxidant used to two equivalents increased the
yield marginally from 17 to 27% but depleted the amount of
starting material recovered (Table 2, entry 3). A further
increase in the amount of oxidant used did not lead to an
additional increase in product yield (Table 2, entry 4).
A substantial increase in productivity was observed when
the solvent was switched to DMF (Table 2, entry 5) and the
temperature was increased to 1208C (entry 6). Other qui-
nones with sufficient bulk (e.g. 16; Table 2, entry 8) gave the
product in comparable yields. However, the key parameter to
the success of the sequence was a short reaction time, typically
under half an hour, at an elevated temperature. The most
consistent results were obtained when the reaction flask
containing substrate, catalyst, oxidant, and solvent was heated
by rapid immersion in a preheated oil bath. Slow heating of
the reaction mixture up to the required temperature resulted
in poorer yields and mass recovery. The reaction concen-
tration and catalyst loading were also significant, and
optimization studies showed that a concentration of 0.02m
and a 5 mol% loading of the catalyst [Pd(MeCN)2Cl2] led
to consistently high-yielding reactions at the short contact
1 h
6
120
120
120
120
120
120
20 min
20 min
25 min
1.5 h
30 min
25 min
7[b]
8
9[c]
10[c,d]
11[c,e]
10
5
DMF
DMF
[a] Reaction conditions, unless otherwise specified: 12 (125 mmol,
0.1m), anhydrous solvent, N2 atmosphere. [b] The reaction was carried
out in an open flask with reagent-grade dimethylformamide (DMF).
[c] The reaction was carried out with 1 mmol of 12. [d] The reaction was
carried out at a 0.01m concentration of 12. [e] The reaction was carried
out at a 0.02m concentration of 12.
times required at 1208C (Table 2, entry 11). It was pleasing to
note that unlike in our previous carboamination studies,
electron-withdrawing substituents were not necessary for
diene functionalization.
Initial exploration of the scope of the reaction under these
optimized conditions focused on varying the substituent on
the indole ring (Table 3, entries 1–9). In general, electron-rich
and electron-neutral systems performed better than electron-
poor systems. The reaction is tolerant of halogen substituents
(Table 3, entries 4 and 5) as well as esters, nitriles, and
aldehydes (entries 6–8). The vinyl-substituted substrate 31
gave the desired product in moderate yield (Table 3, entry 9).
Extension of the alkyl chain to four CH2 units severely
affected the cyclization, which gave only very small quantities
of the Stemona alkaloid related product 34 (Table 3, entry 10).
The application of this methodology to seven-membered-ring
formation is a limitation that is currently under investigation.
Chain branching in the alkyl tether is tolerated (Table 3,
entry 11), although a gem-dimethyl group adjacent to the
reactive diene center greatly impeded reactivity (entry 12).
Pleasingly, this reaction proved general in terms of the
heterocycles present in the substrate, thus enabling rapid
access to a range of novel structures. Thiophene- and pyrrole-
containing products were readily obtained in good yield
(Table 3, entries 13 and 14), and both furan and indole
moieties can be replaced by pyrrole units, as in 43 (entry 15).
One limitation appears to be the use of phenyl rings as the p-
2
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Table 3: Scope of the reaction.[a]
Table 3: (Continued)
Entry
Starting
material
Product(s)
Yield
[%]
Entry
Starting
material
Product(s)
Yield
[%]
18[b]
84
1
2
3
4
5
6
7
8
9
12 R=H
13 R=H
81
79
71
55
52
32
30
49
26
17 R=OMe
19 R=Me
21 R=F
18 R=OMe
20 R=Me
22 R=F
23 R=Cl
24 R=Cl
25 R=CO2Me
27 R=CN
29 R=CHO
26 R=CO2Me
28 R=CN
30 R=CHO
77
(d.r. 3:2)
19[b]
=
=
31 R=CH CH2
32 R=CH CH2
10
11
1
[a] Reaction conditions: starting material (100 mmol–1.46 mmol,
0.02m), [Pd(MeCN)2Cl2] (5 mol%), 15 (2 equiv), anhydrous DMF, N2,
1208C. Reactions proceeded to completion as observed by TLC. See the
Supporting Information for scale and reaction times. [b] Oxidant 16
(1.1 equiv) was used in place of 15.
82
allyl-trapping partner; even the electron-rich system 45 gave
the product in only 4% yield (Table 3, entry 16).
We next revisited the pyrrole–furan substrates. Disap-
pointingly, these substrates performed less well than expected
under the optimized conditions. For example, in Table 3,
entry 17, the cyclized system 48 was obtained in only 19%
yield. Upon examination of this reaction mixture, the unusual
side product 53 (Figure 1) was identified. This compound is
12
13
14
12
57
49
Figure 1. X-ray crystal structure of side product 53.
15
39
seemingly formed by the interception of a reaction inter-
mediate by a molecule of the ortho-benzoquinone 15, and its
formation is still not well understood.[10] Similar side products
incorporating o-BQ 15 were not identified in other low-
yielding cyclizations.
As the production of 53 depended upon the o-BQ 15, the
reaction was carried out again with just 1.1 equivalents of p-
BQ 16. This quinone had been found to operate similarly in
the previous screening (Table 2, entry 8). Pleasingly, the non-
oxidized product 49 was obtained almost exclusively and
isolated in 84% yield; only a trace amount (ca. 1%) of the
fully oxidized analogue was observed (Table 3, entry 18). It
16
17
4
19
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had already been observed that mixtures of oxidized and non-
oxidized products could be obtained with similar systems (9a,
for example), but this was the first time that clean conversion
into the non-oxidized product, containing two adjacent
stereocenters, had been observed. Furthermore, the cycliza-
tion appears to be highly diastereoselective during the
central-ring-forming process (no other diastereomer of 49
was detected). It was found that a loading of quinone 16 at just
1.1 equivalents gave optimal yield and reproducibility. The
methyl-branched diene 50 was also shown to cyclize effi-
ciently (Table 3, entry 19). Although once again the stereo-
selectivity in the formation of the central ring was excellent,
the methyl group unfortunately afforded little diastereose-
lectivity during the initial pyrrole/diene cyclization step.
A plausible mechanism for this cascade sequence is
from simple starting materials by a palladium(II)-catalyzed
À
C H activation/cascade sequence. Present studies are con-
cerned with improvement of the yields for seven-membered-
ring formation and the application of this transformation in
the synthesis of Stemona alkaloids.
À
Keywords: C H activation · domino reactions · heterocycles ·
homogeneous catalysis · palladium
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insertion, possibly assisted by prior coordination of the PdII
center to the diene, to give a PdII species 55. Cyclization by
syn-carbometalation of the diene to form the p-allyl system 56
is followed by attack of the second heterocyclic ring onto this
electrophilic complex to give 57 with the release of Pd0. Loss
of a proton from 57 then leads to rearomatization of the
heterocyclic ring and the formation of 58.
Depending on the nature of the substrate, or the oxidant
used, 58 can either be isolated or react further. In the majority
of cases, further oxidation of the central ring in 58 is facile,
and the fully aromatized systems 59 are isolated. This
oxidation is clearly a rapid process, as decreasing the
amount of added quinone did not result in the isolation of
significant amounts of 58: merely incomplete reactions and
lower yields of 59 were observed.
In conclusion, we have developed novel methodology for
the rapid construction of a large range of polyheterocycles
4
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Received: February 3, 2015
Published online: && &&, &&&&
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Communications
Domino Cyclization
S. P. Cooper,
K. I. Booker-Milburn*
&&&& — &&&&
À
A Palladium(II)-Catalyzed C H Activation
Cascade Sequence for Polyheterocycle
Formation
Don’t overdo it: A palladium(II)-catalyzed
oxidant. In some cases the use of one
equivalent of the oxidant enabled isola-
tion of the dihydro species as a single
isomer (see scheme; X=NMe, O, S).
À
C H activation cascade sequence for the
synthesis of polyheterocycles is reported.
Aromatization of the initially formed
dihydro species occurred with a quinone
6
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