Palladium-catalyzed cyclization of bromoenynamides to tricyclic azacycles: Synthesis of trikentrin-like frameworks

Article abstract of DOI:10.1039/c3cc45634j

Palladium-catalyzed cascade cyclization of bromoenynamides equipped with an additional alkyne or ynamide substituent affords azatricyclic products. Using 5- to 7-membered ring tethers, this chemistry offers a regiospecific route to highly-functionalized azacycles. Elaboration to the trikentrin B skeleton is achieved from the arylsilane cyclization products. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc45634j

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Palladium-catalyzed cyclization of bromoenynamides to tricyclic
azacycles: Synthesis of trikentrin-like frameworks
Craig D. Campbell,a Rebecca L. Greenaway,a Oliver T. Holton,a Helen A. Chapmanb and Edward A.
Anderson*,a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Palladium-catalyzed cascade cyclization of bromoenynamides
equipped with an additional alkyne or ynamide substituent
affords azatricyclic products. Using 5- to 7-membered ring
10 tethers, this chemistry offers a regiospecific route to highly-
functionalized azacycles. Elaboration to the trikentrin B
skeleton is achieved from the arylsilane cyclization products.
N
N
H
H
cis-trikentrin B
herbindole B
The trikentrin and herbindole families of natural products,
isolated from the marine sponges Trikentrion flabelliforme[1a] and
15 Axinella sp.,[1b] display a range of bioactivities including
antimicrobial, antifeedant and cytotoxic properties. The heavilyꢀ
substituted tricyclic indole systems which feature in these
compounds (e.g. cisꢀtrikentrin B and herbindole B, Scheme 1)
represent a particular synthetic challenge that has inspired a
20 number of elegant solutions.1
In recent work, we have developed a number of routes to
azabicycles from ynamides, including via ynamide
carbopalladation.2 We have also reported a strategy to access the
tricyclic 7,6,5ꢀCDE ring cores of rubriflordilactones A and B,
25 which contain pentaꢀ and tetrasubstituted arenes respectively,
R
n
n
Br
cat. Pd(0)
base
TsN
m
N
X
Ts
m
R
X
1
2
50
Scheme 1 cisꢀTrikentrin B, herbindole B, and the general
bromoenynamide cyclization strategy.
and 5b were synthesized from 1,6ꢀheptadiyne by monosilylation
then bromination. Both trimethylsilyl and benzyldimethylsilyl
groups were installed, which we anticipated would enable various
55 strategies for the attachment of trikentrinꢀlike sidechains
following cyclization. These building blocks were coupled using
Hsung’s copperꢀcatalyzed methodology for ynamide formation,8
which provided ynamides 1aꢀc in moderate to good yield, albeit
through
palladiumꢀcatalyzed
cascade
cyclization
of
bromoenediynes.3 We noted that the combination of these two
methodologies could provide access to the tricyclic indole core of
the trikentrins, via cyclization of a bromoenynamide equipped
30 with a remote alkyne (1→2, Scheme 1). The construction of
fused ring arenes in this manner4 has rarely been employed in
synthetic endeavours,3 and in the context of ynamides offers a
useful alternative to the elegant cyclotrimerization methodology
pioneered by Witulski,5 which has recently been applied to the
35 herbindole system.1c This sequenced carbopalladation strategy
offers advantages over intramolecular cyclotrimerization, where
long tethers restrict the formation of larger rings, presumably due
to competing intermolecular reactions.6 Here we describe the
development of this novel ynamide chemistry,7 and its
40 application to a number of azatricyclic systems, including azaꢀ
and benzazepine trikentrin analogues. Elaboration to the bisꢀ
desmethylꢀtrikentrin B framework is also described.
Br
RMe2Si
BBr3, CH2Cl2;
AcOH
5a (R = Me)
5b (R = Bn)
n
n
Br
Br
CuSO4•5H2O,
1,10-phen, K3PO4,
PhMe, 70-80 °C
TsN
NHTs
3a (n=1): 62%
3b (n=3): 30%
RMe2Si
n
1a 60% (n=1, R=Me)
1b 52% (n=1, R=Bn)
1c 37% (n=3, R=Bn)
4a (n=1)
4b (n=3)
NTsBoc
1. NBS, AgNO3 (10 mol%),
acetone
2. TFA, CH2Cl2
91%
Br
We first set about the synthesis of a series of bromoenynamide
alkynes suitable for cyclization, through the preparation of
45 appropriate sulfonamide and bromoalkyne precursors (Scheme
2). The bromoalkenyl sulfonamides 3a and 3b were prepared
from alkynes 4a and 4b via bromoboration / protodeborylation
(with simultaneous Boc deprotection), whilst bromoalkynes 5a
1d
1. Hex
CuSO4•5H2O, 1,10-phen,
K3PO4, PhMe, 80 °C, 44%
Br (15 equiv.),
Br
TsN
2. 3a, CuSO4•5H2O, 1,10-phen,
K3PO4, PhMe, 80 °C, 60%
TsHN
Hex
NTs
6
60 Scheme 2 Preparation of ynamide and bisꢀynamide cyclization substrates.
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Table 1 Bromoenynamideꢀalkyne Cascade Cyclizations.a
concentration (70%, Entry 10).
35
With efficient access to azatricycles established, we aimed to
demonstrate the utility of the methodology by preparing a natural
product analogue – bisꢀdesmethylꢀtrikentrin B 13 (see Scheme
3) – from the 5,6,5ꢀindolines 2a or 2b. This required installation
of the requisite butenyl sidechain, and conversion of the protected
Pd(PPh3)4 (5-10 mol%)
R
n
n
Br
(See Table)
TsN
R
N
X
Et3N (6 equiv.), MeCN,
80 °C, 16 h
Ts
X
40 indoline to the free indole. For the former of these tasks, we
recognised the synthetic value of the silane present in 2a/b, which
enables a variety of sidechain attachment strategies. We first
addressed Hiyama crossꢀcoupling of 2b, which offers a direct
route to the butenyl substituent and is an attractive alternative to
45 other coupling methods (e.g. Stille, Suzuki) due to the low
toxicity of silicon and its stability to multistep synthesis.9 To our
knowledge, no Hiyama couplings between arylbenzyl
dimethylsilanes and alkenyl halides have been reported, with only
the reverse process being described (i.e. the coupling of
50 alkenylbenzyldimethylsilanes with aryl halides).10
Standard conditions for the coupling of alkenyl
benzyldimethylsilanes (TBAF, Pd2dba3•CHCl3 or Pd(dba)2),10
using either βꢀstyrenyl iodide 7a or butenyl iodide 7b as the
halide partner, afforded no crossꢀcoupling product (Entries 1, 2).
55 As benzylsilanes are ‘safetyꢀcatch’ silanols, and indeed are
hydrolysed to the latter on treatment with TBAF, alternative
conditions for the coupling of alkenylsilanols11 were also
investigated, without success (Entry 3). In all of these trials,
mixtures of silanol, disiloxane, and desilylated arene were
60 recovered,12 suggesting that the aryl silanol revealed on
unmasking of the benzylsilane was resistant to transmetallation.
The addition of Ag2O has been reported by Hiyama to accelerate
transmetallation,13 and we were delighted to find that the
coupling of styrenyl iodide 7a under these conditions smoothly
65 afforded the styrenyl trikentrin framework 8a (68%).
Disappointingly, only desilylated arene was returned on
attempted coupling with butenyl iodide 7b, which for this study
presented an insurmountable limitation.
1a-d
2a-d
Catalyst
loading
Entry Substrate (mol%)
Product
Yield (%)b
SiMe3
1
2
3
10
5
90
78
88
2a
1a
1b
1c
1d
N
5c
Ts
SiMe2Bn
2b
4
5
10
5
90
73
N
Ts
SiMe2Bn
d
6
7
10
10c
–
2c
78
N
Ts
Hex
8
10
5
5c
49
52
70
2d
9
N
NTs
Ts
10
a
b
Reaction concentration 0.017 M unless indicated otherwise. Isolated
yield. c Reaction concentration 0.16 M. d Complex mixture.
5
accompanied by a degree of desilylation in the case of TMSꢀ
substituted diyne 5a. To further extend the cyclization
methodology, we targeted a substrate featuring two ynamides,
which would lead to an azaꢀtrikentrin (pyrroloindoline)
framework. The bisꢀynamide 1d was readily prepared in four
10 steps from 4a by bromination / carbamate deprotection (to afford
the sulfonamide 6), followed by sequential Hsung couplings –
firstly with 1ꢀbromoꢀoctꢀ1ꢀyne (used in excess to minimize
intermolecular homocoupling of 6), then with sulfonamide 3a.
With a selection of substrates in hand, the cascade cyclizations
15 were investigated (Table 1). Using our previously reported
conditions (10 mol% Pd(PPh3)4, Et3N, 0.017 M in MeCN,
80 °C),3 we were pleased to obtain the 5,6,5ꢀtricyclic trikentrin
frameworks 2a and 2b in excellent yields (90%, Entries 1, 4). The
catalyst loading could be lowered to 5 mol% with a slight
20 reduction in yield (Entries 2, 5); however, by increasing the
concentration (to 0.16 M), catalytic efficiency was restored, with
2a isolated in 88% yield (Entry 3).
A more classical route to install the butenyl sidechain was thus
70 developed (Scheme 3).14 Aryltrimethylsilane 2a was subjected to
a FriedelꢀCrafts acylation, which proceeded with exclusive ipsoꢀ
selectivity to give ketone 9 (79%). This ketone then underwent a
highꢀyielding reduction / dehydration sequence to deliver the
Table 2 Hiyama Crossꢀcoupling of Arylsilane 2b.
SiMe2Bn
R
7a (R = Ph)
7b (R = Et)
I
R
N
N
Ts
Ts
THF, 22 h
Conditions
(See Table)
8a (R = Ph)
8b (R = Et)
2b
75
Cyclization to the challenging 7,6,5ꢀtricyclic analogue of the
trikentrin framework was next attempted. At higher catalyst
25 loading and dilution, the desired tricycle 2c was obtained as a
component of a complex mixture (Entry 6). However, by
performing this reaction at higher concentration, 2c was formed
as the sole product in excellent yield (Entry 7), a result that
highlights the advantages of the sequenced carbopalladation
30 strategy. Finally, diynamide 1d was subjected to the range of
reaction conditions (Entries 8ꢀ10). To our delight, tricycle 2d,
which represents the first example of such a pyrroloindoline
framework, was isolated in high yield when reacted at the higher
Alkenyl
Iodide
TBAF
Yield
Entry
1
[Pd] cat. (mol %)
Temp (°C)
(equiv.)
(%)a
Pd2dba3•CHCl3 (2.5)
b
2.2
20→50
–
7a
or Pd(dba)2 (5)
b
2
3
4
5
a
Pd2dba3•CHCl3 (2.5) 2.2
20→50
20→50
20
–
7b
7a
7a
7b
b
(allylPdCl)2 (2.5)
2.2
–
Pd(PPh3)4 (5), Ag2Oc 1.1
68
Pd(PPh3)4 (5), Ag2Oc 1.1
20
–
d
b
Isolated yield. A mixture of silanol, disiloxane, and desilylated arene
was recovered. c 1.1 equiv. Ag2O. d Desilylated 2b was isolated (67%).
2
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O
T. G. Ruiz and L. F. Silva, Chem. Eur. J. 2012, 18, 16890. (b) W.
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SiMe3
butyryl chloride
AlCl3
N
N
9
PhMe
79%
Ts
Ts
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2a
NaBH4, CH2Cl2 / MeOH
96%
OH
p-TsOH
N
N
8b
PhMe, 80 °C
10
12
Ts
Ts
82%
Na / naphthalene
THF, –78 °C
Pd/C
PhMe
N
H
N
80 °C
56% (2 steps)
11
H
Scheme 3. Synthesis of bisꢀdesmethylꢀtrikentrin B
4. For the development of bromoendiyne cyclizations, see: (a) W. M.
Tokan, F. E. Meyer, S. Schweizer, P. J. Parsons and A. de Meijere,
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Chem. Commun. 2000, 1965. (c) B. Witulski and C. Alayrac, Angew.
Chem. Int. Ed. 2002, 41, 3281. For recent examples of ynamides in
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Sevrin, G. Ricci, M. Malacria, C. Aubert and V. Gandon, Chem. Eur.
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targeted butenyl sidechain (8b). Completion of the synthesis now
required indoline detosylation and oxidation to reveal the indole
moiety. However, all attempts to oxidise 8b to the corresponding
sulfonyl indole were unsuccessful, leading mainly to
degradation.15 Inverting this sequence of events resolved this
issue; although Mg/MeOH/sonication (which is usually effective
for such detosylations)2a,16 effected partial deprotection (<25%),
5
10 treatment of 8b with sodium naphthalenide gave the deprotected
indoline 11 with high efficiency. Somewhat surprisingly, 11
underwent rapid aerobic decomposition, presumably due to the
indolineꢀenhanced reactivity of the electronꢀrich styrene,17 and
isolation of the pure indoline proved difficult. However, we were
15 pleased to find that direct dehydrogenation of the crude indoline
using Pd/C in degassed toluene completed the synthesis, giving
bisꢀdesmethylꢀtrikentrin 12 in good yield over the two steps.
In conclusion, we have developed a facile method for the
preparation of azatricycles from bromoalkenyl ynamides. The
20 reaction enables formation of fiveꢀ to sevenꢀmembered rings, and
offers an attractive alternative to cyclotrimerization strategies.
The utility of this chemistry is demonstrated by installation of the
trikentrin B alkenyl sidechain in a further four steps using
FriedelꢀCrafts ipsoꢀsubstitution of the arylsilane cyclization
25 products. As an alternative, we report the first example of an
alkenyl iodide / arylbenzylsilane Hiyama crossꢀcoupling, which
affords a styrenylꢀtrikentrin analogue.
8. X. Zhang, Y. Zhang, J. Huang, R. P. Hsung, K. C. M. Kurtz, J.
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Tanemura, S. Noyori and K. Takagi, Org. Lett. 2009, 11, 3546. (d) C.
Morrill and N. S. Mani, Org. Lett. 2007, 9, 1505.
We thank the EPSRC (EP/H025839/1, CDC; EP/E055273/1,
Advanced Research Fellowship to E.A.A.), and Syngenta Ltd. for
30 a studentship (to R.L.G.).
11. (a) S. E. Denmark and L. Neuville, Org. Lett. 2000, 2, 3221. (b) S. E.
Denmark and W. J. Pan, J. Organomet. Chem. 2002, 653, 98.
12. See the Supporting Information for details.
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2000, 65, 5342.
14. Alternative strategies, such as the use of ynamides already featuring
the trikentrin B sidechain, were not investigated in this study, which
targeted a system enabling skeletal diversification at a late stage.
15. Oxidation using MnO2, Mn(OAc)3, DDQ, or AIBN/NBS led to
complete degradation of material; Co(salen)/O2 led to no reaction.
16. G. H. Lee, I. K. Youn, E. B. Choi, H. K. Lee, G. H. Yon, H. C. Yang
Notes and references
a Chemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, OX1 3TA, U.K. Fax: (+44) 1865 285002; Tel: Fax: (+44)
1865 285000; E-mail: edward.anderson@chem.ox.ac.uk
35 b Syngenta Ltd., Jealott's Hill International Research Centre, Bracknell,
Berkshire, RG42 6EY, U.K.
† Electronic Supplementary Information (ESI) available: Experimental
details, characterization and copies of H and 13C NMR spectra for novel
1
compounds. See DOI: 10.1039/b000000x/
and C. S. Pak, Curr. Org. Chem. 2004, 8, 1263
17. Aldehydeꢀcontaining byproducts, presumably arising from cleavage
of the alkene sidechain, were noted in this decomposition process.
.
1. For recent approaches to the trikentrins and herbindoles, see: (a) I. R.
M. Tébéka, G. B. Longato, M. V. Craveiro, J. E. de Carvalho, A. L.
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