Exploiting adamantane as a versatile organic tecton: Multicomponent catalytic cascade reactions

Article abstract of DOI:10.1039/c2cc35054h

3- And 9-component Pd(0) catalysed assembly of allenes, aryl iodides and N-nucleophiles with concomitant installation of trisubstituted Z-alkenes is readily achieved. This journal is

Full text of DOI:10.1039/c2cc35054h

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Chemical Communications
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Volume 48 | Number 94 | 7 December 2012 | Pages 11469–11584
ISSN 1359-7345
COMMUNICATION
Ronald Grigg et al.
Exploiting adamantane as a versatile organic tecton: multicomponent
catalytic cascade reactions
1359-7345(2012)48:94;1-Q

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COMMUNICATION
Exploiting adamantane as a versatile organic tecton: multicomponent
catalytic cascade reactionsw
Ronald Grigg,*a Elghareeb E. Elboray,ab Moustafa F. Alyb and Hussien H. Abbas-Temirekb
Received 14th July 2012, Accepted 21st August 2012
DOI: 10.1039/c2cc35054h
3- And 9-component Pd(0) catalysed assembly of allenes, aryl
iodides and N-nucleophiles with concomitant installation of
trisubstituted Z-alkenes is readily achieved.
An early seminal paper by Tsuji and Shimizu8a reported some
examples of simple 3-component cascades of monosubstituted
allenes only two of which gave rise to stereoselective forma-
tion of a trisubstituted alkene and in these latter cases the
stereochemistry was not identified. Stereochemical control of
such reactions is an ever present problem linked to the
mechanism.8b,9 In an earlier paper8b we successfully applied
multivariate analysis to enhance E/Z selectivity. In extreme
cases 1 : 1 mixtures of E- and Z-isomers can arise.8c This
problem does not arise with allene gas10 but highlights the
potential pitfalls involved in cascades involving 1–3. In this
paper we report harnessing the untapped power of the cata-
lytic cascade chemistry of allenes to the functionalisation of 1
and 3. Initially we studied the three component cascade
reactions (Scheme 1) of a range of aryl iodides 5 individually
with 1 and a range of novel allenes (purine allene 4a, uridine
allene 4b and thymidine allene 4c) selected for their bio-
chemical interest and prepared by a modified Crabbe reaction.11
Under Pd catalysis [Pd2(dba)3, tri-2-furylphosphine (TFP),
K2CO3 in MeCN at 80 1C for 2–5 h] the cascades proceeded
smoothly to afforded the Z-products 6a–i stereoselectively in
69–83% yield (Table 1).
Applications of tetrahedral 1,3,5,7-tetra-substituted adamantanes
span an eclectic field ranging from atomic force microscopy,1a,b
redox active self assembly monolayers,1c gas storage and
separation,1d,e semiconductor sensitisation1f and photochromics1g
through to drug design and drug carriers.2a–c The adamantyl
group is present in seven marketed drugs e.g. the anti-influenza
drugs amantadine 1 and rimantadine 2,3a and is attracting
ongoing interest for application to drug discovery applied to
the hepatitis C virus p7 ion channel3b and the M2 ion channel
of the influenza A virus.3c,d Chemistry accessing second and
third generation HYDRAmers, multiple linked adamantane
cores, has been reported recently.4 Additionally the applica-
tion of a range of palladium catalysed cross-coupling reactions
of 1,3,5,7-tetrakis(4-iodophenyl)adamantane 3, including the
Suzuki–Miyaura,5a–c Sonogashira6a–d and Mizoroki–Heck,7
have been reported (Fig. 1).
However, to our knowledge, the application of catalytic cascade
chemistry to 1–3 has not been reported despite the many advantages
that such chemistry can bestow e.g. 3 is an ideal organic tecton
with its rigid Td symmetry, non-polar core and stability.
When entry 7 was repeated using 2.0 equiv. of thymidine
allene 4c, 2.2 equiv. of iodobenzene 5g and 1.0 equiv. of 1 the
sole product was 6g i.e. no further functionalisation of the NH
moiety of 6g was observed under our standard conditions. The
successful realisation of the 3-component cascade opens new
approaches to drug discovery related to the hepatitis C virus
p7 ion channel and the M2 ion channel.
Next, we explored the extended polyfunctional reaction of 3
with a series of different allenes and nitrogen nucleophiles
(Scheme 2) under Pd(0) catalysis. The latter 9-component
cascade involves assembly of the adamantane core 3 with four
equivalents of allene 4 and four equivalents of nucleophile 7.z
In the case of both Schemes 1 and 2 products we note that:
(i) trisubstituted Z-double bonds are cleanly installed indicating
Fig. 1 Adamantane scaffolds.
a School of Chemistry, University of Leeds, Leeds, LS6 9JT, UK.
E-mail: r.grigg@leeds.ac.uk; Fax: +44 (0)113 343 6501;
Tel: +44 (0)113 343 6401
b Department of Chemistry, Faculty of Science at Qena,
South Valley University, Qena, Egypt
w Electronic supplementary information (ESI) available: Full charac-
terisation of all new compounds with HRMS data for the 9-component
products. See DOI: 10.1039/c2cc35054h
Scheme 1 Three component cascades.
c
11504 Chem. Commun., 2012, 48, 11504–11506
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Table 1 Three component cascade productsa
Entry Allene Aryl iodide
Product Yieldb (%)
1
6a
6b
6c
78
69
91
2
3
Scheme 2 Nine component cascades.
the orthogonal fixed spatial disposition of the four reactive
arms suppresses any tendency to lose control of the E/Z
stereochemistry of the trisubstituted alkenes, (ii) in the case
of primary aliphatic amine nucleophiles the reaction only
occurs once at nitrogen (Table 2, entries 2–5), (iii) in the
absence of primary amines secondary amines with appropriate
pKa’s react cleanly (Table 2, entries 1, 6–9), (iv) aliphatic
hydroxyl groups are not competitive in the presence of
primary amines (Table 2, entry 4), (v) the installation of the
Z-double bond not only adds additional rigidity to the
tectonic display but also provides opportunities for further
functionalisation if desired, (vi) the ability to incorporate both
amino acid esters and peptides (Table 2, entries 3–5) directly
into the cascade presages almost limitless further extension of
these cascades e.g. as a carrier of probes for cell, metal or
nanoparticle surfaces.12
4
5
6
7
8
6d
6e
6f
77
86
87
99
The data in Table 2 indicate a relationship between the pKa
of the nucleophile and the yield of the product under our
standard conditions.13 1-Aminoadamantane gave the highest
yield, pKa 10.76, whereas L-tryptophan methyl ester, pKa 6.96,
afforded the lowest yield (Table 2, entries 2 and 3). Addition-
ally, methyl glycyl-L-leucinate, pKa 7.64 (entry 5), afforded a
higher yield than L-tryptophan methyl ester and L-serine
methyl ester, pKa 6.39 (Table 2, entries 3 and 4). However,
the sterically congested 3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-
4-yl)-8-azabicyclo[3.2.1]-octane, pKa 10.71, (Table 2, entries 1, 6
and 8) produced lower yields compared to 8-fluoro-2,3,4,4a,5,9b-
hexahydro-1H-pyrido[4,3-b]indole, pKa 9.85, (Table 2, entries 7
and 9), respectively. That NH2-nucleophiles reacted only
once might be due to a combination of steric congestion of
the product and lower nucleophilicity of the product NH
group.
6g
6h
93
87
In conclusion, we have demonstrated that both 1-amino-
adamantane and 1,3,5,7-tetrakis(4-iodophenyl)adamantane
are versatile, selective participants in Pd(0) catalysed multi-
component cascade reactions. The ability to concurrently
create four trisubstituted Z-double bonds brings additional
synthetic opportunities by creating further rigidity in the
tecton arms whilst permitting additional post-cascade function-
alisation. Further work on these cascades is under way in our
laboratory.
9
6i
a
Reaction carried out at 80 1C in MeCN for 2–5 h and employed
substituted allene (0.50 mmol), aryl iodide (0.60 mmol), 1 (0.60 mmol),
Pd2(dba)3 (2.5 mol%), TFP (10 mol%) and K2CO3 (3 equiv.). b Isolated
yield.
We thank the Egyptian Government and South Valley
University for funding to (E.E.E) and Leeds University for
support.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11504–11506 11505

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Table 2 Nine component cascade productsa
Entry Allene Nucleophile
Notes and references
Product Yieldb (%)
z General Procedure for Pd catalysed 9-component cascades. A
mixture of substituted allene 4 (4 equiv.), 1,3,5,7-tetrakis-(4-iodophenyl)-
adamantane 3 (1 equiv.), nucleophile 7 (4.4 equiv.), Pd2(dba)3
(2.5 mol%), TFP (tri-(2-furyl)phosphine) (10 mol%), and K2CO3
(6 equiv.) in MeCN or DMF was stirred and heated at 80 1C (oil bath
temperature) for 3–32 h. The mixture was filtered and the inorganic
precipitate washed with MeCN. The solvent was removed under
reduced pressure, the residue dissolved in CHCl3 and washed with
H2O. The organic layer was dried over anhydrous MgSO4, filtered, and
the filtrate evaporated under reduced pressure. The residue was purified
by flash chromatography.
1
8a
8b
8c
52
87
45
2
3
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4
5
8d
8e
49
55
6
7
8
8f
56
8g
62
8h
69
74
9
8i
a
Reaction carried out at 80 1C in MeCN or DMF for 3–24 h and
employed substituted allene (0.40 mmol), 3 (0.10 mmol), nucleophile
(0.48 mmol), Pd2(dba)3 (2.5 mol%), TFP (10 mol%) and K2CO3
b
13 Predicted pKa values were calculated using the ACD/I-Lab web
service (ACD/pKa 12.0).
(6 equiv.). Isolated yield.
c
11506 Chem. Commun., 2012, 48, 11504–11506
This journal is The Royal Society of Chemistry 2012