Pyridines via solid-supported [2 + 2 + 2] cyclotrimerization

Article abstract of DOI:10.1039/b515901f

The formation of pyridines via a crossed [2 + 2 + 2] cycloaddition has been achieved on a solid-support for the first time. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b515901f

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Pyridines via solid-supported [2 + 2 + 2] cyclotrimerization{
Ramesh S. Senaiar,{ Douglas D. Young{ and Alexander Deiters*
Received (in Bloomington, IN, USA) 8th November 2005, Accepted 24th January 2006
First published as an Advance Article on the web 13th February 2006
DOI: 10.1039/b515901f
tetramethylammonium oxide (TMAO)31 as a catalyst activating
The formation of pyridines via a crossed [2 + 2 + 2]
cycloaddition has been achieved on a solid-support for the
first time.
additive. The reaction mixture was heated to 80 uC and
CpCo(CO)2 (20 mol%) was added every 12 h for 48 h. Due to
the pseudo-high dilution conditions on the resin surface, no
pyridines resulting from the double incorporation of 1 were
observed. Moreover, pyridines that result from the cyclotrimeriza-
tion of two molecules of 2 and one molecule of 3 were removed in
the workup step since they are not immobilized on the resin. The
formation of benzenes through the reaction of 1 with two alkynes
2 was suppressed by using the catalyst CpCo(CO)2 which favors
pyridine formation in conjunction with an excess of nitrile 3.13
Therefore a highly chemoselective crossed [2 + 2 + 2] cycloaddition
towards 4 was achieved. The pyridine was then cleaved under mild
conditions using 1% TFA in DCM yielding clean TFA-salts of the
products 5. These salts were converted into the free bases by
passing them through an ion exchange resin (Dowex 50WX8-100).
We recently initiated a program in developing solid-supported
multicomponent reactions (MCRs)1–6 for the rapid construction of
small molecule libraries. This approach combines the advantages
of solid-supported chemistry (easy automatization, parallelization,
and purification)7–9 with the high convergence of MCRs. A
classical MCR, the [2 + 2 + 2] cyclotrimerization towards highly
substituted pyridine rings has surprisingly not received much
attention in combinatorial chemistry.10–13 The commercial avail-
ability of a wide range of alkynes and nitriles makes this reaction
an ideal candidate for the rapid assembly of diverse heterocyclic
libraries.9,14 Pyridine rings are found in many biologically relevant
structures including compounds with antiviral (HIV),15 antimicro-
bial,16,17 anticancer,18 and protein kinase inhibition activity.16,17
Catalyst systems applied in cyclotrimerizations towards pyridine
synthesis are mainly based on cobalt, and recent developments
have led to mild reaction conditions applicable to organic
synthesis.19,20,21–26 However, major problems are still associated
with this reaction, including chemo- and regioselectivity issues.13,27
The catalytic solution-phase cyclotrimerization of two alkynes and
a nitrile results in the formation of mixtures of products including
crossed pyridines (from the incorporation of two different alkynes)
and homo pyridines (from the incorporation of two identical
alkynes), as well as potential benzene byproducts. We resolved
these problems by immobilizing one alkyne reaction partner on a
polystyrene resin, thereby accomplishing the first catalytic crossed
cyclotrimerization of this type. Specifically, propargyl alcohol was
immobilized on a polystyrene resin (100–200 mesh)28 using an acid
labile trityl linker29,30 under standard conditions (pyridine, THF,
rt, 12 h). Resin 1 was obtained with a loading of 0.8 mmol g21 as
determined by GC-MS analysis of a sample cleaved with 1% TFA
in CH2Cl2.
1
The pyridines 5 were then analyzed by H NMR, LC-MS, and
GC-MS. They are observed in 43–85% yield (typical solution-
phase yields are about 65%13) and excellent purity of generally
>90%. By using a set of six different alkynes (6–11) and three
different niriles (12–14) an array of 18 pyridines (15–32) was
rapidly assembled. The reaction tolerates a variety of substituents,
including alkyl groups (Me, Et, and Bu), aryl groups (Ph), hydroxy
groups, alkoxy groups (CH2OMe), and carbamates (BocNH).
Free amines were not compatible with the reaction conditions;
however, the Boc protecting group was conveniently removed
from the corresponding carbamate in the cleavage step. Even
alkynes which are less reactive due to sterical demand (9) or an
internal triple bond (11) underwent cyclotrimerization. Crossed
cyclotrimerizations lead to the formation of complex mixtures of
Scheme 1 illustrates the generalized reaction of 1 with an alkyne
2 and a nitrile 3 yielding the immobilized pyridine 4. Only one
regioisomer is displayed; however, regioselectivities observed in
solution-phase reactions are typically low.11–13 The resin 1 was
swelled in degassed toluene in the presence of the alkyne 2, the
nitrile 3 (1 : 10 ratio to favor pyridine formation), and
North Carolina State University, Department of Chemistry, Campus
Box 8204, Raleigh, NC 27695-8204, USA.
E-mail: alex_deiters@ncsu.edu; Fax: ++1-919-515-5079;
Tel: ++1-919-513-2958
{ Electronic supplementary information (ESI) available: Mechanistic
discussion of regioisomer formation, the cyclotrimerization protocol,
and 1H NMR spectra and MS data of compounds 15–32. See DOI:
10.1039/b515901f
Scheme 1
{ These authors contributed equally to this work.
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Fig. 1 Alkynes (6–11) and nitriles (12–14) employed in solid-supported [2 + 2 + 2] cyclotrimerizations with 1 yielding pyridines 15–32. Yields and ratios of
regioisomers are shown in parentheses. The regioisomeric ratios were determined by GC-MS (compounds 15–20, 23–29, and 32) and 1H NMR (21–22 and
30–31) analysis. The structure of only one (out of several possible) 2,4,6-regioisomer is shown. 2,4,6-Regioisomers generally represent the major substitution
1
pattern as determined for 21–23 by H NMR. Compound purities are generally >90% as determined by GC-MS and H NMR.
1
regioisomers, which can be explained with a generally accepted
reaction mechanism (see Supplementary Data{).13 In these cases
an assignment of regioisomers was not possible by spectroscopic
means and a chromatographic separation was not feasible.
However, the alkyne reaction partners 8 and 11 greatly simplify
the formation of possible regioisomers and allow for an assign-
ment of the major pyridine (the structure shown in Fig. 1). In the
case of 8, a regioselectively less challenging homocyclotrimerization
was performed leading to the predominant formation (67–90%) of
the 2,4,6-substituted homo-pyridines 21–23. This is in agreement
with literature observations in the solution phase.13 The reaction
proceeds through a 2,4-disubstituted cobaltacyclopentadiene as the
major reactive species followed by regioselective insertion of the
nitrile under carbon–carbon bond formation with the less sterically
hindered C-atom attached to the metal (see Supplementary
Data{). The 2,3,6-trisubstituted pyridine (not shown) is the minor
regioisomer (10–33%).
In the case of a crossed [2 + 2 + 2] cyclotrimerization with the
symmetrical alkyne 11, only two regioisomeric pyridines were
obtained with the shown 2,3,4,6-pyridines 30–32 (Fig. 1) being the
major isomers and the 2,3,5,6-pyridines (not shown) being the
minor isomers. This regioselectivity was established via extensive
NMR experiments and can be explained by the mechanism
depicted in Scheme 2.
Scheme 2
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Using a symmetric and a terminal alkyne, two regioisomeric
cobaltacyclopentadienes 33 and 34 can be potentially formed.
However, the 2,3,4-cyclopentadiene 34 is the minor isomer due to
steric interactions between the A and the B substituent. The major
2,3,5-isomer 33 reacts with the nitrile towards the regioisomeric
2,3,4,6- and 2,3,5,6-pyridines, 35 and 36 respectively. The
regioisomers 37 and 38 were not observed in the cyclotrimeriza-
tions described in Fig. 1. The ratio of 35/36 was about 2 : 1 due to
similar sterical demand of the two substituents. The slightly higher
amount of 35 can potentially be attributed to the sterical demand
of the trityloxy group. We are currently designing novel linker
strategies in which the substituent A consists of sterical demanding
groups thereby imposing a high regioselectivity on the reaction
leading to the predominant formation of 35. Ideally, these linker
groups will be cleaved in a traceless fashion.
In summary, we demonstrated the first crossed [2 + 2 + 2]
cyclotrimerization reaction leading to the formation of highly
substituted pyridines. The reaction was conducted on a solid-
support facilitating its application in the multi-component
synthesis of combinatorial libraries with good yields and excellent
purities. We are currently expanding its scope by using additional
reaction partners (e.g. isocyanates) and are synthesizing a variety
of small molecule arrays. The obtained heterocyclic structures will
be subsequently screened for biological activity.
D. D. Y. thanks the Department of Education for a GAANN
fellowship.
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