Sulfone-mediated synthesis of polysubstituted pyridines

Article abstract of DOI:10.1016/j.tetlet.2005.02.105

Base-mediated and/or palladium(0)-catalysed bis(allylation) of alkyl 2-(tolylsulfonyl)acetates gives 1,6-dienes, which upon ozonolytic cleavage of the double bonds and ammonolysis give 2,6-disubstituted pyridine-4-carboxylic esters. Decarboxylation of one

Full text of DOI:10.1016/j.tetlet.2005.02.105

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2559–2562
Sulfone-mediated synthesis of polysubstituted pyridines
Donald Craig* and Gavin D. Henry
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
Received 17 January 2005; accepted 16 February 2005
Abstract—Base-mediated and/or palladium(0)-catalysed bis(allylation) of alkyl 2-(tolylsulfonyl)acetates gives 1,6-dienes, which
upon ozonolytic cleavage of the double bonds and ammonolysis give 2,6-disubstituted pyridine-4-carboxylic esters. Decarboxylation
of one of the 1,6-diene intermediates followed by deprotonation–alkylation and ozonolysis–ammonolysis gives a 2,4,6-trisubstituted
pyridine.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Pyridines are ubiquitous, important structural motifs in
a wide range of biologically important compounds, and
the development of efficient, versatile methods for their
synthesis remains a significant goal.1 We became inter-
ested in identifying new ways to synthesise pyridines in
which an arylsulfonyl group would serve both to facili-
tate C–C bond-forming reactions and as a leaving group
in the final, aromatisation step. We recognised that if the
key 1,5-dicarbonyl intermediates in the classical Han-
tzsch strategy2 could be made in a modified way by
incorporation of a leaving group at C3, rather than at
C2 as in the Kro¨hnke synthesis,3 then the following con-
densation with ammonia in the oxidation step would no
longer be necessary (Scheme 1). This letter describes the
realisation of these plans.
pointed towards routes involving sequential bis(allyl-
ation) of a one-carbon unit bearing the leaving group.
It seemed likely that 2-(tolylsulfonyl)acetic esters would
combine the required nucleofugality of the arylsulfonyl
group4,5 with facile conjugate base generation.6 Also,
there would be the option to retain or dispose of the car-
boxyl group at the 1,6-diene stage, opening the way to
additional, non-carboxylic substitution at the 4-
position.
Initial studies involved mono-allylation of methyl7,8 or
ethyl9 2-(tolylsulfonyl)acetate 1a,b to provide 2 by expo-
sure to excess base (2 equiv unless stated otherwise) fol-
lowed by addition of allylic chlorides, bromides or
tosylates (1 equiv unless stated otherwise), usually in
the presence of sub-stoichiometric amounts (0.1 equiv)
of tetra-n-butylammonium iodide. Extensive experimen-
tation identified DBU–DMF as the best base–solvent
combination for the majority of cases, in terms of both
operational simplicity and yield, with minimal forma-
tion of bis(allylated) material 3 observed even with
excess (2–8 equiv) base. Incorporation of the second
It occurred to us that the 3-substituted-1,5-dicarbonyl
compounds required for our study might be accessible
by oxidative cleavage of the double bonds in 1,6-dienes
bearing a leaving group at the 4-position. This approach
was particularly attractive because of the functional
group symmetry present in such compounds, which
Scheme 1.
Keywords: Allylation; 1,6-Dienes; Palladium-catalysed; Pyridines; Sulfone.
*
Corresponding author. Tel.: +44 20 7594 5771; fax: +44 20 7594 5868; e-mail: d.craig@imperial.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.105

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D. Craig, G. D. Henry / Tetrahedron Letters 46 (2005) 2559–2562
Table 1. Mono-allylation reactions of tosylacetic esters 1
allylic substituent using these conditions proved to be
more difficult, an observation consistent with the clean
mono-allylation described above. Attention was turned
to palladium-catalysed allylation reactions, and eventu-
ally it was established that room temperature treatment
of 2 with NaH in THF followed by addition of allylic
chlorides, bromides or tosylates10 in the presence of
sub-stoichiometric quantities of [Pd(PPh3)4] resulted in
clean, and in many cases near-quantitative conversion
into the bis(allylated) products 3. These conditions
could be employed for efficient, one-pot symmetrical
bis(allylation) reactions also; 3j (R1 = R2 = Ph) was
made directly from 1a and 2-phenylallyl tosylate in
80% yield. Potassium tert-butoxide was generally less
effective than NaH in these transformations. Finally, it
was found in the single example attempted that sequen-
tial mono-allylation and unsymmetrical bis(allylation)
could be achieved in high yield (96%) by the one-pot,
stepwise combination of 1a with methallyl methyl car-
bonate followed by allyl methyl carbonate in the pres-
ence of Pd2(dba)3 (0.05 equiv) and PPh3 (0.5 equiv) in
THF at 60 ꢁC,11 giving 1,6-diene 3e. Related conditions,
in which PPh3 was replaced by [2,4,6-(MeO)3C6H2]3P12
were effective for the one-step synthesis of 3k
(R1 = R2 = Me) from 1a using bis(methallyl) carbonate
alone. The allylation reactions of 1 are depicted in
Schemes 2 and 3 and the results collected in Tables 1
and 2.
Entry
R
R1
X
Product (% yield)
1
2
3
4
5
6
Me
Me
Et
H
Br
Cl
2a (70)a
2b (77)
2c (93)b,c
2d (72)c
2e (99)d,e
2f (84)e,f
Me
Me
Et
Cl
Me
Et
OTs
OTs
OTs
Et
Ph
Me
a Bis(allylated) product (5%) was also obtained.
b Toluene, instead of DMF, was used as solvent.
c 1 equiv of n-Bu4NI was used.
d The reaction was carried out in the absence of n-Bu4NI; 16 equiv of
allylic tosylate was used.
e 8 equiv of DBU was used.
f 5 equiv of allylic tosylate was used.
Table 2. Allylation reactions of mono-allylated tosylacetic esters 2
Entry Substrate R1
R2
X
Product (% yield)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2b
2d
2d
2d
H
H
Br
Cl
Cl
3a (99)
3b (54)
3c (62)
H
Et
Ph
H
H
Me
n-C8H17 OTs 3d (99)a,b
H
Br
OTs 3f (99)
Cl
3g (99)c
3e (95)
Me Ph
Et
Et
Et
Me
Et
OTs 3h (99)
OTs 3i (96)
Ph
a Allylic tosylate (1.3 equiv) was used.
b [Pd(PPh3)4] (0.05 equiv) was used.
c 2 equiv of methallyl chloride was used.
With robust syntheses of the required 1,6-dienes 3 in
hand, attention was turned to the ozonolysis–ammonol-
ysis sequence necessary to access pyridines. It was found
that 3 could be converted into the intermediate 3,3-
disubstituted-1,5-dicarbonyl compounds 4 in moderate
to good yields by brief ozonolysis in MeOH–CH2Cl2
at 0 ꢁC, followed by mild, reductive work-up using tri-
phenylphosphine. In general, compounds 4 were found
to be unstable over several hours at room temperature
but could be stored in a freezer for limited periods. Con-
version of 4 into pyridines 5 was most effectively carried
out by treatment of dichloromethane solutions of the
dicarbonyl compounds with 2 M ethanolic ammonia13
at ambient temperature overnight followed by straight-
forward purification either by passage through SCX2
cartridges14 or by conventional flash column chroma-
tography on silica gel. Compounds 4a and j failed to
give viable yields of 5; in these cases stable intermediates
6 and 7 respectively were isolated from the reaction mix-
tures. For a number of examples (3b,d,e,k), the ozonol-
ysis and ammonolysis steps could be carried out in one-
Scheme 2.
Scheme 3.
Scheme 4.

D. Craig, G. D. Henry / Tetrahedron Letters 46 (2005) 2559–2562
Table 3. Ozonolysis–ammonolysis reactions of bis(allylated) tosylacetic esters 3
2561
Entry
Ozonolysis substrate
R1
R2
Ozonolysis
product (% yield)
Ammonolysis
product (% yield)
One-pot ozonolysis–ammonolysis
product (% yield)
1
3a
3b
3c
3d
3e
3f
H
H
Et
4a (76)
—
5a (7)
—
—
5b (42)
—
2
H
3
H
Ph
4c (77)
—
—
5c (82)
—
—
4
H
n-C8H17
Me
Ph
5d (56)
5e (58)
—
5
H
6
Me
Me
Et
Et
Ph
Me
4f (57)
4g (57)
4h (80)
4i (74)
4j (76)
4k (86)
5f (80)
5g (90)
5h (97)
5i (83)
5j (13)
5k (83)a
7
3g
3h
3i
Et
Et
—
—
8
9
Ph
Ph
—
—
10
11
3j
3k
Me
5k (83)
a The ammonolysis was carried out at ꢀ33 ꢁC ! rt.
Scheme 5.
pot; in these cases the ozonolysis reactions were con-
ducted at ꢀ78 ꢁC and worked up by PPh3 treatment
prior to addition of ethanolic ammonia and warming
to room temperature. The pyridine-forming reactions
are depicted in Scheme 4 and the results summarised
in Table 3.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.02.105.
The final part of this study was devoted to evaluating
the efficiency of the decarboxylation–alkylation of inter-
mediates 3 in order to access 2,4,6-trisubstituted pyr-
idines without the carboxylic functional group at C4.
To this end, 1,6-diene 3k was subjected to decarboxyl-
ation under standard Krapcho conditions15 to give the
corresponding sulfone in virtually quantitative yield.
Treatment of this with n-BuLi followed by 1-iodonon-
ane gave the corresponding 4-substituted compound 8
in good yield, though these reactions invariably failed
to reach completion. Treatment of 8 under the now stan-
dard one-pot ozonolysis–ammonolysis conditions gave
2,6-dimethyl-4-nonylpyridine 9 in high yield (Scheme 5).
References and notes
1. Recent review of de novo methods for pyridine synthesis:
Henry, G. D. Tetrahedron 2004, 60, 6043.
2. Hantzsch, A. Ann. Chem. 1882, 215, 1.
3. Kro¨hnke synthesis: Katritzky, A. R.; Abdel-Fattah, A. A.
A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12,
2114.
4. Creary, X. J. Org. Chem. 1985, 50, 5080.
5. Bradley, P. J.; Grayson, D. H. J. Chem. Soc., Perkin
Trans. 1 2002, 1794.
6. The pKa of methyl (phenylsulfonyl)acetate has been
estimated as being in the range 12–13: Trost, B. M.;
Warner, R. W. J. Am. Chem. Soc. 1983, 105, 5940.
7. Back, T. G. J. Org. Chem. 1998, 63, 7908.
8. Langler, R. F. Aust. J. Chem. 1994, 47, 1641.
9. Sun, X.; Wang, L.; Zhang, Y. Synth. Commun. 1998, 28,
1785.
10. Bromo-2-propene and 1-chloro-2-methyl-2-propene were
purchased from Aldrich Chemical Co. and were distilled
prior to use. 2-Methylenebutanol, 2-phenyl-2-propenol
and 2-methylenedecanol were made from commercially
available 2-bromo-2-propenol (Aldrich Chemical Co.) and
the appropriate Grignard reagent using nickel-catalysed
cross-coupling methodology: Organ, M. G.; Murray, A. P.
J. Org. Chem. 1997, 62, 1523.
11. Tsuji, J.; Shimizu, I.; Minami, I.; Ohsahi, Y.; Sugiura, T.;
Takahashi, K. J. Org. Chem. 1985, 50, 1523.
12. Wada, M.; Higashizaki, S. J. Chem. Soc., Chem Commun.
1984, 482.
In conclusion, we have uncovered a new synthesis of
pyridines from simple precursors which are assembled
in a modular fashion from readily available starting
materials.16 Ongoing studies are directed towards the
synthesis of pyridines possessing substitution patterns
not readily accessible using the direct allylation methods
described herein, including natural products. The results
of these studies will be reported shortly.
Acknowledgements
We thank EPSRC and Aventis CropScience (additional
funding for Quota Studentship to G.D.H.) for support.

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D. Craig, G. D. Henry / Tetrahedron Letters 46 (2005) 2559–2562
13. Purchased from Aldrich Chemical Co. and used as
supplied.
14. Isolute SCX-2 cartridges were purchased from Argonaut
Technologies Ltd.
15. Krapcho, A. P. Synthesis 1982, 805, 893.
phere at rt followed by stirring for 10 min. After 20 h of
stirring at rt saturated aqueous NH4Cl (15 mL) and Et2O
(15 mL) were added, turning the solution a darker brown
colour. The aqueous layer was separated and extracted
with Et2O (2 · 20 mL). The combined organic layers were
washed with water (1 · 25 mL), brine (1 · 25 mL) and
dried (MgSO4). Concentration under reduced pressure
and chromatography gave methyl 4-methylene-2-(2-meth-
ylenebutyl)-2-(toluene-4-sulfonyl)hexanoate 3h (615 mg,
99%) as a colourless crystalline solid; mp 62–63 ꢁC
(CHCl3).
Typical procedure for ozonolysis of compound 3: to a
stirred solution of compound 3h (408 mg, 1.12 mmol,
1 equiv) in CH2Cl2 (36 mL) and MeOH (4 mL) at 0 ꢁC was
bubbled O2 (10 min), then O3 (20 min) until the solution
turned blue, followed by O2 (10 min). PPh3 (881 mg,
3.36 mmol, 3 equiv) was added and the solution was
stirred for 1 h at 0 ꢁC followed by 18 h at rt. Concentra-
tion under reduced pressure and chromatography (33%
EtOAc–petrol) gave methyl 4-oxo-2-(2-oxobutyl)-2-(tolu-
ene-4-sulfonyl)hexanoate 4h (0.329 g, 80%) as a colourless
crystalline solid; mp 57–59 ꢁC (EtOAc).
16. Typical procedure for mono-allylation of compound 1: a
solution of 2-methylenebutyl tosylate (2.11 g, 8.8 mmol,
1.0 equiv) in DMF (5 mL) was added dropwise over
10 min to a stirred solution of methyl tosylacetate 1a
(2.00 g, 8.8 mmol, 1.0 equiv), n-Bu4NI (0.486 g, 8.8 mmol,
1.0 equiv) and DBU (2.66 mL, 2.71 g, 17.6 mmol,
2.0 equiv) in DMF (25 mL), causing the solution to turn
brown and to evolve heat. After 18 h at rt, CH2Cl2
(100 mL) was added and the mixture was washed with
aqueous HCl (2 M; 75 mL). The layers were separated and
the aqueous layer was extracted with CH2Cl2 (3 · 50 mL).
The combined organic layers were then washed with water
(200 mL), separated and dried (MgSO4). Concentration
under reduced pressure and chromatography gave methyl
4-methylene-2-(toluene-4-sulfonyl)hexanoate 2d (1.87 g,
72%) as a yellow oil which later crystallised as a colourless
crystalline solid; mp 57–58 ꢁC (EtOAc–petrol).
Typical procedure for allylation of compound 2: to a
colourless solution of ester 2d (501 mg, 1.69 mmol,
1.0 equiv) and 2-methylenebutyl tosylate (447 mg,
1.86 mmol, 1.1 equiv) in dry THF (5 mL) was added
sodium hydride (60% dispersion in mineral oil, 0.214 g,
5.35 mmol, 2.0 equiv) under a nitrogen atmosphere with
stirring at rt, turning the reaction mixture a yellow colour
with a frothy consistency. To this solution was added a
yellow solution of tetrakis(triphenylphosphine)palla-
dium(0), made from the addition of triphenylphosphine
(221 mg, 0.85 mmol, 0.5 equiv) to a solution of tris(diben-
Typical procedure for conversion of 1,5-dicarbonyl com-
pounds 4 into pyridines 5: to a solution of diketone 4h
(69 mg, 0.179 mmol, 1 equiv) in CH2Cl2 (3 mL) at room
temperature was added NH3 (2 M in ethanol, 1.5 mL),
turning the solution from colourless to yellow. After
stirring for 16 h, TLC showed complete consumption of
the starting material and then CH2Cl2 (5 mL) was added.
The reaction mixture was washed with H2O (5 mL), the
aqueous layer was extracted with CH2Cl2 (3 mL) and the
combined organic layers were dried (MgSO4). Concentra-
tion under reduced pressure and chromatography (33%
EtOAc–petrol) gave methyl 2,6-diethylpyridine-4-carbox-
ylate 5h (0.051 g, 97%) as a yellow oil.
zylideneacetone)dipalladium(0)
0.05 equiv) in dry THF (3 mL) under a nitrogen atmos-
(78 mg,
0.09 mmol,