Double decarboxylative Claisen rearrangement reactions: Microwave-assisted de novo synthesis of pyridines

Article abstract of DOI:10.1039/b805078c

Microwave-assisted double decarboxylative Claisen rearrangement of bis(allyl) 2-tosylmalonates provides substituted 1,6-heptadienes, which may be alkylated, and then converted into pyridines by ozonolysis followed by reaction with ammonia generated in sit

Full text of DOI:10.1039/b805078c

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Double decarboxylative Claisen rearrangement reactions:
microwave-assisted de novo synthesis of pyridinesw
Donald Craig,*a Federica Painaa and Stephen C. Smithb
Received (in Cambridge, UK) 26th March 2008, Accepted 15th April 2008
First published as an Advance Article on the web 14th May 2008
DOI: 10.1039/b805078c
Microwave-assisted double decarboxylative Claisen rearrange-
ment of bis(allyl) 2-tosylmalonates provides substituted 1,6-
heptadienes, which may be alkylated, and then converted into
pyridines by ozonolysis followed by reaction with ammonia
generated in situ under microwave conditions.
Since its discovery over 35 years ago, the Ireland–Claisen
rearrangement1 has become established as a strategy-level
transformation for the stereoselective and regiospecific forma-
tion of C–C bonds. It has emerged as the Claisen rearrange-
ment variant of choice because of the ready availability of the
allylic ester substrates, and the mildness of the rearrangement
conditions.2 In recent years, we have been developing a
catalysed version of the Ireland–Claisen rearrangement: the
decarboxylative Claisen rearrangement (dCr) reaction in-
volves exposure of allylic tosylacetates 1 to N,O-bis(trimethyl-
silyl)acetamide (BSA) and potassium acetate under relatively
mild thermal conditions, and provides homoallylic sulfones 2
in good to excellent yields (Scheme 1).3–7 In many instances
BSA and KOAc may be used in sub-stoichiometric
amounts.8,9
Scheme 1 Decarboxylative Claisen rearrangement reaction.
undergo the second dCr reaction much less readily.13 This
work had shown that substrate 3a could selectively be con-
verted into the mono-rearranged product 5a and therefore 3a
was used to optimise the one-pot, double-rearrangement
(Scheme 3, Table 1).
Initially a mixture of 3a, BSA (1.0 equiv.) and KOAc
(0.1 equiv.) was subjected to conventional heating in toluene
under reflux for several hours (entry 1). Progressive decom-
position of BSA and starting material was observed, while
only trace amounts of 4a were detected, with predominant
formation of the mono-rearrangement product 5a. When the
reaction was carried out under microwave conditions in
dichloromethane (entry 2) only the product of mono-rearran-
gement could be isolated (47%) alongside unreacted starting
material 3a (42%). Use of a better microwave absorber such as
It occurred to us that two sequential dCr reactions might
take place in one pot on exposure of analogous bis(allyl)
2-tosylmalonates to the BSA–KOAc reagent combination.
The products of these transformations would be substituted
1,6-heptadienes, which would be converted into pyridines by
an ozonolysis–ammonolysis sequence developed previously in
our laboratory.10 In this earlier work, the position of pyridine
substitution had been constrained by the use of enolate-
mediated and allylpalladium-based methods for the C-allyla-
tion of tosylacetic esters. In contrast, use of a double dCr
reaction strategy in principle would enable access to pyridines
substituted at C-3 and/or C-5 because of the regiospecific
nature of the allylation process taking place in the rearrange-
ment step (Scheme 2).
The syntheses of substrates 3 required for this study were
carried out using a modification11 of our published4 proce-
dure.12 Previous investigations had shown that the first re-
arrangement of bis(allyl) 2-tosylmalonates takes place at
ambient temperature, and that the mono-rearranged products
a Department of Chemistry, Imperial College London, South
Kensington Campus, London, UK SW7 2AZ.
E-mail: d.craig@imperial.ac.uk; Fax: +44 (0)20 7594 5868;
Tel: +44 (0)20 7594 5771
b Syngenta, Crop Protection Research Chemistry, Jealott’s Hill
International Research Centre, Bracknell, Berkshire, UK RG42 6EY
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterisation of compounds 3b–f, 4a–f, 5b,d,
6a–c, 3-phenyl-4-(p-toluenesulfonyl)heptane-2,6-dione, and 7a–i. See
DOI: 10.1039/b805078c
Scheme 2 Synthesis of pyridines using 4-tosyl-1,6-heptadienes.
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Scheme 3 Double dCr reaction of 3a.
Scheme 4 Double dCr reactions of bis(allylic) 2-tosylmalonates 3b–f.
Table 2 Double dCr reactions of bis(allylic) 2-tosylmalonates 3b–f
1,2-dichlorobenzene14 (entry 3) resulted in the formation of 4a
as the major product. Optimisation of these reaction condi-
tions led to the isolation of diene 4a in 86% yield as a 1 : 1
mixture of diastereoisomers when the reaction was carried out
in the absence of solvent (entry 5). This transformation could
be performed on several-gram scales without any loss in
efficiency, and the solvent-free procedure was adopted as the
method of choice.
Entry Substrate R2 R3 R5 R6 Yield
of 4 (%)a conditions
Reaction
1
2
3
4
3b
3c
3d
3e
Me Ph H
Me Ph H
H
4b: 77b
Me 4c: 70
4 Â 3 min @ 200 1C
2 Â 3 min @ 240 1C
6 Â 1 min @ 180 1C
4 Â 3 min @ 220 1C;
3 Â 2 min @ 240 1C
6 Â 1 min @ 190 1C
Me Ph Me Me 4d: 56c
Me H –(CH2)4– 4e: 62
Further experimentation showed the use of microwave
acceleration to be essential for the realisation of efficient
double dCr reactions (Scheme 4, Table 2). In some cases,
reactions were stopped prior to the complete consumption of
malonate, in order to minimise contamination of the dienes
with decomposition products (entries 1 and 3). It was found
that carrying out irradiation in a number of short pulses rather
than over longer, continuous periods gave higher and more
reproducible yields.14,15 The rate-enhancing effect of a phenyl
group versus a hydrogen atom in the R3 position13 was high-
lighted by the significantly harsher conditions required to
effect transformation of substrate 3e (entry 4). All diene
products were formed as mixtures of two (R3 or R5 = H) or
four (R3, R5 a H) diastereoisomers.
With a route to di-, tri- and tetrasubstituted 1,6-heptadienes
established, it occurred to us that incorporation of a fifth
substituent might be possible by alkylation a- to the tosyl
group (Scheme 5).10,17 This would allow the synthesis of
pyridines substituted additionally at the 4-position. While
exposure of 4a to nBuLi followed by 1-iodononane provided
diene 6a in good yield, significantly lower yields were obtained
for more highly substituted substrates. The disubstituted
heptadiene 4b gave trisubstituted analogue 6b in only 40%
yield under similar conditions, and benzylation of 4b using
PhCH2Br gave a 56% yield of 6c (Table 3). Dienes which were
substituted additionally at the 6-position failed to yield any
4-substituted products using this approach.
5
3f
H
Ph –(CH2)4– 4f: 58
a
b
Isolated yield. Mono-rearranged product was isolated also
(7%).16 c Mono-rearranged products were isolated also (23%).
Scheme 5 4-Alkylation of 1,6-heptadienes 4a,b.
Table 3 4-Alkylation of 1,6-heptadienes 4a,b
Substrate
R2
R4X
Product
Yield (%)a
4a
4b
4b
H
Me
Me
nC9H19
nC9H19
PhCH2Br
I
I
6a
6b
6c
86
40
56
a
Isolated yield.
particularly when the intermediate dicarbonyl compounds
contained aldehyde groups (R2 and/or R6 = H). The results
are summarised in Table 4.
For one substrate the efficiency of the pyridine formation
step on its own was evaluated by ammonolysis of 3-phenyl-4-
tosylheptane-2,6-dione, obtained in 72% isolated yield by
ozonolysis of 4c. The diketone was converted into pyridine
7c in 98% yield, both by using ammonia in methanol
(rt, overnight)10 and with NH4HCO3 in methanol (microwave,
100 1C, 10 min) as the source of ammonia.
Dienes 4 and 6 were converted into pyridines by ozonolysis
with mild reductive work-up, followed by exposure of the
18
crude 1,5-dicarbonyl products to excess NH4HCO3 in
methanol with microwave irradiation for 10 min at 100 1C
(Scheme 6). Longer reaction times resulted in lower yields,
Table 1 Optimisation of double dCr reaction of 3a
Entry
Solvent
Equiv. BSA
Reaction conditions
Yield of 4aa (%)
By-product
1
2
3
4
5
PhMe
CH2Cl2
1,2-Cl2C6H4
Cl(CH2)2Cl
None
6
1
1
Reflux, 53 h
0%
0%
66%
50%
86%
5ab
Microwave, 110 1C, 15 min
Microwave, 180 1C, 5 min
Microwave, 170 1C, 15 min
Microwave, 170 1C, 4 min
5ac (47%)
—
—
—
1
3d
a
b
Isolated yield. Compound 5a and unidentified decomposition products were isolated, together with unreacted starting material. Unreacted
c
d
starting material was also isolated (42%). The reaction was carried out under solvent-free conditions.
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3. D. Bourgeois, D. Craig, N. P. King and D. M. Mountford,
Angew. Chem., Int. Ed., 2005, 44, 618.
4. D. Craig and F. Grellepois, Org. Lett., 2005, 7, 463.
5. D. Craig, F. Grellepois and A. J. P. White, J. Org. Chem., 2005,
70, 6827.
6. D. Craig, N. P King, J. T. Kley and D. M. Mountford, Synthesis,
2005, 3279.
7. D. Bourgeois, D. Craig, F. Grellepois, D. M. Mountford and A. J.
W. Stewart, Tetrahedron, 2006, 62, 483.
Scheme 6 Formation of pyridines 7.
8. For the first report of Ireland–Claisen rearrangement of an allylic
a-phenylsulfonylacetate followed by decarboxylation, which took
place in a separate step, see: A. H. Davidson, N. Eggleton and
I. H. Wallace, J. Chem. Soc., Chem. Commun., 1991, 378.
9. For a report of the mechanistically distinct Carroll rearrangement
of an allylic a-phenylsulfonyl ester under strongly basic condi-
tions, see: M. A. Hatcher and G. H. Posner, Tetrahedron Lett.,
2002, 43, 5009.
Table 4 Formation of pyridines 7 from 4-tosyl-1,6-heptadienes
Entry
Diene
R2
R3
R4
R5
R6
Yield
of 7 (%)a
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
6a
6b
6c
H
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
H
H
H
H
H
H
nC9H19
nC9H19
PhCH2
H
H
H
H
Me
Me
7a: 53
7b: 86
7c: 73
7d: 81
7e: 37
7f: 63
7g: 98
7h: 100
7i: 75
10. D. Craig and G. D. Henry, Tetrahedron Lett., 2005, 46, 2559.
11. The previously reported (ref. 4) tosylation of methyl allylic
malonates required the use of 4.5 equiv. substrate, 4.0 equiv. tBuOK
and 1.0 equivalent of tosyl fluoride in DMSO (2 M solution). In this
study, the ratios of substrate:tBuOK:TsF were improved to 2 : 2 : 1
for the synthesis of diallylic tosylmalonates 3a–f (see ESIw).
12. For recent reports of sulfonylation a- to carbonyl groups
mediated by enols/enolates, see: (a) A. S. Kende and
J. S. Mendoza, J. Org. Chem., 1990, 55, 1125; (b) V. P Sanda-
nayaka, A. Zask, A. M. Venkatesan and J. Baker, Tetrahedron
Lett., 2001, 42, 4605; (c) A. R. Katritzky, A. A. A. Abdel-Fattah,
A. V. Vakulenko and H. Tao, J. Org. Chem., 2005, 70, 9191;
(d) M. Kreis, M. Nieger and S. Braese, J. Organomet. Chem., 2006,
691, 2171; (e) D. Kumar, S. Sundaree, V. S. Rao and R. S. Varma,
Tetrahedron Lett., 2006, 47, 4197; (f) R. Kumar, S. Saingar,
P. Joshi and Y. C. Joshi, Indian J. Heterocycl. Chem., 2005, 14,
353; (g) A. M. Venkatesan, J. M. Davis, G. T. Grosu, J. Baker,
A. Zask, J. I. Levin, J. Ellingboe, J. S. Skotnicki, J. F. DiJoseph,
A. Sung, G. Jin, W. Xu, D. J. McCarthy and D. Barone, J. Med.
Chem., 2004, 47, 6255; (h) J. K. Bin, J. S. Lee and K. Kim, Org.
Lett., 2004, 6, 4297.
Me
Me
Me
Me
H
H
Me
Me
H
Me
–(CH2)4–
–(CH2)4–
H
H
H
H
H
H
a
Isolated yield based on 4 or 6.
In summary, we have developed a new, microwave-assisted
method for the synthesis of substituted pyridines using the
double dCr reaction as a key step. Ongoing studies are directed
towards expanding the scope of this chemistry to accommo-
date the synthesis of bicyclic analogues, and of chiral pyridines
possessing benzylic stereocentres. The results of these investi-
gations will be reported in due course.
This research was supported by EPSRC (responsive mode
grant GR/T10268) and Syngenta (supported DTA studentship
to F.P.).
13. D. Craig, M. I. Lansdell and S. E. Lewis, Tetrahedron Lett., 2007,
48, 7861.
14. T. Durand-Reville, L. B. Gobbi, B. L. Gray, S. V. Ley and
J. S. Scott, Org. Lett., 2002, 4, 3847.
15. J. Siu, I. R. Baxendale and S. V. Ley, Org. Biomol. Chem., 2004,
160.
16. The mono-rearranged product was that of rearrangement of the
cinnamyl group.
17. For recent reports of sulfone alkylation a- to a tosyl group, see:
(a) M. H. Weston, K. Nakajima, M. Parvez and T. G. Back,
Chem. Commun., 2006, 3903; (b) H. Comas and E. Pandolfi,
Synthesis, 2004, 2493.
Notes and references
1. R. E. Ireland and R. H. Mueller, J. Am. Chem. Soc., 1972, 94,
5897 For reviews of the Ireland–Claisen rearrangement, see:
(a) S. Pereira and M. Srebnik, Aldrichimica Acta, 1993, 26, 17;
(b) Y. Chai, S. Hong, H. A. Lindsay, C. McFarland and
M. McIntosh, Tetrahedron, 2002, 58, 2905.
2. For
a
A. M. Castro, Chem. Rev., 2004, 104, 2939.
recent review of the Claisen rearrangement, see:
18. J. Lu, Y.-J. Bai, B.-Q. Yang and H.-R. Ma, Chin. J. Org. Chem.,
2000, 20, 514.
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