Synthesis of di-, tri-, and tetrasubstituted pyridines from (phenylthio)carboxylic acids and 2-[aryl(tosylimino)methyl]acrylates

Article abstract of DOI:10.1021/ol503360q

An isothiourea-catalyzed Michael addition-lactamization followed by the sulfide oxidation-elimination/N- to O-sulfonyl transfer sequence for the formation of 2,3,5- and 2,3-substituted pyridine 6-tosylates from (phenylthio)acetic acids and α,β-unsaturated

Full text of DOI:10.1021/ol503360q

Letter
pubs.acs.org/OrgLett
Synthesis of Di‑, Tri‑, and Tetrasubstituted Pyridines from
(Phenylthio)carboxylic Acids and 2‑[Aryl(tosylimino)methyl]acrylates
Daniel G. Stark,† Timothy J. C. O’Riordan,‡ and Andrew D. Smith*,†
†EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, Fife, KY16 9ST, United Kingdom
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, RG42, 6EY, United Kingdom
S
* Supporting Information
ABSTRACT: An isothiourea-catalyzed Michael addition−
lactamization followed by the sulfide oxidation−elimination/
N- to O-sulfonyl transfer sequence for the formation of 2,3,5-
and 2,3-substituted pyridine 6-tosylates from (phenylthio)acetic
acids and α,β-unsaturated ketimines is described. Incorporation
of the valuable 2-sulfonate group allows derivatization to a range
of di-, tri-, and tetrasubstituted pyridines.
he pyridine motif is a heterocycle class that forms the core
of many biologically active molecules and is widespread
Scheme 1. Isothiourea-Mediated Synthesis of Pyridines
T
in both agrochemicals and pharmaceuticals.1 Due to the broad
synthetic and medicinal application of these molecules there
has been much effort directed toward their synthesis.2,3 Despite
these advances, the catalytic preparation of diverse and highly
functionalized pyridines from easily accessible starting materials
still remains a key focus within the synthetic community.
Following the seminal nucleophilic-catalyzed aldol lactoniza-
tion (NCAL) work by Romo and co-workers using ammonium
enolates4 generated from carboxylic acids,5 we have previously
used isothioureas6 to catalyze the Michael addition−lactonization/
lactamization of arylacetic and alkenylacetic acids with electron-
deficient Michael acceptors.7 This strategy was used to produce
2,4,6-substituted pyridines from (phenylthio)acetic acid via
a Michael addition−lactamization/PhSH-elimination/N- to
O-sulfonyl transfer cascade sequence (Scheme 1a).8 To extend
this methodology beyond 2,4,6-substituted pyridines, alkyl 2-
[aryl(tosylimino)methyl]acrylates were identified as potential
Michael acceptors to access 2,3,6-substituted pyridines. Additionally,
while α,α-disubstituted acetic acids are typically recalcitrant in this
methodology, we envisioned that the absence of a β-substituent in
the Michael acceptor may facilitate their use and provide access to
2,3,5,6-functionalized pyridines (Scheme 1b).
Scheme 2. Three-Stage Preparation of Pyridines
To investigate this route to diversely functionalized pyridines,
a series of alkyl 2-[aryl(tosylimino)methyl]acrylates were pre-
pared.9 Model studies treated (phenylthio)acetic acid 1 with
pivaloyl chloride to make the corresponding mixed anhydride
in situ, which upon treatment with DHPB (3,4-dihydro-2H-
pyrimido[2,1-b]benzothiazole) 2 (20 mol %) and excess i-Pr2NEt
at rt promoted Michael addition−lactamization with ketimine 3
to give dihydropyridinone 4 in 70% yield after 1 h (Scheme 2).10
In contrast to our previous studies, PhSH elimination was not
observed in this reaction process either at elevated temperatures
or in the presence of excess Et3N. These observations are in con-
gruence with those of Donohoe et al. in a related system.11 It
was therefore envisioned that a sulfide oxidation−elimination and
Received: November 19, 2014
Published: December 8, 2014
© 2014 American Chemical Society
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Letter
thermal-assisted N- to O-sulfonyl transfer could be used to pro-
duce the desired pyridines.12,13 Pleasingly, the oxidation of dihydro-
pyridinone 4 with m-CPBA (1.1 equiv) and excess Na2CO3 in
CH2Cl2 at 0 °C gave the desired sulfoxide in situ which, upon
warming to rt, underwent a sulfoxide elimination to give pyridone
5 (Scheme 2). Finally, heating pyridone 5 in THF at 80 °C for 1 h
promoted complete N- to O-sulfonyl transfer, providing pyridine 6
in 88% yield (62% over three steps). An attempted one-pot pro-
cedure of Michael addition−lactamization, in situ oxidation−
elimination, and N- to O-sulfonyl transfer gave a complex mixture
of the corresponding dihydropyridinone sulfide, sulfone, and
the desired pyridine indicating that isolation of the intermediate
dihydropyridinone 4 is necessary to achieve selective pyridine
formation in high yield.
in good yield for pyridine 14 (59% yield). A benzyl ester
substituent can also be used, giving pyridine 16 in 45%
yield.14
The use of α,α-disubstituted (phenylthio)acetic acids in this
methodology to generate 2,3,5-substituted pyridine 6-tosylates
was next investigated (Table 2). Pleasingly, (phenylthio)phenyl
acetic acid is well tolerated, reacting with ketimine 3 under the
previously optimized conditions to give excellent conversion
into intermediate dihydropyridinone 17 (69% yield) after 1 h
at rt. Subsequent oxidation−elimination and N- to O-sulfonyl
transfer proceeded well, giving pyridine 18 in 63% yield over
the three steps. (Phenylthio)phenyl acetic acid was then used in
this protocol with a range of alkyl 2-[aryl(tosylimino)methyl]-
acrylates containing various aromatic substituents. Highly sub-
stituted pyridines 20, 26, 28, 30, and 34 with electron-rich,
halogen (p-Br and p-Cl), or heteroaromatic substituents were
all formed in good yield (44−72%) over the three-step pro-
tocol. The purification of 3-tolyl, 3,5-xylyl, and 2-naphthalene
substituted intermediate dihydropyridinones 21, 23, and 31
proved difficult leading to a crude mixture of ∼80% purity
being carried forward into the oxidation−elimination/N- to
O- sulfonyl transfer step, giving pyridines 22, 24, and 32 in
overall slightly reduced yields (56%, 44%, and 55% yield,
respectively) compared with the previous examples.15 Alterna-
tive α-aryl (phenylthio)acetic acids are also tolerated in this
methodology, giving the corresponding pyridines 36 and 38 in
(64% and 45% yield, respectively). The ester substituent was
also varied to give pyridine 40 with a benzyl ester in the 3-
position in good yield (58% yield). Disappointingly, the use of
2-(phenylthio)propanoic acid and 3-methyl-2-(phenylthio)-
butanoic acid did not give conversion to the desired dihydro-
pyridinones.
With an effective three-stage sequence to functionalized
pyridines established, the scope of this methodology was evaluated.
First, the synthesis of 2,3-substituted pyridine 6-tosylates was
undertaken from (phenylthio)acetic acid and a range of alkyl
2-[aryl(tosylimino)methyl]acrylates (Table 1). Typically the
Table 1. Reaction Scope: Synthesis of 5,6-Substituted
a
Pyridine 2-Tosylates
A key feature of this process is the incorporation of the
sulfonyl group derived from the ketimine component into a
synthetically useful tosylate functional handle in the product.
To display that this feature allows the rapid assembly of a diverse
range of highly substituted pyridine scaffolds a selection of
derivatizations were undertaken (Scheme 3). Protodetosylation,16
Pd-catalyzed Heck coupling,17 and nucleophilic aromatic sub-
stitution18 reactions with pyridines 6 and 18 gave the correspond-
ing products 41−46 in excellent yields, demonstrating concise
routes to 2,3-, 2,3,6-, 2,3,5-, and 2,3,5,6-substituted pyridines.
The reaction mechanism is thought to proceed by initial
formation of mixed anhydride 47 from the requisite carboxylic
acid and pivaloyl chloride in the presence of base, with
subsequent N-acylation of DHPB 2 generating the correspond-
ing acyl isothiouronium ion 48 (Figure 1). Deprotonation
generates an intermediate ammonium enolate 49, which
undergoes Michael addition with the alkyl 2-[aryl(tosylimino)-
methyl]acrylate 50, followed by lactamization, to generate the
corresponding dihydropyridinone 51 and regenerate DHPB.
Treatment of this product with m-CPBA results in oxidation
into the corresponding sulfoxide 52, which readily eliminates to
provide pyridone 53. Finally, thermally promoted intra-
molecular N- to O-sulfonyl migration affords the desired
functionalized pyridine 54 (Figure 1).
a
Conditions A: t-BuCOCl (3.0 equiv), i-Pr2NEt (3.0 equiv), CH2Cl2,
0 °C, 10 min then DHPB (20 mol %), i-Pr2NEt (1.5 equiv), rt, 1−4 h.
Conditions B: (i) m-CPBA (1.1 equiv), Na2CO3 (39 equiv), CH2Cl2,
b
0 °C−rt, 30 min; (ii) THF, 80 °C, 1 h. Isolated yield over 3 steps.
c
Carried forward as crude residue of ∼80% purity.
Michael addition−lactamization step proceeded in good
isolated yields (62−68%), with the subsequent oxidation−
elimination and N- to O-sulfonyl transfer steps progressing
with excellent yields (88−93% over two steps). The
methodology tolerates electron-neutral aryl substituents,
giving good yields for pyridines 8 and 10 (62% and 56%
over three steps, respectively). Halogen substituted aromatics
are also accepted with pyridine 12 formed in good yield (56%
yield), while heteroaromatic 2-thienyl can also be integrated
In conclusion, we have demonstrated a route to highly func-
tionalized pyridines from (phenylthio)acetic acids and a range
of alkyl 2-[aryl(tosylimino)methyl]acrylates. This process pro-
ceeds via an isothiourea-catalyzed Michael addition−lactamization
to yield a dihydropyridinone. Subsequent sulfoxide elimination
and N- to O-sulfonyl transfer provide the desired pyridine
products wherein the N-sulfonyl group is transformed into a
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Letter
Table 2. Reaction Scope
a
Conditions A: t-BuCOCl (3.0 equiv), i-Pr2NEt (3.0 equiv), CH2Cl2, 0 °C, 10 min then DHPB (20 mol %), i-Pr2NEt (1.5 equiv), rt, 1−4 h.
b
c
Conditions B: (i) m-CPBA (1.1 equiv), Na2CO3 (39 equiv), CH2Cl2, 0 °C−rt, 30 min; (ii) THF, 80 °C, 1 h. Isolated yield over 3 steps. Carried
forward as crude residue of ∼80% purity.
Scheme 3. Derivatization of 2,3-Pyridine 6-Tosylate 6 and
2,3,5-Pyridine 6-Tosylate 18
synthetically valuable functional handle. Functionalization of
this group allows access to a diverse range of novel 2,3-, 2,3,5-,
2,3,6-, or 2,3,5,6-substituted pyridines. Current research from
Figure 1. Synthetic route and proposed mechanism.
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Letter
624−636. (h) Morrill, L. C.; Smith, S. M.; Slawin, A. M. Z.; Smith, A.
D. J. Org. Chem. 2014, 79, 1640−1655. (i) Smith, S. R.; Leckie, S. M.;
Holmes, R.; Douglas, J.; Fallan, C.; Shapland, P.; Pryde, D.; Slawin, A.
M. Z.; Smith, A. D. Org. Lett. 2014, 16, 2506−2509. (j) Belmessieri,
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Chem.Eur. J. 2014, 20, 9762−9769. (k) Morrill, L. C.; Stark, D. G.;
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C.; Shapland, P.; O’Riordan, T. J. C.; Smith, A. D. Org. Biomol. Chem.
2014, 12, 9016−9027.
this laboratory is directed toward developing new applications
of isothioureas in catalysis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all novel
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M. Z.;
O’Riordan, T. J. C.; Smith, A. D. Angew. Chem., Int. Ed. 2013, 52,
11642−11646.
AUTHOR INFORMATION
Corresponding Author
■
(9) (a) Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem.Eur. J. 2010,
16, 1968−1972. (b) Liu, H. M.; Zhang, Q. M.; Wang, L. M.; Tong, X.
F. Chem. Commun. 2010, 46, 312−314. (c) Jiang, X.; Liu, L.; Zhang,
P.; Zhong, Y.; Wang, R. Angew. Chem., Int. Ed. 2013, 52, 11329−
11333.
*E-mail: ads10@st-andrews.ac.uk.
Notes
The authors declare no competing financial interest.
(10) See Supporting Information for Michael addition−lactamization
reaction optimization.
ACKNOWLEDGMENTS
■
(11) For selected methods where acidifying groups are required for
related eliminations, see: (a) Donohoe, T. J.; Fishlock, L. P.;
Procopiou, P. A. Org. Lett. 2008, 10, 285−288. (b) Donohoe, T. J.;
Fishlock, L. P.; Procopiou, P. A. Synthesis 2008, 2665−2667.
(12) For processes involving elimination of a sulfoxide to generate
pyridones, see: (a) Nishimura, T.; Unni, A. K.; Yokoshima, S.;
Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 418−419. (b) Fujii, M.;
Nishimura, T.; Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett.
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(13) For examples of N- to O-sulfonyl transfers, see: (a) Hamer, M.;
Lira, E. P. J. Heterocycl. Chem. 1972, 9, 215−218. (b) Chou, S. S. P.;
Wang, H. C.; Chen, P. W.; Yang, C. H. Tetrahedron 2008, 64, 5291−
5297. (c) Mertens, M. D.; Pietsch, M.; Schnakenburg, G.; Gutschow,
M. J. Org. Chem. 2013, 78, 8966−8979. (d) Fu, Z.; Jiang, K.; Zhu, T.;
Torres, J.; Chi, Y. R. Angew. Chem., Int. Ed. 2014, 53, 6506−6510.
(14) Synthesis of alkyl 2-[aryl(tosylimino)methyl] acrylates contain-
ing electron-withdrawing substituents within the aryl substituent
proved difficult in our hands and so are not reported in this
manuscript.
We thank the Royal Society (ADS), Syngenta/EPSRC (DGS),
and the EPSRC National Mass Spectrometry Facility at
Swansea University.
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