Isothiourea-mediated one-pot synthesis of functionalized pyridines

Article abstract of DOI:10.1002/anie.201306786

Acids to bases: The synthesis of 2,4,6-trisubstituted pyridines from (phenylthio)acetic acid and a range of α,β-unsaturated ketimines is reported. This process proceeds by intermolecular Michael addition/ lactamization, thiophenol elimination, and N- to O

Full text of DOI:10.1002/anie.201306786

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Angewandte
Communications
DOI: 10.1002/anie.201306786
Heterocycles
Hot Paper
Isothiourea-Mediated One-Pot Synthesis of Functionalized Pyridines**
Daniel G. Stark, Louis C. Morrill, Pei-Pei Yeh, Alexandra M. Z. Slawin,
Timothy J. C. OꢀRiordan, and Andrew D. Smith*
Pyridines are an extremely privileged heterocyclic class
commonly found in natural products and functional materials.
They are also important building blocks in both the agro-
chemical and pharmaceutical industries.[1] Consequently,
a vast array of synthetic methods has been successfully
developed to access these useful molecules.[2] Despite many
recent advances, novel methods for the synthesis of highly
functionalized pyridines in a selective and high yielding
manner from accessible starting materials remains an impor-
tant goal within the synthetic community.[3]
Following the demonstration by Romo and co-workers of
generating ammonium enolates[4] from carboxylic acids,[5] we
have shown that isothioureas[6,7] catalyze the intermolecular
Michael addition/lactonization/lactamization of arylacetic
acids and electron-deficient Michael acceptors.[8] To expand
Scheme 1. Proposed strategy for functionalized pyridines. LB=Lewis
this mode of activation, we questioned whether this method-
ology could be used to access functionalized pyridines.
Conceptually, an isothiourea-catalyzed reaction of an acetic
acid bearing an a-leaving group with a suitably electron-
deficient a,b-unsaturated ketimine 1[9] would result in
Michael addition/lactamization with subsequent elimination
to form the pyridones 2 (Scheme 1).[10] Subsequent N- to O-
sulfonyl migration[11] would allow the pyridines 3 to be
accessed directly in one pot. Importantly, in this process the
activating sulfonyl group on the ketimine would be trans-
formed into a synthetically useful functional handle (the 2-
sulfonate group) in the resultant pyridines, thus allowing
subsequent derivatization into a variety of products.
base.
process. Treatment of 4 with pivaloyl chloride and iPr2NEt
gave the corresponding mixed anhydride in situ. Subsequent
addition of the a,b-unsaturated ketimine 5[13] in the presence
of the isothiourea DHPB (6; 20 mol%) in CH2Cl2 at 08C for
4 hours afforded the pyridine 7 in only 7% yield after
chromatographic purification,[14] despite complete consump-
tion of 5 (Table 1, entry 1). Optimization of this process
showed that a combination of increased temperature and
changing the solvent gave a higher yield of the isolated
pyridine (entries 2–4). The increased temperatures are neces-
sary to promote effective N- to O-sulfonyl migration in this
process, with lower temperatures leading to mixtures of the
intermediate pyridone and desired pyridine. The use of
a microwave reactor led to good product yields (entry 5),
and alternative reaction concentrations or catalysts (8–10)
had a negative effect upon the yield of the isolated product
(entries 6–10). Using 6 and extending the reaction time to
16 h in THF at 808C was determined to be the optimal
reaction conditions, thus giving 7 in 67% yield (entry 10).[15]
The generality of this process was next investigated
(Table 2). Under optimized reaction conditions, this process
tolerates a variety of a,b-unsaturated ketimines. The N-
sulfonyl group (benzenesulfonyl and tosyl) can be altered,
whilst a variety of different esters (methyl, ethyl, and benzyl)
are also tolerated at the b position. Additionally, a range of
aryl groups bearing electron-withdrawing (-NO2, -CN,-CF3),
electron-donating (-OMe, -Me), and halogen (-F, -Cl) sub-
stituents are efficient substrates in this process, along with
alkyl substitution. The functionalized trisubstituted pyridines
7 and 11–21 are formed in moderate to good yields following
the three consecutive synthetic transformations in one pot.
Given the wide interest in the preparation of functional
heterocycles containing a trifluoromethyl unit, this protocol
After initial screening,[12] commercially available (phenyl-
thio)acetic acid 4 was identified as a suitable acid in this
[*] D. G. Stark, L. C. Morrill, P.-P. Yeh, Prof. A. M. Z. Slawin,
Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
Dr. T. J. C. O’Riordan
Syngenta, Jealott’s Hill International Research Centre
Bracknell, RG42 6EY (UK)
[**] We thank the Royal Society (ADS), Syngenta/EPSRC (DGS), and The
Carnegie Trust for the Universities of Scotland (LCM) for funding,
and the EPSRC National Mass Spectrometry Service Centre
(Swansea). The research leading to these results has received
funding from the ERC under the European Union’s 7th Framework
Programme (FP7/2007-2013)/ERC grant agreement no. 279850.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306786.
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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Table 1: Reaction optimization.
Table 3: Reaction scope using trifluoromethyl a,b-unsaturated ketimi-
nes.[a]
Entry
Cat.
Solvent
T [8C]
t [h]
Yield [%][a]
1
2
3
4
6
6
6
6
6
6
8
9
10
6
CH2Cl2
CH2Cl2
1,4-dioxane
THF
THF
THF
THF
THF
THF
THF
0
4
4
16
4
2
4
4
4
4
7
RT
80
80
80[b]
80
80
80
80
80
30
52
49
52
10
13
–
5
6[c]
7
8
9
10
[a] Yield is that of the product isolated after chromatography. [b] 48 h.
Np=Naphthyl, Ts=p-toluenesulfonyl.
36
67
16
[a] Yield of isolated 7 following chromatography. [b] Biotage Initiator with
a program of heating to 808C at maximum power of 150 W. [c] 0.0067m
in the ketimine 5 (typically 0.067m). DBU=1,8-diazabicyclo[5.4.0]undec-
7-ene, DHPB=(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole),
DMAP=4-(N,N-dimethylamino)pyridine, TBD=1,5,7-triazabicyclo-
[4.4.0]dec-5-ene.
a 26 mmol scale using 6 (20 mol%) to generate 5.2 g of
product (51% yield). The pyridine 22 can also be accessed
from the corresponding (Z)-ketimine under standard reaction
conditions in 54% yield. In addition, the isomeric pyridine 33
could be isolated in 40% yield from the corresponding
ketimine after heating for 48 h.[18]
The proposed reaction mechanism proceeds by initial
formation of the mixed anhydride 34 from 4 and pivaloyl
chloride with subsequent N-acylation of DHPB to generate
the corresponding acyl isothiouronium ion 35 (Figure 1).
Deprotonation generates the (Z)-enolate 36, which under-
goes Michael addition with the a,b-unsaturated ketimine 37
and subsequent intramolecular lactamization to generate the
Table 2: Reaction scope.[a]
[a] Yield is that of the product isolated after chromatography.
Np=Naphthyl, Ts=p-toluenesulfonyl.
was extended to the synthesis of 4- and 6-trifluoromethyl-
containing pyridines. Trifluoromethyl-containing a,b-unsatu-
rated ketimines were readily prepared from the correspond-
ing enones and used in this protocol, thus giving pyridines in
acceptable yields (40–66%; Table 3). Variation of the sulfonyl
unit, as well as incorporation of heteroaryl (2-furyl and 2-
thiophenyl) and aryl substituents was explored, with the
incorporation of 3- and 4-bromosubstituted aromatics tar-
geted to allow the possibility of derivatization by cross-
coupling.[16,17] This pyridine-forming protocol is readily appli-
cable to large-scale synthesis, thus forming the pyridine 22 on
Figure 1. Proposed reaction mechanism.
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corresponding dihydropyridinone 38 and regenerate DHPB.
Subsequent elimination of thiophenol gives the pyridone 39,
which undergoes thermally promoted N- to O-sulfonyl
migration to afford the pyridine 40.[19]
Within the literature, sporadic examples of the key N- to
O-sulfonyl rearrangement utilized in this process have been
observed, usually as an undesired nonproductive pathway in
thermally promoted Diels–Alder reactions of sulfonyl pyr-
idones.[11] To understand this process further, a crossover
experiment was performed to determine if the N- to O-
sulfonyl migration process involves an intra- or intermolec-
ular transfer (Scheme 2). Reaction of 4 (1 equiv) with a 50:50
Scheme 3. Product derivatizations. a) HCO2H (3 equiv), Pd(OAc)2
(5 mol%), dppp (5 mol%), Et3N (5 equiv) DMF, 608C, 1 h. b) morpho-
line (10 eq), Et3N (2 equiv), toluene, 1108C, 16 h. c) N-vinylacetamide
(4 equiv), [Pd(dba)2] (5 mol%), dppf (5 mol%), Cy2NMe (3 equiv), 1,4-
dioxane, 1008C, 16 h. d) ArB(OH)2 (2 equiv), Pd(OAc)2 (2 mol%),
BrettPhos (2 mol%), K3PO4·H2O (3 equiv), toluene, 1108C, 2 h. e) 4-
MeOC6H4MgBr, (1.5 equiv), [Pd(dba)2] (2.5 mol%), PinP(O)H
(5 mol%), 1,4-dioxane, 808C, 24 h. f) n-C6H13MgBr (1.5 equiv), FeCl3
(5 mol%), NMP (9 equiv), THF, À108C, 10 min. Boc=tert-butoxycar-
bonyl, Cy=cyclohexyl, dba=dibenzylideneacetone, dppp=1,3-bis(di-
phenylphosphino)propane, NMP=N-methyl-2-pyrrolidone, Pin=pina-
col, THF=tetrahydrofuran.
Scheme 2. Crossover experiment to determine intra- or intermolecular
N- to O-sulfonyl transfer.
from the a,b-unsaturated ketimine 49 (14% overall yield
from commercially available starting materials, Scheme 4).
In conclusion, we have developed an isothiourea-cata-
lyzed, one-pot synthesis of 2,4,6-substituted pyridines bearing
a readily derivatized 2-sulfonate functionality from (phenyl-
thio)acetic acid and range of a,b-unsaturated ketimines. This
process proceeds by intermolecular Michael addition/lactam-
ization, thiophenyl elimination, and N- to O-sulfonyl migra-
tion, wherein the N-sulfonyl activating group within the a,b-
unsaturated ketimine is transformed into a valuable 2-
sulfonate functional handle in the resulting pyridine. Func-
tionalization of this group allows the rapid assembly of both
novel and biologically relevant pyridines. Current research
mixture of the ketimines 41 and 42 under the optimized
reaction conditions led exclusively to the pyridines 24 and 28,
respectively, in a 50:50 mixture, and is consistent with
intramolecular N- to O-sulfonyl transfer from an intermediate
pyridone being involved within this process.
The synthetic utility of the newly installed 2-sulfonate
functional handle was next demonstrated through a series of
product derivatizations to install H, aryl, heteroaryl, alkyl,
and amino substituents (Scheme 3). For example, 22 can be
reduced to give the 2,4-substituted pyridine 43 in 89%
yield,[20] and it also readily undergoes SNAr with morpholine
to give 44 in 85% yield.[21,22] The pyridine substrates are
compatible with traditional cross-coupling methodologies,
thus leading to diverse 2,4,6-substituted pyridines. For exam-
ple, 22 undergoes a Mizoroki–Heck reaction with N-vinyl-
acetamide to afford the pyridine 45 in 76% yield,[23] Suzuki
coupling to give 46 in 81% yield,[24,25] and Kumada cross-
coupling to give 47 in 66% yield.[26] In addition to sp2–sp2
coupling reactions, iron-catalyzed sp2–sp3 coupling of 22 with
n-hexylmagnesium bromide gives 48 in 74% yield.[27,28]
Finally, the utility of this approach for the synthesis of
medicinally relevant pyridine-containing molecules was illus-
trated. For example, the pyridine 50, which possesses activity
as a COX-2 inhibitor (< 0.5 mm activity, > 100 fold selectivity
for COX-2 versus COX-1)[29] for the treatment of depressive
disorders, can be made in 49% yield over two synthetic steps
Scheme 4. Rapid assembly of the biologically active pyridine 50.
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Received: August 2, 2013
Published online: September 17, 2013
Keywords: cyclization · heterocycles · isothiourea · Lewis base ·
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organocatalysis
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[12] Initially, bromo- and chloroacetic acid were tested in this
protocol although neither resulted in any conversion into the
pyridine 7.
[13] All ketimines were prepared in three steps from commercially
available starting materials by established literature methods.
See the Supporting Information for full details.
[14] The structure of 7 was unambiguously confirmed by X-ray
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obtained free of charge from The Cambridge Crystallographic
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afford the desired pyridine products, but instead led to isolable
dihydropyridinones or pyridones. See the Supporting Informa-
tion for details.
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[19] At the moment we cannot unambiguously distinguish between
the N-acylation/deprotonation mechanism to generate 36 as
depicted in Figure 1 and the alternative process which proceeds
by ketene formation and addition of DHPB.
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full details.
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