The Guareschi-Thorpe Cyclization Revisited - An Efficient Synthesis of Substituted 2,6-Dihydroxypyridines and 2,6-Dichloropyridines

Article abstract of DOI:10.1055/s-0037-1609685

DBU as base is key in a practical modified Guareschi-Thorpe cyclization of β-keto esters and 2-cyanoacetamide to allow the synthesis of substituted pyridones in good to excellent yields. The chlorination of DBU salts of pyridones with POCl ₃ in the presence of a quaternary ammonium salt under standard atmospheric reflux conditions as opposed to the typical pressure equipment led to high yields of substituted 2,6-dichloropyridines.

Full text of DOI:10.1055/s-0037-1609685

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
M. C. Eriksson et al.
Letter
Synlett
The Guareschi–Thorpe Cyclization Revisited – An Efficient
Synthesis of Substituted 2,6-Dihydroxypyridines and
2,6-Dichloropyridines
Magnus C. Eriksson*a
O
O
R
Xingzhong Zenga
Jinghua Xua
Diana C. Reevesa
Carl A. Busaccaa
Vittorio Farinab
Chris H. Senanayakea
CN
O
R
OR1
NH2
DBU
+
n-PrOH, reflux
DBUH+O–
N
H
NC
O
R
R = aryl, alkyl, fluoroalkyl
CN
Cl
POCl3, BnMe3NCl
toluene, reflux
11 examples
39–95% yield
Cl
N
a Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Old Ridgebury Road/P. O. Box 368,
Ridgefield, Connecticut 06877-0368, USA
magnus.eriksson@boehringer-ingelheim.com
b Janssen Pharmaceuticals PRD, Turnhoutseweg 30, 2340
Beerse, Belgium
Received: 26.12.2017
Accepted after revision: 22.03.2018
Published online: 09.05.2018
available via chlorination of the dihydroxy pyridine 4 or the
potassium salt of 9b (Scheme 1 and Scheme 2). To support
our research and development programs, we had particular
interest in pyridine derivatives with fluorinated side chains,
and for our development work on 1 we needed access to
larger quantities of 2,6-dichloropyridine 10b.2
The original discovery route to 4 involved the cyclocon-
densation of a difluoro alkynoate 5 and 2-cyanoacetamide3
using ethanolic potassium hydroxide to afford the pyridone
potassium salt of 9b in 77% yield (Scheme 2). Whereas this
protocol was suitable for small scale, the synthesis of 5
starting from methyl propiolate could not be conveniently
scaled up due to cryogenic reaction conditions (e.g., –78 °C)
and multiple column purifications.
DOI: 10.1055/s-0037-1609685; Art ID: st-2017-r0923-l
Abstract DBU as base is key in a practical modified Guareschi–Thorpe
cyclization of β-keto esters and 2-cyanoacetamide to allow the synthe-
sis of substituted pyridones in good to excellent yields. The chlorination
of DBU salts of pyridones with POCl3 in the presence of a quaternary
ammonium salt under standard atmospheric reflux conditions as op-
posed to the typical pressure equipment led to high yields of substitut-
ed 2,6-dichloropyridines.
Key words fluoroalkyl compounds, β-keto esters, DBU, pyridines,
chlorination, Guareschi–Thorpe cyclization
In the course of our research program on IκB kinase β
(IKKβ) inhibitors for the treatment of immunological
diseases,1 such as rheumatoid arthritis, compound 1 was
identified as a lead candidate for development. Retro-
synthetically, 1 is readily disconnected into three main
fragments, thioacetamide 2, sulfonylpiperidine 3 and the
key intermediate dichloropyridine 10b, which in turn is
Although the cyclization of alkynoate 5 with 2-cyanoac-
etamide proceeded in good yield, the subsequent chlorina-
tion of the potassium salt of 9b using POCl3 and Me4NCl to
dichloropyridine 10b required pressure vessels for high
conversion and yield. Chlorination under atmospheric re-
flux conditions gave incomplete reactions and low yields.
We therefore sought to develop a more practical synthesis
F
F
F
F
NH2
CN
Cl
O
NH
+
+
CONH2
HS
NH2
MeO2S
S
N
N
Cl
N
10b
1
2
3
MeO2S
F
F
CN
OH
HO
N
4
Scheme 1 Retrosynthetic analysis of compound 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
M. C. Eriksson et al.
Letter
Synlett
F
F
O
O
KOH
CN
O
MeO
CN
+
H2N
EtOH, r.t.
F
K+O-
N
F
5
77%
H
9b K-salt
Jones
oxidation
BuLi, then
n-propanal
O
O
O
DAST
CH2Cl2
MeO
MeO
MeO
acetone
–78 °C, THF
O
OH
Scheme 2 Discovery synthesis of 5; DAST = diethylaminosulfur trifluoride
of dihydroxypyridine 4 or its salt as well as a chlorination
procedure that would avoid the use of pressure equipment.
In this letter, we report the discovery and development of a
DBU-promoted cyclocondensation of β-keto esters and 2-
cyanoacetamide in high yield and the conversion of the re-
sulting DBU salt of 2,6-dihydroxypyridines into the corre-
sponding 2,6-dichloropyridines by chlorination under nor-
mal atmospheric reflux conditions.
Among the many methods available to synthesize pyri-
dines,4 the Guareschi–Thorpe synthesis5 is attractive be-
cause it features the condensation of a simple β-keto ester
(or a β-diketone) with 2-cyanoacetamide to furnish a sub-
stituted pyridone (i.e., 2,6-dihydroxypyridine), as exempli-
fied with ethyl acetoacetate in Scheme 3.
Table 1 Synthesis of γ,γ-Difluoro β-Keto Esters 8 from α-Keto Esters 6
via Fluorination/Claisen Condensation
O
O
O
O
DAST or
NaH
THF
Deoxo-Fluor®
O
R
R
R
OR1
OR1
OR1
+
CH2Cl2
OR1
F
F
F
F
O
6
7
8
α-Keto ester 6
α,α-Difluoro ester 7 γ,γ-Difluoro β-keto ester 8
–
7a R = Me, R1 = Eta
7b 89%
8a R1 = Et, 77%
8b R1 = n-Bu, 89%
8c R1 = Et, 65%
6b R = Et, R1 = n-Bu
6c R = Ph, R1 = Et
a Commercially available.
7c 90%
CN
O
CN
O
base
strong inorganic base, e.g., KOH in alcohol solvent.8 When
these conditions were attempted to synthesize 4 from 8b (R
= Et and R1 = n-Bu), yields in the 10–30% range were usually
obtained. Even after some optimization work, only 43%
yield was obtained after heating in n-butanol at 110 °C for
20 h, Scheme 4.
O
O
+
solvent
HO
N
H2N
OEt
H
Scheme 3 The Guareschi–Thorpe cyclization with a β-keto ester
Given the ready availability of β-keto esters and/or the
relative ease of their synthesis, it was decided to investigate
this method to make pyridines such as 4. The γ,γ-difluoro
β-keto esters were not commercially available and were
synthesized via Claisen condensations of the fluorinated es-
ters as shown in Table 1.
Commercially available α-keto esters 6 were fluorinated
with either diethylaminosulfur trifluoride (DAST) or bis(2-
methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®) in di-
chloromethane using published procedures to obtain α,α-
difluoro esters 7 except in the case of 7a (R = Me; R1 = Et)
which was available from Oakwood. The Claisen condensa-
tion of 7 was conducted with butyl acetate or ethyl acetate
in the presence of sodium hydride to afford γ,γ-difluoro-β-
keto esters 8.6
F
F
O
O
CN
O
KOH
CN
O
OBu
+
H2N
EtOH or BuOH, reflux
F
F
K+O–
N
H
10–43%
8b
Scheme 4 Initial screening results for the Guareschi–Thorpe
cyclization of 8b under typical conditions
During our search for an improved cyclization proce-
dure we came across a paper by Bobbitt and Scola where
piperidine9 was used to cyclize ethyl acetoacetate and 2-cy-
anoacetamide in 95% yield in refluxing methanol. When
this method was applied to commercially available ethyl
trifluoromethylacetoacetate, a 61% yield of the pyridone
piperidine salt was obtained after reflux in methanol. How-
ever, in stark contrast, the yield for 8b was only 18% and for
8a (R = Me and R1 = Et) it was 67%.
The Guareschi–Thorpe cyclization of β-keto esters and a
carbonyl compound such as 2-cyanoacetamide to pyridones
occurs under enolizing reaction conditions and the mecha-
nism has been studied.7 Typical conditions are to use a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
M. C. Eriksson et al.
Letter
Synlett
The pKa’s for 8a and 8b were calculated: 8.18 for 8a-enol,
8.19 for 8b-enol, 8.93 for 8a-keto, and 8.91 for 8b-keto tau-
tomers. Given that they were virtually identical,10 we were
somewhat baffled by the difference in cyclization outcome.
Our hypothesis at the time was that the success of the cy-
clization may be influenced by the choice of solvent and ke-
to/enol tautomerism of the β-keto ester so this ratio was de-
termined by 1H NMR at room temperature for 8b in different
solvents in the absence of base and is shown in Table 2.
Table 3 Cyclization of 8b in DMSO-d6 Using Organic Bases by 1H NMR
Spectroscopy
F
F
O
O
CN
O
base
CN
OH
+
OBu
DMSO-d6, 100 °C
H2N
F
F
MO
N
8b
M = BH+
Base
pKa
Pyridone observed (%)a
Table 2 Keto/Enol Ratios by 1H NMR Analysis in Selected Solvents
DABCO
DMAP
DIPEA
DBU
8.6
9.7
<5
<5
OH
O
O
O
10.4
13.2
0
+
OBu
OBu
F
F
F
F
ca. 20
a The conversion was estimated from comparison of known product peaks
and unreacted starting material in the 1H NMR spectra.
Solvent
Keto form
Enol form
CDCl3
50
75
43
33
50
25
57
67
Table 4 Cyclization of 8a and 8b in Isopropanol-d8 or n-Propanol
Using Organic Bases
DMSO-d6
THF-d8
MeOH-d4
F
R
F
O
O
CN
O
base
CN
OH
R
+
OBu
As expected, the ratio of keto form vs. enol form of the
β-keto ester depends on the solvent. In CDCl3, the ratio is
1:1. In DMSO, the ratio is 3:1, and in MeOH it is only 1:2. To
challenge the typical choice of solvent (e.g., alcohol) and its
influence on the keto/enol ratio, the cyclization was studied
ROD (ROH), 90 °C
H2N
F
F
MO
N
M = BH+
Base
pKa
R = Et (8b)
R = Me (8a)
yield (%) of pyridonea yield (%) of pyridoneb
1
by H NMR spectroscopy in DMSO/KOH. Complete forma-
morpholine
DIPEA
8.3
0
10
18
84
11
79
67
99
tion of the potassium enolate salt of the β-keto ester was
observed within 2 h at 85 °C without any conversion into
the pyridone. About 25% conversion into pyridone was ob-
served after 20 h at 85 °C. The reaction appeared more slug-
gish in DMSO than in n-butanol and isolation of the product
as the dihydroxypyridine was not successful.
10.4
11.1
13.2
piperidine
DBU
a Reactions in ROD = isopropanol-d8.
b Reactions in ROH = n-propanol.
We next turned our attention to organic bases in DMSO
1
and studied the cyclization by H NMR spectroscopy using
The reaction was then conducted on multigram scale in
n-butanol with DBU as the base and gave a smooth cycliza-
tion to the DBU salt of the pyridone after 10 h at 110 °C. In
this case, the corresponding dihydroxy pyridine was isolat-
ed as a solid by filtration after acidification with aq. HCl and
stirring in methyl tert-butyl ether/H2O mixture (Scheme 5).
The cyclization promoted by DBU appears general for
alcohol solvents. Complete conversion was obtained in re-
fluxing n-butanol, n-propanol, isopropanol, or ethanol. Pro-
panol was used for all reactions to get faster reaction rates,
and the DBU salts of the corresponding pyridones were iso-
lated by precipitation and filtration from propanol/methyl-
cyclohexane (Scheme 6).
As seen from Scheme 6 the cyclization is general for a
wide range of alkyl, fluoro alkyl, and aryl β-keto esters. In-
terestingly, the yields for aryl β-keto esters are lower. In the
case of ethyl benzoyl acetate the yield under our standard
conditions (A) was only 31%. The use of excess DBU gave
32% yield whereas the yield jumped to 74% when excess cy-
DMAP, DABCO, DIPEA, and DBU (Table 3).
A correlation between base strength and pyridone for-
mation was observed with DBU, the only base to provide
any significant amounts of cyclization product after heating
for 18–80 h. With these results in hand we returned to
1
study the cyclization in alcohol solvent by H NMR in iso-
propanol-d8 using morpholine, piperidine, DIPEA, and DBU
(Table 4). Although a 79% yield of cyclized product was ob-
tained for 8a using DIPEA in propanol, only 10% was ob-
served for 8b. However, a significant increase in yield for 8b
from 18% with piperidine to 84% with DBU was observed,
thus confirming the advantage of alcohol solvent over
DMSO for the cyclization. Similarly, in the case of 8a, a yield
increase from 67% with piperidine to 99% with DBU was
noted in n-propanol.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
M. C. Eriksson et al.
Letter
Synlett
F
F
CN
O
O
F
F
HCl
DBU
+
CN
OH
CN
OH
OBu
H2N
O
MTBE/H2O
BuOH
110 °C, 10 h
F
F
8b
MO
N
HO
N
>95%
>70%
M = DBUH+
Scheme 5 Cyclization in n-butanol using DBU as base
anoacetamide was used in addition to excess DBU (B). In
contrast, two recent literature procedures report 93%8a and
90%12 yield of the corresponding pyridone, using KOH in re-
fluxing ethanol for 15 min and catalytic (1 mol%) DABCO in
refluxing ethanol for 1.5 h, respectively. Our attempts to re-
produce these protocols were disappointing. The KOH/etha-
nol method gave 5% yield, and the catalytic DABCO proce-
dure gave no pyridone at all. An older patent procedure that
used KOH/ethanol reported 42% isolated yield after 20 h re-
flux,13 suggesting that more forcing conditions are neces-
sary in the case of aryl β-keto esters.
With a successful method for pyridine formation in
hand, our attention turned to the chlorination conditions
for the synthesis of 10. Chlorination of hydroxypyridines
and/or pyridones are typically performed using phosphorus
oxychloride (POCl3) at elevated temperature, e.g. >106 °C,
the boiling point at atmospheric pressure. Therefore, this
transformation typically needs to be performed under pres-
sure and sometimes with additives in order to achieve high
conversion and yield of the desired product. Our initial syn-
thesis of 10b involved the chlorination of the potassium salt
of 9b in a Parr pressure vessel in the presence of large ex-
cess POCl3 and one equivalent Me4NCl to give 85–90% iso-
lated yield. When this reaction was repeated at atmospheric
pressure at reflux temperature in a flask, the conversion
was lower and the yield only 65%. Interestingly, the chlori-
nation of DBU salt 9f under reflux conditions in the pres-
ence of Me4NCl gave 88% isolated yield (Table 5). The yield
in this case without Me4NCl was 50% whereas 91% was ob-
tained in the presence of BnMe3NCl as additive.
R
CN
O
CN
O
O
O
DBU
+
R
OR1
DBUH+O–
N
H
PrOH, 90–100 °C
method A or B
H2N
8
9
F
F
F
F
n-Pr
CN
O
CN
CN
O
Table 5 Effect of Ammonium Salts on Chlorination of 9fa
DBUH+O–
N
DBUH+O–
N
O
DBUH+O–
N
H
H
H
9a (95%)
9b (87%)
9c (67%)
CN
O
CN
Cl
F
F
chlorination conditions
reflux
Ph
CF3
DBUH+O–
N
H
Cl
N
CN
O
CN
O
CN
O
9f
10f
DBUH+O–
N
DBUH+O–
N
H
DBUH+O–
N
H
H
9d (89%)
9e (90%)
9f (90%)
Conditions
Isolated yield (%)
OMe
F
F
Ph
POCl3/none
50
88
91
CN
O
CN
O
CN
O
POCl3/Me4NCl
POCl3/BnMe3NCl
DBUH+O–
N
H
DBUH+O–
N
H
DBUH+O–
N
H
aReaction conditions: 1.0 equiv 9f, 4.0 equiv POCl3, 1.0 equiv additive, 8 h
reflux.
9g (93%)
9h (95%)
9i (31%)
OMe
NO2
The hydrolysis of excess POCl3 can be slow under certain
conditions potentially leading to unsafe operating condi-
tions, especially on scale. A detailed study on the safe hy-
drolysis of POCl3 has been published.14 In the current chlo-
rination reaction, water was added slowly to control the
exotherm to <40 °C during quench. Too rapid water addi-
tion led to an uncontrolled exotherm and partial hydrolysis
of 10. The optimized chlorination conditions were quite
general as can be seen from Table 6.15
Ph
CN
O
CN
O
CN
O
DBUH+O–
N
DBUH+O–
N
DBUH+O–
N
H
H
H
9i method B (74%)
9j method B (46%)
9k method B (39%)
Scheme 6 DBU-promoted cyclization of β-keto esters to pyridine DBU
salts11 Reagents and conditions: Method A: 1.0 equiv ester, 1.0–1.05
equiv 2-cyanoacetamide, 1.05 equiv DBU, 0.5 M in n-propanol, 16 h at
95 °C. Method B: 1.0 equiv ester, 3.0 equiv 2-cyanoacetamide, 3.0
equiv DBU, 0.5 M in n-Propanol, 16 h at 95 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
M. C. Eriksson et al.
Letter
Synlett
Table 6 Chlorination of 9 in the Presence of Benzyltrimethylammoni-
(5) (a) Guareschi, I. Memorie Reale Accad. Sci. Torino II 1896, 46, 7.
(b) Guareschi, I. Memorie Reale Accad. Sci. Torino II 1896, 46, 11.
(c) Guareschi, I. Memorie Reale Accad. Sci. Torino II 1896, 46, 25.
See also: (d) Guareschi, I. Ber. Dtsch. Chem. Ges. 1896, 29, 654.
(e) Thole, F. B.; Thorpe, J. F. J. Chem. Soc., Trans. 1911, 99, 422.
(f) Guareschi, I. Atti R. Accad. Sci. Torino 1900, 36, 443.
um Chloridea
R
R
POCl3 (4 equiv)
BnMe3NCl (1 equiv)
CN
O
CN
Cl
reflux
DBUH+O–
N
H
(6) Representative Procedure for the Formation of Alkyl γ,γ-
Difluoro β-Keto Esters 8
Cl
N
9
10
Sodium hydride (7.43 g, 60%, 1.25 equiv, 185.6 mmol) was
charged to a 500 mL flask fitted with mechanic stirrer, thermo-
couple, reflux condenser, and nitrogen outlet. Tetrahydrofuran
(150 mL) was added, and the mixture stirred at room tempera-
ture. Butyl 2,2-difluorobutyrate (7b, 30 g, 89.2 wt%, 1.0 equiv,
148.5 mmol) was followed by butyl acetate (26.4 mL, 200.5
mmol, 1.35 equiv) The resulting white slurry was stirred under
nitrogen at 25 °C for 5 min and then at 40 °C for 6 h. GC analysis
indicated 90% conversion. Additional sodium hydride (1.188 g,
60%, 0.2 equiv) and butyl acetate (5.87 mL, 200.5 mmol, 0.3
equiv) were added. GC analysis 1 h later showed full conversion.
The reaction mixture was cooled to room temperature and
quenched carefully with aq. NH4Cl (150 mL) followed by conc.
HCl (16.0 mL, 1.29 equiv) to adjust pH to 5–6. The layers were
separated and the light yellow aqueous layer was extracted with
EtOAc (100 mL). The combined red-orange organic layer (261.2
g, ca. 300 mL) was concentrated on Rotavapor at 60 °C to give an
orange oil that was purified by fractional distillation under
reduced pressure (bp 62–69 °C, 5 mmHg) to give 8b as a color-
less oil (29.5 g, 89% yield). 1H NMR indicated a mixture of about
1:1 of the keto ester and the enol ester. LC–MS (medium polar
method), Rt = 1.08 min, MH+ (100%) = 223.0. 1H NMR (500 MHz,
CDCl3): δ = 11.98 (s, 1 H), 5.50 (s, 1 H), 4.19 (t, J = 6.75 Hz, 2 H),
3.70 (s, 3 H), 2.01–2.18 (m, 2 H), 1.6–1.71 (m, 2 H), 1.32–1.45
(m, 2 H), 1.01 (t, J = 7.69 Hz, 3 H), 0.95 (t, J = 7.48 Hz, 2 H). 13C
NMR (125 MHZ, CDCl3): δ = 193.62, 172.30, 167.47 (m), 165.91,
(121.26, 120.74), (118.84, 118.24), (116.43, 115.74), 90.33 (t, J =
5.21 Hz), (65.64, 64.82), 43.45, (30.63, 30.43), 27.99 (t, J = 25.4
Hz), 25.75 (t, J = 23.2 Hz), (19.09, 18.95), 13.62, 6.08 (t, J = 5.03
Hz), 5.39 (t, J = 5.51 Hz). 19F NMR (470 MHz, CDCl3): δ: –108.23,
–108.32.
Pyridone salt
Isolated yield (%)b
9a
9b
9e
9f
83
97
89
91
85
95
9i
9k
a Reaction conditions: 1.0 equiv pyridine salt 9, 4.0 equiv POCl3, 1.0 equiv
BnMe3NCl, 8 h reflux.
b Isolated yields after column purification.
To summarize, a practical synthesis of substituted 2,6-
dihydroxypyridines was developed. The use of DBU as base
was instrumental to achieve high yields, and the products
were isolated as the corresponding DBU salts. In addition, a
modified chlorination under standard reflux conditions of
the DBU salts was established that avoid the use of special
pressure equipment while still giving good to excellent
yields of substituted 2,6-dichloropyridines.
Acknowledgment
We are grateful to Dr. Jörg Bentzien for calculation of pKa’s for β-keto
esters.
(7) Mišić-Vuković, M.; Radojković-Veličković, M. J. Chem. Soc.,
Perkin Trans. 2 1992, 1965.
Supporting Information
(8) (a) Faty, R. A. M.; Youssef, A. M. S. Curr. Org. Chem. 2009, 13, 1577.
(b) Sarkar, T. K.; Panda, N.; Basak, S. J. Org. Chem. 2003, 68, 6919.
(c) Portnoy, S. J. Org. Chem. 1965, 30, 3377. (d) Roch, J.; Muller, E.;
Narr, B.; Nickl, J.; Haarmann, W. DE 264375, 1978. (e) Grozinger,
K. G.; Hargrave, K. D.; Adams, J. US 5200522, 1993.
(9) (a) Bobbitt, J. M.; Scola, D. A. J. Org. Chem. 1960, 25, 560.
(b) Stevens, J. R.; Beutel, R. H. J. Am. Chem. Soc. 1943, 449.
(c) Ziener, U.; Breuning, E.; Lehn, J.-M.; Wegelius, E.; Rissanen,
K.; Baum, G.; Fenske, D.; Vaughan, G. Chem. Eur. J. 2000, 6, 4132.
(10) The predicted pKa for R = CH3CF2 and R = C8H17CF2 is 8.95±0.46
according to SciFinder literature search. No predicted pKa for
R = CH3CH2CF2 is available but it is reasonable to expect that it
would be similar.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609685.
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u
p
p
ortioInfgrmoaitn
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p
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ortiInfogrmoaitn
References and Notes
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Chen, Z.; Cywin, C.; Emeigh, J.; Foerst, M.; Ginn, J.; Hrapchak,
M.; Hickey, E.; Hao, M.-H.; Kashem, M.; Li, J.; Liu, W.; Morwick,
T.; Nelson, R.; Marshall, D.; Martin, L.; Nemoto, P.; Potocki, I.;
Liuzzi, M.; Peet, G. W.; Scouten, E.; Stefany, D.; Turner, M.;
Weldon, S.; Zimmitti, C.; Spero, D.; Kelly, T. A. Bioorg. Med.
Chem. Lett. 2009, 19, 5547. (b) Ginn, J. D.; Sorcek, R. J.; Turner,
M. R.; Young, E. R. R. US 0293533, 2007.
(2) A synthesis of deuterium- and C14-labelled 10b and 1 has been
described, see: Latli, B.; Eriksson, M.; Hrapchak, M.; Busacca, C. A.;
Senanayake, C. H. J. Labelled Compd. Radiopharm. 2016, 549, 300.
(3) Jünemann, W.; Opgenorth, H.-J.; Scheuermann, H. Angew.
Chem., Int. Ed. Engl. 1980, 19, 388.
(11) Representative Procedure for the Cyclization of β-Keto Esters
to Pyridine DBU Salts 9
Butyl 4,4-difluoro-3-ketohexanoate (8b, 11.3 g, 48.1 mmol) was
added to a suspension of 2-cyanoacetamide (4.29 g, 50.5 mmol)
in propanol (50 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU,
7.69 mL, 50.5 mmol) was added and the mixture heated at reflux
for 20 h to afford a dark brown solution. The solution was con-
centrated on Rotavapor to an oil that was stirred at room tem-
perature for 16 h with a ca. 20% propanol/methylcyclohexane
(4) Gilchrist, T. L. Heterocyclic Chemistry; Addison Wesley Longman:
Essex, 1997.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
M. C. Eriksson et al.
Letter
Synlett
(v/v) solution (60 mL) to afford 9b as a light brown solid in 87%
yield (15.2 g); mp 133–135 °C. 1H NMR (500 MHz, DMSO-d6): δ =
10.1 (br s, 1 H), 9.55 (br s, 1 H), 5.13 (s, 1 H), 3.52–3.58 (m, 2 H),
3.48 (t, J = 5.8 Hz, 2 H), 3.26 (t, J = 5.8 Hz, 2 H), 2.62–2.67 (m, 2 H),
2.08–2.23 (m, 2 H), 1.88–1.96 (m, 2 H), 1.56–1.72 (m, 6 H), 0.92
(t, J = 7.4 Hz, 3 H). 13C NMR (125 MHz, DMSO-d6); 165.6, 165.4,
164.3, 149.9 (t, JC-F = 25 Hz), 122.4 (t, JC-F = 243 Hz), 120.3, 96.03 (t,
JC-F = 8.0 Hz), 69.73, 53.40, 47.87, 37.62, 29.53 (t, JC-F = 27 Hz),
28.22, 25.89, 23.29, 18.85, 6.53 (t, JC-F = 5.0 Hz). 19F-NMR
(470 MHz, DMSO-d6); –98.6.
327 mmol) were added to a 100 mL flask fitted with a stir bar
and a reflux condenser connected to an argon bubbler. The
mixture was stirred and heated in an oil bath (120 °C) for about
8 h and then cooled to 20–25 °C. The mixture was diluted with
toluene (200 mL) and quenched by careful slow addition of
water (200 mL), keeping internal temperature <40 °C. The two-
layer mixture was stirred vigorously for about 20 min and the
layers allowed to separate. The aqueous layer was drained and
the small ‘rag’ layer was left with the organic layer. The organic
layer was washed with dilute (4–5 wt%) aq. sodium carbonate
(2 × 200 mL) followed by water (200 mL), leaving any ‘rag’ layer
with the organic. The organic layer was filtered through Celite
and the pad rinsed with toluene (40 mL). The filtrate was con-
centrated to dryness on a Rotavapor to afford 13.4 g (97%) light
brown solid with 99.4 wt% purity. The solid was recrystallized
from 2.5% n-propanol/methylcyclohexane (27 mL, v/v) to afford
11.4 g (83%) light tan solid with 99.9 wt% purity; mp 68–70 °C.
1H NMR (DMSO-d6): δ = 7.98 (s, 1 H), 2.34 (m, 2 H), 1.03 (t,
J = 7.4 Hz, 3 H). 13C NMR (DMSO-d6): δ = 153.7, 153.2, 152.1 (t,
JC-F = 28 Hz), 121.4 (t, JC-F = 7 Hz), 120.9 (t, JC-F = 246 Hz), 112.7,
106.0 (t, JC-F = 3.5 Hz), 29.94 (t, JC-F = 25 Hz), 5.84 (t, JC-F = 5.0 Hz).
19F NMR (DMSO-d6); –97.2.
(12) Heravi, M. M.; Tahershamsi, L.; Oskooie, H. A.; Baghernejad, B.
Chin. J. Chem. 2010, 28, 670.
(13) Roch, J.; Muller, E.; Narr, B.; Nickl, J.; Haarmann, W. DE 264375,
1978.
(14) Achmatowicz, M. M.; Thiel, O. R.; Colyer, J. T.; Hu, J.; Elipe, M. V.
S.; Tomaskevitch, J.; Tedrow, J. S.; Larsen, R. D. Org. Process Res.
Dev. 2010, 14, 1490.
(15) Representative Procedure for the Chlorination of Pyridine
DBU Salts to 2,6-Dichloropyridines 10
5-Cyano-4-(1,1-difluoro-propyl)-6-oxo-1,6-dihydropyridin-2-
olate2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepin-5-ium
(9b, 20.0 g, 54.6 mmol), benzyltrimethylammonium chloride
(10.5 g, 54.6 mmol), and phosphorous oxychloride (30.8 mL,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F