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R
R
OH
N
O
N
O
N
I
21c, g, h
(i)
1
N
N
N
(ii)
19
20
CF3
flow
(iv)
HO
16i
(iii)
c
R = 4-Cl
R = 4-F
R
g
h
i
R = 4-CN
R = 4-CF3
O
4
N
Scheme 5. Synthesis of annulated aryl pyridines 4c, g–i in flow by ihDA/rDA reaction from pyrimidines 1c, g–i. Reagents and conditions: (i) 3-bromo-propyne, NaH, THF,
0 ? 50 °C, 21 h, 86%; (ii) Compound 1c: 21c, piperidine, copper(I) iodide, PdCl2(PPh3)2, rt, 3 h, 79%; Compound 1g: 21g, NEt3, copper(I) iodide, PdCl2(PPh3)2, toluene, 50 °C, 4 h,
49%; Compound 1h: 21h, NEt3, copper(I) iodide, PdCl2(PPh3)2, toluene, rt, 18 h, 98%; (iii) Compound 1i: (a) methane sulfonyl chloride, NEt3, THF, 0 °C, (b) NaI, 16i, KOtBu, THF,
0 ? rt, 18 h, 21%; (iv) flow synthesis, toluene containing 1% (v/v) pentan-3-one, 310 °C, 30 min, 4c: 37%, 4g: 49%, 4h: 89% and 290 °C, 45 min, 4i: 69%.
(Table 1).4 The influence of the substituents on the aromatic ring
was not directly obvious as both 2-fluoro (18a) and 3-fluoro
(18b) substituted pyrimidines provided very similar yields of the
corresponding cycloalka[c]pyridines. However, the slightly lower
yields observed for the 4-chloro (18c) and 4-trifluoromethoxy
(18e) derivatives can be rationalized by the electron-withdrawing
nature of these substituents, which deactivate the acetylenic die-
nophile.12 The unusually low yield in the case of 4-methylphenyl
substituted pyridine 18d was most likely due to instability at ele-
vated temperatures. It is important to note that after the initial
cycloaddition, the more electronically rich moiety (in this case
HCN) is extruded from the tricyclic product, giving rise exclusively
to isomers 18a–e.4,11 All ihDA/rDA reactions were run on a home-
made flow reactor system built from commercially available and
cost-effective components.13 The crude reaction stream was col-
lected and purged by a stream of nitrogen to liberate any HCN
gas through two subsequent wash bottles equipped with a mixture
of sodium hydroxide and sodium hypochlorite (bleach). This proce-
dure enabled to trap the majority of released HCN gas and to run
the process safely even at a larger scale.14 The spectator chlorine
atoms in the bicyclic pyridines 18a–e were subsequently removed
by hydrogenation using an H-CubeÒ system, providing facile access
to the targeted 5-aryl substituted dihydrofuran-annulated pyri-
dines 4a–e.
In order to avoid reductive removal of the two chlorine atoms in
the pyridine core in example 18c, we explored a slightly modified
approach in which the ihDA/rDA reaction was conducted on pyrim-
idine acetylenes devoid of chlorine atoms on the heterocyclic core
(Scheme 5). Thus, alkylation of pyrimidine alcohol 19 with 3-bromo-
prop-1-yne yielded pyrimidine alkyne 20.15 Sonogashira coupling of
the acetylene functionality in 20 with aryl iodide 21c afforded the
corresponding alkyne pyrimidine 1c. Interestingly, the ihDA/rDA
reaction of this substrate yielded the 4-chloropyridine 4c in a mod-
est yield of only 37%, and thus is comparable to the yield obtained
following the two-step process depicted above. In order to evaluate
the scope of this process further, we explored the ihDA/rDA reaction
on additional substrates 1g–i. Gratifyingly, the 4-fluoro (1g), 4-
cycano (1h), and 4-trifluoromethyl (1i) pyrimidine derivatives re-
acted to provide the desired annulated pyridines 4g–i in good to
excellent yields. In the synthesis of 4-trifluoromethyl pyridine 4i
some decomposition was observed at 310 °C, accordingly the reac-
tion temperature was reduced to 290 °C with concomitant exten-
sion of the reaction time to 45 min. The preparation of
dihydrofuran annulated pyridines 4 from parent pyrimidines 1 is
thus a viable synthetic alternative to the process depicted in
Scheme 4 employing dichloropyrimidines.
After successful preparation of a number of dihydro-furan pyr-
idines 4 we also explored the utility of this sequence in the prepa-
ration of annulated lactone 5 and lactam pyridines 6, respectively
(Scheme 6). To access the required starting materials, pyrimidine
carboxylic acid 22 was coupled with phenylprop-2-yn-1-ols 16c,
i, and j to provide the pyrimidine esters 2c, i, and j. Executing
the ihDA/rDA reaction in flow on these latter substances afforded
the lactone products 5c, i, and j in fair yields of 32%, 31%, and
35%. Notably, considering the amount of starting material recov-
ered from these reactions, the yields of 5c, i, and j are 63%, 76%,
and 53%, respectively (Table 1). The moderate outcome in terms
of yield for these lactones can be ascribed to a generally lower
reactivity of ester substrates in the ihDA/rDA reaction. In a similar
fashion, the analogous amides 3c, i, and j were prepared from the
corresponding propynylamines 23c, i, and j, and pyrimidine car-
boxylic acid 22. Interestingly, these substrates afforded in the
ihDA/rDA reaction the annulated lactam pyridines 6c, i, and j in
all cases in better yields of 50%, 53%, and 84%, respectively, com-
pared with their lactone counterparts, demonstrating the higher
reactivity of amide substrates (Table 1). The flow cyclization reac-
tions for all lactone and lactam derivatives were conducted in dry,
deoxygenated toluene at a slightly lower temperature of 290 °C
and slightly increased reaction time of 45 min, both of which
helped to minimize side reactions.11
In summary, we have developed a new advantageous process
that allows the controlled continuous flow synthesis of a number
of fused bicyclic 5-aryl substituted pyridine derivatives that can
serve as useful building blocks in medicinal chemistry. Impor-
tantly, pressurized flow reactors enable the use of toluene as the
reaction solvent, limit the risks and hazards associated with the
use of traditional high-temperature and high-pressure batch
equipment, and thus enabled the re-exploration of this underuti-
lized reaction. A further important advantage of conducting these
reactions in flow is the bypassing of any dangerous built-up during
Martin, Rainer E.
