Published on Web 07/31/2007
Direct Synthesis of Pyridine Derivatives
Mohammad Movassaghi,* Matthew D. Hill, and Omar K. Ahmad
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
The pyridine substructure is one of the most prevalent hetero-
observation suggests competitive deprotonation of intermediate 6
(R ) H) when cyclization to heterocycle 4 is slow.
e
cycles found in natural products, pharmaceuticals, and functional
1
materials. Many powerful methodologies for the synthesis of these
heterocycles rely on condensation of amines and carbonyl com-
pounds or cycloaddition reactions.2 Cross-coupling chemistry also
,3
4
allows introduction of substituents to activated heterocycles. Herein
we report a mild, convergent, and single-step procedure for the
5
conversion of readily available N-vinyl and N-aryl amides to the
corresponding substituted pyridines and quinolines, respectively
(
eq 1).
We next examined the direct condensation of enol ethers with
N-vinyl and N-aryl amides (eq 3). While ethyl vinyl ether (3a) could
be used as a π-nucleophile when heating is not required (Table 1,
4p and 4u), we found triphenylsilyl vinyl ether (3b) to provide
superior results in more challenging cases (Table 1, 4v-x). The
use of excess nucleophile can be beneficial and provides an
improved yield of the product (Table 1, 4u). Importantly, the use
of silyl ether 3b in place of ethyl vinyl ether 3a eliminates the
competitive addition of EtOH, generated in conversion of 7 to 4
(eq 3), to the activated intermediate 5. Both acyclic and cyclic
trimethylsilyl enol ethers can be used in direct condensation with
amides (Table 1, 4q-t). However, when desilylation competes with
cyclization of oxonium ion 7 (eq 3), the use of more robust silyl
enol ether derivatives is preferred. Condensation of amide 1a with
enol ether 3e at 23 °C predominantly gave the vinylogous amide 8
Previously we reported a two-step synthesis of pyridines and a
single-step synthesis of pyrimidines from readily available amides.6
These methodologies were made possible in part because of the
recognition of the unique electrophilic activation of amides with
trifluoromethanesulfonic anhydride (Tf
2
were employed in our pyrimidine synthesis using nitriles as
σ-nucleophiles.6b The current study focuses on the direct condensa-
tion of amides 1 with a wide range of π-nucleophiles (2 or 3) to
provide the corresponding pyridine derivatives 4 (eq 1) in a single
step.
6
b
7
2
O) in the presence of
8
-chloropyridine (2-ClPyr) as the base additive. A variety of amides
(
1
eq 4, 78%, 8/4y, >99:1) while heating the reaction mixture at
40 °C for 2 h11 provided the desired quinoline (eq 4, 53%, 4y/8,
>99:1).
We began our studies by investigating the use of alkoxy and
silyloxy acetylenes in direct condensation with amides upon
activation with Tf
2
O and 2-ClPyr.6b Under optimum reaction
conditions, these electron-rich π-nucleophiles provided the desired
pyridine and quinoline derivatives in one step from the correspond-
ing N-vinyl and N-aryl amides (Table 1, 4a-e). Similarly, the use
of ynamide 2d and ynamine 2e readily provided the 4-amino
pyridine derivatives in a single step (Table 1, 4f-l). While phenyl
acetylene was not sufficiently nucleophilic, the more electron rich
derivatives 2f and 2g served as π-nucleophiles in this pyridine
synthesis (Table 1, 4m-o). Importantly, both electron-rich and
electron-deficient N-aryl amides can be condensed with π-nucleo-
philes 2a-g (Table 1, compare 4i and 4j).
Consistent with cyclization of intermediate 7 (eq 3), exposure
of amide 8 to the standard reaction conditions provided <10% yield
of 4y. Whereas the use of triisopropylsilyl ether derivatives was
not optimal due to slow cyclization, the use of tert-butyldimeth-
ylsilyl ethers and microwave irradiation extends this chemistry to
less reactive amide substrates (Table 1, 4y-cc). The use of enol
ethers as the π-nucleophile in conjunction with electron deficient
N-aryl amides (Table 1, compare 4y-aa) in this azaheterocycle
synthesis is less efficient as compared to the use of acetylenic
derivatives as the nucleophile (vide supra). Additionally, it should
be noted that formamides do not give the corresponding pyridines
with alkynyl or alkenyl π-nucleophiles owing to rapid isocyanide
formation.
Based on mechanistic findings in our pyrimidine synthesis,6b we
propose this single-step pyridine synthesis proceeds by π-nucleo-
philic addition of acetylenes 2a-g to an activated electrophile 59
followed by expulsion of 2-ClPyr•HOTf and annulation of the
highly reactive intermediate 6 (eq 2). The condensation of the
terminal alkyne 2f with an N-(4-nitrophenyl) amide gave the desired
quinoline 4o in low yield (Table 1, 42% yield) along with 32%
yield of cyclohex-1-yl-3-(4-methoxyphenyl)-propynone, the hy-
drolysis product of the corresponding alkynyl imine.10 This
The example shown in eq 5 highlights the greater efficiency of
this chemistry when nucleophilic acetylenes are employed in place
of enol derivatives. Activation of amide 1m under standard
conditions and the use of silyl enol ether 3b provided the
intramolecular annulation product 9 rather than the expected
quinoline product. However, activation of amide 1m under identical
conditions and the use of nucleophile 2d provided the desired
quinoline derivative 4dd without detectable formation of phenan-
thridine 9 (eq 5). The synthesis of pyridine 4ee from the corre-
10096
9
J. AM. CHEM. SOC. 2007, 129, 10096-10097
10.1021/ja073912a CCC: $37.00 © 2007 American Chemical Society
Movassaghi, Mohammad
