Synthesis of nitrogen heterocycles by the ring opening of pyridinium salts

Article abstract of DOI:10.1002/anie.200602996

(Chemical Equation Presented) The century-old ring-opening reaction of pyridinium salts with tethered nucleophiles has been harnessed for a synthesis of substituted indoles and related nitrogen heterocyles. Extension of this method could lead to oxygen- and sulfur-containing heterocycles and carbocycles, as well as to applications in natural product synthesis and medicinal chemistry.

Full text of DOI:10.1002/anie.200602996

Angewandte
Chemie
Heterocycle Synthesis
DOI: 10.1002/anie.200602996
Synthesis of Nitrogen Heterocycles by the Ring
Opening of Pyridinium Salts**
Aaron M. Kearney and Christopher D. Vanderwal*
The ring-opening reaction of pyridinium salts dates back over
a century to the pioneering work of Zincke and König.[1]
Activation of pyridines as their pyridinium salts renders the
heterocycle electrophilic at the 2- and 4-positions and enables
a diverse range of productive chemistry, with or without ring
opening.[2] Treatment of appropriately activated pyridinium
salts, such as 1 (Scheme 1), with primary amines leads to the
Scheme 1. Proposed use of tethered nucleophiles to induce pyridinium
ring opening leading to substituted heterocycles. A=generic activating
group.
formation of new pyridinium salts (2), whereas the use of
secondary amines cleanly affords the products of ring open-
ing.[3,4] Both the ring-opening process and the product 5-
amino-2,4-pentadienals (3),[4a] now known as Zincke alde-
[*] A. M. Kearney, Prof. C. D. Vanderwal
Department of Chemistry
University of California-Irvine
1102 Natural Sciences II, Irvine, CA92697-2025 (USA)
Fax: (+1)949-824-2210
E-mail: cdv@uci.edu
[**] We would like to thank the School of Physical Sciences of the
University of California, Irvine, for generous startup funding.
Acknowledgment is made to the donors of the American Chemical
Society Petroleum Research Fund for partial support of this research
through a Type G Starter Grant. New faculty awards from Amgen
and Eli Lilly are also gratefully acknowledged. We also thank Joel
Silverston for experimental assistance.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Formation of substituted indoles from pyridinyl anilines.
hydes, appear ideally suited for manifold
applications in synthesis; to date, however,
this potential has remained largely unreal-
ized.[5]
We anticipated that the ring opening of
activated pyridines by nucleophiles tethered
at pyridine C3 would generate a range of
useful heterocycles bearing a versatile prope-
nal side chain at C3 of the newly formed ring
(4!5, Scheme 1). By rendering the initial step
of this process intramolecular, we hoped to
extend the range of nucleophiles beyond
simple secondary amines. Thus, the appropri-
ate selection of tether and nucleophile would
provide access to a variety of different hetero-
cycles. Our initial progress toward this goal,
which entails a nonobvious route to nitrogen
heterocycles from pyridines, is the subject of
this communication.
The indole nucleus is ubiquitous in natural
products and medicinal chemistry. As a result,
numerous different approaches to this ring
system exist, each offering different levels of
practicality for varying applications;[6] indeed,
new methods are continually being devel-
oped.[7] We expected that a convergent biaryl
coupling/pyridine ring opening sequence
would provide access to a family of indole
derivatives of significant utility, while concur-
Entry
1
Product
Yield [%] Entry
Product
Yield [%]
78
78[a]
73[b]
80
5
6
7
8
2
3
4
65
74
80
63
[a] In a single 110-mmol experiment, a 60% yield was obtained, affording over 10 g of 7a.
[b] Performed at 0.8 mm; the typical procedure is performed at 0.10m.
rently providing proof of principle for our general heterocycle
synthesis.
subjected to these conditions. Avariety of substituents of
varying electronic nature are tolerated, and good to excellent
yields are observed in nearly every case. The sole outlier is
entry 2 of Table 1, wherein the formation of a stable imine
condensation product of the aniline and the indole product 7b
occurs under standard conditions, thus preventing completion
of the reaction. This problem was easily circumvented by
using more dilute reaction conditions, which served to
minimize this undesired bimolecular condensation.
The strength of this strategy lies in its ability to deliver
benzene-ring-substituted indoles with the propenal side chain
at C3. The location of such a versatile handle at this position
distinguishes this method of indole construction; one could
imagine a myriad of uses for the enal function. Very useful
[4+2] cycloaddition reactivity of either the enal (as
dienophile) or the aminopentadienal (as diene) is
anticipated for these and related products. In addi-
tion, recent work of MacMillan and co-workers
suggests that a number of useful enantioselective
transformations might be performed on the unsatu-
rated aldehyde moiety of these indole products.[11,12]
Although the results in Table 1 clearly demon-
Aseries of pyridinyl-aniline precursors of type
6
(Scheme 2) were synthesized efficiently by Suzuki biaryl
[9]
couplings.[8] Avariety of activating agents were screened,
and inexpensive cyanogen bromide emerged as the reagent of
choice for indole formation (6!7). Thus, treatment of a
variety of pyridinyl anilines with cyanogen bromide in warm
ethanol rapidly afforded the desired indoles (7) after hydro-
lysis of the presumed N-cyanoimine intermediate (Table 1). A
plausible mechanism to account for the formation of these
products is provided in Scheme 2.[10]
To date, this indolization procedure has proven to be
general; Table 1 lists every substrate of type 6 that we have
strate versatility with respect to substitution on the
carbocyclic ring of the indole, we anticipated that the
use of functionalized pyridines would enable the
introduction of substituents on the enal side chain.
The preliminary experiment shown in [Eq. (1)] sup-
ports this idea as the 4-methylpyridine derivative 11
is converted into 12 in a yield comparable to those
Scheme 2. Presumed reaction course for the conversion of pyridinyl anilines into indoles.
obtained with unsubstituted pyridines. In addition,
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The use of the century-old pyridinium-ring-opening
reaction with tethered nucleophiles has led to a convergent
two-step synthesis of a series of indole-3-propenals. Prelimi-
nary experiments with tethered amides have indicated that,
with the correct choice of experimental parameters, variation
of nucleophile/tether combinations is also tolerated. There-
fore, this reaction of pyridinium salts represents not simply a
new indole synthesis, but rather the first step towards a
potentially general protocol for heterocycle synthesis. We
envision extension to oxygen- and sulfur-containing hetero-
cycles, and carbocycles, as well as applications in natural-
product synthesis and medicinal chemistry.
this reaction works especially well in the formation of a 7-
azaindole (14, [Eq. (2)]) starting from the interesting bipyr-
idine 13. Given the importance of azaindoles in medicinal
chemistry,[13] this is a significant result.
Experimental Section
General procedure for cyanogen bromide mediated pyridine ring
opening: (E)-3-(1H-Indol-3-yl)-propenal (7a): To a 100-mL round-
bottom flask equipped with a magnetic stir bar was added 2-pyridin-3-
ylphenylamine (1.05 g, 6.2 mmol) and absolute ethanol (55.0 mL).
The light-yellow solution was warmed to 408C before the addition of
cyanogen bromide (1.31 g, 12.4 mmol) as a solution in EtOH (5 mL).
After 20 min 10% aqueous ammonium chloride (20.0 mL) was added
to the dark-red solution, which was allowed to stir at 408C for 3 h. The
crude reaction mixture was concentrated in vacuo, and the residue
was taken up in EtOAc, washed with saturated NaHCO3, concen-
trated in vacuo, preloaded onto silica gel, and purified by flash
chromatography (40%!60% EtOAc/hexanes) to afford pure 7a as a
orange solid (695 mg, 70%): m.p. 108–1108C (EtOAc); 1H NMR
(500 MHz, CD3OD, 298 K): d = 9.53 (d, J = 8.1 Hz, 1H), 8.71 (d, J =
15.7 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J = 7.2 Hz,
1H), 7.30–7.23 (m, 2H), 6.75 (dd, J = 8.1, 15.7 Hz, 1H); 13C NMR
(125 MHz, CD3OD, 298 K): d = 196.8, 150.9, 139.6, 133.9, 126.7, 124.4,
Initial efforts to expand this reactivity to pyridines bearing
non-aniline nucleophiles, such as 3-(2-ethylamino)-pyridine
(15), led, as anticipated, to exclusive N-cyanation of the
primary amine. We considered the balance of nucleophilicity
associated with anilines of type 6 and expected that, by
depressing the nucleophilicity of the tethered amine in
substrates such as 15, our strategy might be amenable to the
synthesis of other nitrogen heterocycles. With the N-benzoyl
amide of 3-(2-ethylamino)-pyridine (16), no productive
reactivity was observed upon exposure to the optimal
conditions for indole formation. However, generation of the
N-arylated pyridinium salt 17, and subsequent treatment of
this activated pyridine with excess dimethylamine with
warming in an open flask, led to N-benzoyl dihydropyrrole
18 in 57% yield over two steps (Scheme 3). This trans-
formation may proceed through an initial pyridinium ring
opening by dimethylamine to form 19, followed by cyclization
of the amide onto the conjugated iminium ion to afford 20
with release of volatile dimethylamine; this iminium ion is
hydrolyzed upon workup to afford 18. Other mechanisms
have not been ruled out.
124.1, 122.9, 121.2, 114.6, 113.5; IR (KBr) 3252, 2238, 1651, 1609 cmꢀ1
TLC Rf = 0.80 (100% EtOAc); LRMS (ESI) m/z (relative intensity):
172 (100); HRMS (CI) m/z calcd for C11H10NO [M+H]+, 172.0762,
found 172.0760.
;
Received: July 25, 2006
Published online: October 30, 2006
Keywords: biaryls · cyclization · indoles · nitrogen heterocycles ·
.
pyridinium salts
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[2] For selected examples of reactions that
occur without ring opening, see the
following leading references: a) D. L.
Comins, J. J. Sahn, Org. Lett. 2005, 7,
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A. B. Charette, Org. Lett. 2006, 8, 2985 –
2988.
[3] Please see the Supporting Information
for plausible mechanisms for these
transformations.
Scheme 3. The synthesis of N-protected dihydropyrrole 18 exemplifies alternative pyridine
activation strategy for weak nucleophiles. Ar=2,4-dinitrophenyl, Bz=benzoyl.
[4] For reviews, please see: a) J. Becher,
Synthesis 1980, 589 – 613; b) W.-C.
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Communications
Cheng, M. J. Kurth, Org. Prep. Proced. Int. 2002, 34, 587 – 608;
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[9] Typical activating agents include 2,4-dinitrochlorobenzene, cya-
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[10] The conversion of 9 into 10 could conceivably occur through an
electrocyclic pathway or a simple ionic mechanism; either would
be followed by simple alkene geometrical isomerizations.
[11] Y. Huang, A. M. Walji, C. H. Larsen, D. W. C. MacMillan, J. Am.
Chem. Soc. 2005, 127, 15051 – 15053, and references therein.
Although we suspect that the reactivity of products of type 7 will
almost certainly be different from regular a,b-unsaturated
aldehydes owing to the conjugation of the indole nitrogen, the
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might result in reasonable reactivity in iminium-based asym-
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reference [12].
[12] An indole-3-propenal was used in an asymmetric organocata-
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Kinsman, M. A. Kerr, J. Am. Chem. Soc. 2003, 125, 14120 –
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Huang, F. Zhao, S. Ranadive, B. S. Robinson, Y.-F. Gong, K.
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