A synthesis of N-bridged 5,6-bicylic pyridines via A mild cyclodehydration using the Burgess reagent and discovery of A novel carbamylsulfonylation reaction

Article abstract of DOI:10.1021/ol8011748

(Chemical Equation Presented) Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.

Full text of DOI:10.1021/ol8011748

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2897-2900
A Synthesis of N-Bridged 5,6-Bicylic
Pyridines via A Mild Cyclodehydration
Using the Burgess Reagent and
Discovery of A Novel
Carbamylsulfonylation Reaction
Jie Jack Li,*,† James J. Li,‡ Jun Li, Ashok K. Trehan,† Henry S. Wong,†
Subramanian Krishnananthan,† Lawrence J. Kennedy,‡ Qi Gao,† Alicia Ng,†
Jeffrey A. Robl,‡ Balu Balasubramanian,§ and Bang-Chi Chen§
DiscoVery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway,
Wallingford, Connecticut 06492, DiscoVery Chemistry, Bristol-Myers Squibb Company,
311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, and DiscoVery
Chemistry, Bristol-Myers Squibb Company, Route 206 & ProVince Line Road,
Princeton, New Jersey 08543
jack.li@bms.com
Received May 22, 2008
ABSTRACT
Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including
pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A
novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent,
producing the corresponding sulfonylcarbamate adduct.
Pyrolo-, imidazo-, and triazolopyridines, belonging to a class
of N-bridgehead 5,6-bicylic heterocycles, are important
motifs in medicinal chemistry. For instance, pyrrolopyridine
(indolizine) is the core structure of 5-HT3 receptor antagonists
such as 1,1a calcium channel blockers,1b H3 receptor
antagonists,1c 15-lipoxygenase inhibitors,1d and phosphatase
inhibitors.1e On the other hand, imidazopyridine is present
in loprinone (Olprinone), a phosphodiesterase 3 (PDE-3)
inhibitor,2a zolpidem (2, Ambien), and a γ-aminobutyric acid
(GABA) modulator.2b Furthemore, triazolopyridines are
found in MAP kinase inhibitors,3a growth hormone
secretagogues,3b and CCR5 inhibitors such as [1,2,4]tria-
zolo[4,3-a]pyridine 3.3c
Conventional cyclodehydrations of substrate 4 to form
bicyclic heterocycle 5 involve toxic, strong acidic, and/or
corrosive reagents such as POCl3,4a SOCl2,4b Ph3PCl2,4c and
(1) (a) Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.; King,
F. D.; Miner, W. D.; Sanger, G. J. J. Med. Chem. 1990, 33, 1924–1929.
(b) Gubin, J.; de Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux,
J.; Rosseels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain, P. J. Med.
Chem. 1993, 36, 1425–1433. (c) Chai, W.; Breitenbucher, J. G.; Kwok,
A.; Li, X.; Wong, V.; Carruthers, N. I.; Lovenberg, T. W.; Mazur, C.;
Wilson, S. J.; Axe, F. U.; Jones, T. K. Bioorg. Med. Chem. Lett. 2003, 13,
1767–1770. (d) Teklu, S.; Gundersen, L.-L.; Larsen, T.; Malterud, K. E.;
Rise, F. Bioorg. Med. Chem. 2005, 13, 3127–3139. (e) Weide, T.; Arve,
L.; Prinz, H.; Waldmann, H.; Kessler, H. Bioorg. Med. Chem. Lett. 2006,
16, 59–63.
† Discovery Chemistry, Wallingford.
‡ Discovery Chemistry, Pennington.
§ Discovery Chemistry, Princeton.
10.1021/ol8011748 CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society

Table 1. Cyclodehydration Using the Burgess Reagent
Figure 1. Examples of N-bridged 5,6-bicyclic pyridines in drugs.
P2O5,4d etc. Cyclodehydration using Lawsson’s reagent5a and
a modified Mitsunobu reaction5b to prepare triazolopyridines
and triazolopyrimidines have been reported recently. The
Burgess reagent [6, (methoxycarbonylsulfamoyl)tri-
ethylammonium hydroxide inner salt] is a neutral, white
crystalline solid. Since Burgess invented the reagent (6) in
1968,6 it had not received much attention from the organic
chemistry community until Wipf used it to carry out
cyclodehydrations of ꢀ-amino alcohols to make the corre-
sponding oxazolines.7 Recently, Nicolaou has incorporated
the Burgess reagent into reaction sequences to make sulfa-
midates, glycosylamines, and sulfamides.8 Several reviews
have appeared during the past few years summarizing the
utility of the Burgess reagent.9 One potential drawback
limiting the use of the Burgess reagent is the cost of the
compound. However, the material can be conveniently
prepared on a large scale,10 and all the starting materials are
readily available and inexpensive.
Scheme 1. Cyclodehydration
We investigated a unified approach of cyclodehydration
using the Burgess reagent to prepare pyrolo-, imidazo-, and
triazolopyridines (Scheme 1). Substrates 4a and 4b in Table
1 were prepared by aldol condensation of 2-pyridinecarbox-
(2) (a) Endoh, M. CardioVasc. Drug ReV. 1993, 11, 432–450. (b) Guzzo,
P. R. GABAA Receptor Agonists for Insomnia: Zolpidem (Ambien ),
Zaleplon (Sonata ), Eszopiclone (Estorra , Lunesta ), and Indiplon in
The Art of Drug Synthesis; Johnson, D. S., Li, J. J., Eds.; Wiley & Sons:
Hoboken, NJ, 2007.
a Indolizidines 5a, 5b, and 5c are unstable under light, and coloration
(blue for 5a, yellow for 5b, and pink for 5c, respectively) readily takes
place if not stored in amber containers.
(3) (a) Dembroski, M. A.; Letvic, M. A.; McClure, K. F. USP Appl.
2004077682. (b) Yu, G.; Li, J.; Ewing, W. R.; Sulsky, R. B.; Li, J. J.;
Tino, J. A. PCT Int. Appl. 2004021984. (c) Kim, D.; Wang, L.; Hale, J. J.;
Lynch, C. L.; Budhu, R. J.; MacCoss, M.; Mills, S. G.; Malkowitz, L.;
Gould, S. L.; DeMartino, J. A.; Springer, M. S.; Hazuda, D.; Miller, M.;
Kessler, J.; Hrin, R. C.; Carver, G.; Carella, A.; Henry, K.; Lineberger, J.;
Schleif, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett. 2005, 15, 2129–
2134.
aldehyde (7) with 2 equiv of methyl ketone 8 as shown in
Scheme 2.11 Also formed was the Claisen-Schmidt adduct
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Org. Lett., Vol. 10, No. 13, 2008

II (entries 1-4 in Table 1), spontaneous cyclization did not
occur, and cyclodehydration with the Burgess reagent was
effected within 0.5 h in refluxing THF. When R )
-C(OCH3)2CH3 for substrate II, no reaction took place
possibly due to steric hindrance. While cyclodehydration of
amide III was complete within 8 h, cyclodehydration of
hydrazide IV was much more sluggish, taking over 18 h to
finish. For substrate 10, no cyclodehydration product was
observed after 2 days of reflux. Presumably, the inactivity
of 10 stems from the electronic effect of the ester. Further-
more, this method is sensitive to steric hindrance as well.
Noteworthy is the observation that sensitive functionalities
present in many of these substrates (e.g., NH-Boc, dimethyl
ketal, OTBDPS) are stable under these conditions. Though
limited in examples, the conditions are also mild enough to
avoid racemization of epimerizable substrates (e.g., entry 5,
Table 1).
Scheme 2. Synthesis of Substrates 4a-c
9 (where R ) Ph-NHBoc), which was hydrogenated to
produce substrate 4c. Substrate V, as a bis-ester, was obtained
by reaction of 7 with ethyl acetoacetate catalyzed by
piperidine followed by hydrogenation (Scheme 3).12 Sub-
strate 4d was prepared using a method similar to that of 4c.
Substrates 4e and 4f were prepared using the DCC-mediated
Interestingly, as shown in entries 3-6 in Table 1, the initial
cyclodehydration products were reactive enough to undergo
an electrophilic substitution with an additional 1 equiv of
the Burgess reagent, giving rise to adducts 5c-f, respectively.
The structures of 5c (shown in Figure 3) and 5e were
Scheme 3. Synthesis of Substrates 10
coupling reactions between pyridin-2-ylmethaneamine and
the corresponding carboxylic acids. Similarly, 4g-i were
readily assembled by the treatment of 2-hydrazinopyridine
with the pivaloyl mixed anhydrides of the corresponding
2-substituted acetic acids.
Figure 3. ORTEP of 5c from X-ray crystallography.
With the substrates 4a-i in hand, cyclodehydration was
carried out by simply adding the Burgess reagent to a THF
solution of the substrate. The resulting solution was heated
to reflux. For different substrates, we observed stark differ-
ences in their reactivities toward cyclization. In the case of
ketone I (see Figure 2) dehydrative cyclization proceeded
unambigeously demonstrated by single-crystal X-ray crystal-
lography (the X-ray coordinates for 5c and 5e may be found
in the Supporting Information). To the best of our knowledge,
this is the first report of these sulfonylcarbamate adducts to
pyrrolo- and imidazopyridines. Although their utility is not
immediately evident, it provides a means for making these
unique heterocyclic sulfonylcarbamates. The scope and
limitations of this novel reaction will be reported in due
course. Attempts were made to stop the electrophilic
substitution by using less than 1 equiv of the Burgess reagent.
Figure 2. Substrates reactivities for cyclodehydration.
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so readily that only the products 5 (Scheme 1 where X )
N, Y ) CH) were observed even during substrate prepara-
tion. In this situation, the Chichibabin indolizine synthesis,13
involving quaternization of 2-substituted pyridine with R-ha-
locarbonyl compounds followed by cyclization of the
quaternary salt, is assumed to have occurred.14 For substrate
(5) (a) Moulina, A.; Martineza, J.; Fehrentz, J.-A. Tetrahedron Lett. 2006,
47, 7591–7594. (b) Roberge, J. Y.; Yu, G.; Mikkilineni, A.; Wu, X.; Zhu,
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Org. Lett., Vol. 10, No. 13, 2008
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However, the sulfonylcarbamate adduct formation seems to
be much faster than the cyclodehydration reaction, and no
pyrrolo- and imidazopyridines were isolated.
Scheme 4. Proposed Mechanism for the Cyclodehydration and
Further Addition of the Second Equivalent of the Burgess
Reagent
The proposed mechanism for the cyclodehydration using
the Burgess reagent is shown in Scheme 4.15 For ketone
substrates 4c,d, a tiny percentage of the molecule might
present in the form of hemiaminal 11. However, addition of
the Burgess reagent to 11 drives the equilibrium to the right
where hemiaminal 11 forms adduct 12. Intramolecular proton
abstraction of 12 takes place to provide aromatized inter-
mediate 13 while losing one molecule of methylcarbonyl-
sulfamic acid. Pyrolopyridines 13 are reactive16 toward the
Burgess reagent. Thus, nucleophilic substitution between 13
and the additional equivalent of the Burgess reagent affords
intermediate 14, which undergoes rapid intramolecular proton
abstraction followed by isomerization to afford sulfonylcar-
bamates 5c,d. Similarly, amide substrates 4e,f and hydrazide
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W. M. Org. Synth. Collect. Ed. 1987, 6, 788–791. (b) Duncan, J. A.;
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substrates 4g-i may undergo mechanistic pathway invovling
a Vilsmeier-type mechanism with iminium salts 15 as the
key intermediates.
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Supporting Information Available: Typical and detailed
experimental procedures, 1H and 13C NMR spectra, and data
of all substrates 4a-i and as cyclodehydration products 5a-i.
X-ray crystallographic details and coordinates of 5c and 5e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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(15) We are grateful to Prof. Phil Baran’s insight into the mechanism.
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