Cyclization of lithiated pyridine and quinoline carboxamides: Synthesis of partially saturated pyrrolopyridines and spirocyclic β-lactams

Article abstract of DOI:10.1021/ol051214u

(Chemical Equation Presented) Lithiation of N-benzyl pyridine and quinoline carboxamides α to nitrogen gives anions that undergo intramolecular attack on the pyridine or quinoline ring, either directly or on activation of the ring by N-acylation. The resu

Full text of DOI:10.1021/ol051214u

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3673-3676
Cyclization of Lithiated Pyridine and
Quinoline Carboxamides: Synthesis of
Partially Saturated Pyrrolopyridines and
Spirocyclic
Jonathan Clayden,*,† Stuart D. Hamilton,† and Rukhsana T. Mohammed‡
â-Lactams
Department of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, UK, and Department of Medicinal Chemistry, AstraZeneca
R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK
clayden@man.ac.uk
Received May 24, 2005
ABSTRACT
Lithiation of N-benzyl pyridine and quinoline carboxamides
r to nitrogen gives anions that undergo intramolecular attack on the pyridine or
quinoline ring, either directly or on activation of the ring by N-acylation. The resulting four-, five-, or six-membered-ring-containing compound
may be oxidized, protonated, alkylated, or acylated to give a range of polycyclic heterocycles, including pyrrolopyridines, pyrroloquinolines,
benzonaphthyridines, and azaspirocyclic
â-lactams.
The addition of nucleophiles to pyridines activated toward
nucleophilic attack (for example by N-acylation or N-
alkylation) is an important method for the synthesis of
functionalized piperidines and has been used in a number
of recent syntheses.1 An intramolecular version of this
reaction could provide a valuable route to ring-fused pip-
eridine derivatives. We have shown that N-benzyl benza-
mides, on lithiation and warming, undergo dearomatizing
cyclization2 to yield 6,5-fused ring systems (partially satu-
rated isoindolones)3 of synthetic value.4 Amide derivatives
of pyrroles5 and thiophenes6 undergo comparable dearoma-
tizing cyclizations and rearrangements. In this paper, we
report that the analogous pyridine derivatives (nicotinamides,
isonicotinamides, picolinamides, and quinoline carboxam-
ides) undergo cyclizations that in some cases mirror the
reactivity of the benzamides, giving partially saturated
pyrrolopyridines by 5-endo/exo cyclization, but in others
yield isomeric spiro-â-lactam products by 4-exo cyclization.
To establish the feasibility of cyclizing a lithiated benzyl
group onto a pyridine ring, the isonicotinamide 1 was made
† University of Manchester.
‡ AstraZeneca R&D Charnwood.
(4) Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317. Clayden,
J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727. Ahmed,
A.; Bragg, R. A.; Clayden, J.; Tchabanenko, K. Tetrahedron Lett. 2001,
42, 3407. Bragg, R. A.; Clayden, J.; Bladon, M.; Ichihara, O. Tetrahedron
Lett. 2001, 42, 3411. Clayden, J.; Knowles, F. E.; Menet, C. J. Tetrahedron
Lett. 2003, 44, 3397. Clayden, J.; Knowles, F. E.; Menet, C. J. J. Am. Chem.
Soc. 2004, 110, 9278. Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am.
Chem. Soc. 2005, 127, 2412. Clayden, J. Total Synthesis of Kainoids by
Dearomatizing Anionic Cyclization. In Strategies and Tactics in Organic
Synthesis; Harmata, M., Ed.; Academic Press: Academic Press, 2004; Vol.
4.
(1) For leading references, see: Kuethe, J. T.; Comins, D. L. J. Org.
Chem. 2004, 69, 5221. Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Bosch, J.
Tetrahedron: Asymmetry 2003, 14, 469. Comins, D. L.; Zheng, X.;
Goehring, R. R. Org. Lett. 2002, 4, 1622. Charette, A. B.; Grenon, M.;
Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829.
Rezgui, F.; Mangeney, P.; Alexakis, A. Tetrahedron Lett. 1999, 40, 6241.
Bosch, J.; Bennasar, M.-L. Synlett 1995, 587.
(2) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon:
Oxford, 2002. Clayden, J.; Kenworthy, M. N. Synthesis 2004, 1721.
(3) Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999, 231.
Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229. Clayden,
J.; Menet, C. J.; Mansfield, D. J. Chem. Commun. 2002, 38. Clayden, J.;
Knowles, F. E.; Menet, C. J. Synlett 2003, 1701.
(5) Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett. 2004, 6, 609.
(6) Clayden, J.; Turnbull, R.; Helliwell, M.; Pinto, I. Chem. Commun.
2004, 2430.
10.1021/ol051214u CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/23/2005

using standard methods and treated with excess LDA7 at
0 °C. A red-brown organolithium was formed, presumably
2. Stirring for 1 h at 0 °C and neutral workup yielded a
product (4a) resulting from dearomatizing cyclization of 2
into the 3-position8 of the pyridine ring and protonation of
the resulting enolate 3. Hydrolysis of the unstable amidate
4a on purification by chromatography on silica yielded the
stable lactam 5a as a single diastereoisomer. Alkylating the
enolate 3 with methyl iodide or acylating with methyl
chloroformate gave, after hydrolysis, lactams 5b and 5c,
respectively, as single diastereoisomers (Scheme 1).9
Scheme 2. Cyclization with Rearomatization of a Lithiated
Isonicotinamide and Picolinamide
Scheme 1. Dearomatizing Cyclization of a Lithiated
Isonicotinamide
lithiation to give 11 and cyclization to 12 within 10 min.
An aqueous quench of the resulting enolate 12 yielded a
mixture of regioisomers of the unstable dihydropyridine
derivatives 14a and 14b. These rearomatized on purification
to yield the pyrrolopyridine 15 in 70% yield from 10.
Acylation of the enolate 12 with methyl chloroformate on
the other hand led to a 5:1 mixture of diastereoisomers of
the unstable dihydropyridine 13 in 96% yield.11
The difference in rate and efficiency of cyclization between
the three isomers 6, 8, and 10 is presumably due to the
additional stabilization afforded to the enolate 12 by delo-
calization of the negative charge onto the nitrogen atom,
something not possible in the analogous enolates derived
from 6 and 8. This difference also accounts for the fact that
the dearomatized enolate 3 acylates at carbon while enolate
12 acylates at nitrogen.12
a Yield on purification by rapid filtration through silica.
Extending the cyclization to other simple pyridine car-
boxamides led to some related products, but the expected
rapid rearomatization of the dihydropyridines initially made
it difficult to isolate dearomatized products. The three
pyridine carboxamides, isonicotinamide 6, picolinamide 8,
and nicotinamide 10, were made straightforwardly from the
appropriate acyl chlorides, and each was treated with an
excess of LDA. On lithiation, the isonicotinamide 6 and the
picolinamide 8 cyclized only slowly, and after a number of
hours, only moderate yields of cyclized and rearomatized
(presumably by oxidation of either the cyclized product or
the intermediate enolate corresponding to 3 or 4) pyrrolopy-
ridines 7 and 9 were isolable (Scheme 2).10
We investigated ways to trap dearomatized products from
isonicotinamide 6 in the manner of those derived from 1 via
3, and during these studies we discovered that the cyclization
of the isonicotinamide 6 could be both redirected and
dramatically accelerated by addition of an acylating agent
directly after lithiation of the amide (Scheme 4). Thus,
treatment of 6 with LDA at -40 °C and addition of methyl
chloroformate led to the formation of a dearomatized product
The nicotinamide 10 cyclized much more rapidly than 1,
6, or 8: even at -40 °C, lithiation with LDA promoted
Scheme 3. Dearomatizing Cyclization of a Lithiated
Nicotinamide
(7) As with most of the reactions described in this paper, use of fewer
equivalents of LDA led to incomplete reaction.
(8) Regioselectivity of the cyclization is in accordance with previous
observations in the field (see: Clayden, J.; Tchabanenko, K.; Yasin, S. A.;
Turnbull, M. D. Synlett 2001, 302. Clayden, J.; Knowles, F. E.; Menet, C.
J. Synlett 2003, 1701). It seems that the organolithium always prefers to
attack ortho rather than para to a π donating group such as OMe, presumably
because at the ortho position inductive σ electron withdrawal at least partially
counterbalances the increased π electron density.
(9) We have proposed that related cyclizations are electrocyclic ring
closures (see: Clayden, J.; Purewal, S.; Helliwell, M.; Mantell, S. J. Angew.
Chem., Int. Ed. 2002, 41, 1049) rather than Baldwin-disfavored (Baldwin,
J. E. Chem. Commun. 1976, 734) intramolecular 5-endo trig conjugate
additions. Calculations suggest that both interpretations of the mechanism
are valid, depending on the starting material structure; see: Ramallal, A.
M.; Lo´pez-Ortiz, F.; Gonza´lez, J. Org. Lett. 2004, 6, 2141. The stereo-
chemistry of 5a-c was assigned by analogy with ref 3.
(10) A similar ring system has been made by cyclization with substitution,
see: Hoarau, C.; Couture, A.; Cornet, H.; Deniau, E.; Grandclaudaon, P.
J. Org. Chem. 2001, 66, 8064.
3674
Org. Lett., Vol. 7, No. 17, 2005

lithiated amide 16 at the pyridine nitrogen rather than the
considerably more basic organolithium center, presumably
for steric reasons. The resulting pyridinium system is
activated toward attack at C4, and the â-lactam results.14
Ozonolysis of 18a gave a single diastereoisomer of the
monocyclic â-lactam 20, while hydrogenation of 18a and
18b yielded saturated 2,7-diazaspiro[3.5]nonan-2-ones 21a
and 21b (Scheme 5).15
Scheme 4. Dearomatizing Cyclization to Form â-Lactams
Scheme 5. Transformations of â-Lactam 18a
a MeOTf.
a Stereochemistry of 20 was confirmed by NOE.
18a in 91% yield. Instead of the 6,5-fused bicycle formed
from 1, however, 18a was a 2,7-diazaspiro[3,5]nonane, a
spiro-linked â-lactam-dihydropyridine.13 Other acylating
agents, namely, benzyl chloroformate and benzoyl chloride,
were equally effective at promoting this new type of
cyclization (giving 18b,c), as was methyl triflate (which gave
18d). Methyl iodide gave significantly lower yields, and no
dearomatized product was obtained on quenching with
ammonium chloride, a good indication that electrophilic
attack at the pyridine nitrogen is needed to promote the
cyclization.
Similar reactivity is exhibited by the quinolines 22 and
26, analogues of 10 and 6, and with 29: with all three
quinolines, cyclization occurs even without the addition of
an electrophile (Scheme 6). Thus, lithiation and cyclization
of the quinoline-3-carboxamide 22 was rapid at -40 °C, and
the product enolate 23 could be protonated to yield, after
air oxidation of the unstable intermediate dihydroquinoline,
the pyrroloquinoline 24. Trapping with methyl chloroformate
yielded, by acylation at nitrogen, the dihydroquinoline 25.
The quinoline-4-carboxamide 26 cyclized diastereoselectively
at 0 °C and yielded, before addition of an electrophile, a
spirocyclic lithium azaenolate 27.16 Alkylation or acylation
at nitrogen gave spirocyclic dihydroquinolines 28a and 28b.
In confirmation that cyclization does not require the presence
of an electrophile, in contrast with the analogous isonicoti-
namides, protonation of 27 yielded a dihydropyridine (28c),
though one unstable to chromatography. Cyclization of
The chlorinated isonicotinamide 19 gave comparable
â-lactams 18e and 18f, and Figure 1 shows the X-ray crystal
structure of 18e.
Scheme 4 outlines the mechanism we propose to account
for this cyclization. Remarkably, the electrophile attacks the
(11) Lack of stereoselectivity in the formation of 13 suggests that 12 is
formed with lower diastereoselectivity than 3. The two regioisomers 14
each appeared to be a single diastereoisomer, however, suggesting that the
regioselectivity of protonation may be dependent on stereochemistry.
Stereochemistries of 13 were not determined unequivocally and are assigned
by analogy with ref 3.
(12) For a related discussion, see: Donohoe, T. J.; McRiner, A. J.;
Helliwell, M.; Sheldrake, P. J. Chem. Soc., Perkin Trans. 1 2001, 1435.
(13) Related spirocyclizations are known, see: Fraenkel, G.; Ho, C. C.;
Liang, Y.; Yu, S. J. Am. Chem. Soc. 1972, 94, 4732 and references therein.
See also: Foos, J.; Steel, F.; Rizvi, S. Q. A.; Fraenkel, G. J. Org. Chem.
1979, 44, 2522.
(14) With MeI as an electrophile, mixtures of products resulting from
N- and C-alkylation are obtained, a result that confirms our proposed order
of events. We have previously observed â-lactam formation on lithiation
and cyclization of an N-benzyl maleamide, see: Clayden, J.; Watson, D.
W.; Helliwell, M.; Chambers, M. Chem. Commun. 2003, 2582.
(15) For discussions of biological interest in spiro- and other R,R-
disubstituted â-lactams, see: Khasanov, A. B.; Ramirez-Whitehouse, M.
M.; Webb, T. R.; Thiruvazhi, M. J. Org. Chem. 2004, 69, 5766. Clader, J.
W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S,; Dugar, S.; Vaccaro,
W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, R. E.; Salisbury, B.; Davis,
H. R. J. Med. Chem. 1996, 39, 3684. Hagmann, W. K.; Kissinger, A. L.;
Shah, S. K.; Finke, P. E.; Dorn, C. P.; Brause, K. A.; Ahe, B. M.; Weston,
H.; Maycock, A. L.; Knight, W. B.; Dellea, P. S.; Fletcher, D. S.; Hand, K.
M.; Osinga, D.; Davies, P.; Doherty, J. B. J. Med. Chem. 1993, 36, 771.
(16) Single isomer of 25 obtained was assigned stereochemistry by
analogy with ref 3. The stereochemistry of 28 is assigned arbitrarily.
Figure 1. X-ray crystal structure of 18e. The (disordered) t-Bu
group has been omitted for clarity.
Org. Lett., Vol. 7, No. 17, 2005
3675

Scheme 6. Cyclization onto Quinolines
Scheme 7. Cyclization of a Quinoline-5-carboxamide
had hoped for cyclization into the C6-position, but lithiation
of 32 led instead to attack on the more electron-deficient
pyridine ring, generating the lithium azaenolate 33. Proto-
nation was followed by oxidation to the quinoline 34.
According to substitution pattern, then, it is possible to
annelate, with or without dearomatization, four-, five-, or
six-membered lactams to pyridine or quinoline carboxamides.
We are currently aiming to expand this methodology for use
in the synthesis of polycyclic alkaloid ring systems.
Acknowledgment. We are grateful to Madeleine Helli-
well for determining the X-ray crystal structure of 18e and
to the EPSRC and to AstraZeneca for funding.
quinoline-2-carboxamide 29 gave an enolate which rearo-
matized to yield quinolopyrrolone 30.
With the aim of exploring a potential route to kainoid
amino acids in the acromelic acid family,17 we made (by
Skraup reaction of 3-amino-4-methoxybenzoic acid 3118) and
cyclized the quinoline-5-carboxamide 32 (Scheme 7). We
Supporting Information Available: Sample experimen-
tal procedure; X-ray crystallographic data for 18f (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J.; Spyvee, M. R.;
Whitehead, R. C.; Wood, M. E. Tetrahedron 1998, 54, 7645.
(18) European Patent EP-A-0498722.
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