2-Pyridones from cyanoacetamides and enecarbonyl compounds: Application to the synthesis of nothapodytine B

Article abstract of DOI:10.1021/jo025546d

The condensation of an enone or enal with cyanoacetamide derivatives and t-BuOK furnishes either 3-cyano-2-pyridones or 3-unsubstituted-2-pyridones, depending on whether the reaction is carried out in the presence or in the absence of O₂. In the first case, in situ oxidation of Michael-type intermediates takes place; in the second case, the products result from "decyanidative aromatization" of such intermediates. A one-step synthesis of 3-alkyl-2-pyridones has been devised on the basis of decyanative union of an enone/enal and a 2-alkylcyanoacetamide. The new reaction forms the centerpiece of an unusually concise synthesis of nothapodytine B (mappicine ketone).

Full text of DOI:10.1021/jo025546d

4304
J . Org. Chem. 2002, 67, 4304-4308
2-P yr id on es fr om Cya n oa ceta m id es a n d En eca r bon yl Com p ou n d s:
Ap p lica tion to th e Syn th esis of Noth a p od ytin e B
Lionel Carles, Kesavaram Narkunan, Se´bastien Penlou, Laurence Rousset,†
Denis Bouchu,† and Marco A. Ciufolini*
Laboratoire de Synthe`se et Me´thodologie Organiques (LSMO)-UMR CNRS 5078,
Universite´ Claude Bernard Lyon 1 and Ecole Supe´rieure de Chimie, Physique,
Electronique de Lyon, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne cedex, France
ciufi@cpe.fr
Received J anuary 22, 2002
The condensation of an enone or enal with cyanoacetamide derivatives and t-BuOK furnishes either
3-cyano-2-pyridones or 3-unsubstituted-2-pyridones, depending on whether the reaction is carried
out in the presence or in the absence of O2. In the first case, in situ oxidation of Michael-type
intermediates takes place; in the second case, the products result from “decyanidative aromatization”
of such intermediates. A one-step synthesis of 3-alkyl-2-pyridones has been devised on the basis of
decyanative union of an enone/enal and a 2-alkylcyanoacetamide. The new reaction forms the
centerpiece of an unusually concise synthesis of nothapodytine B (mappicine ketone).
In tr od u ction
this transformation on significant scales may result in
formation of variable quantities of descyano pyridones
4, which become the major, or even the exclusive,
products with particular substrates (Scheme 1).
Compounds 4 emerge through the fusion of an enecar-
bonyl compound and an active methylene agent, in a [3
+ 3] mode, via “de-cyanidative aromatization” of an
intermediate Michael adduct. 2-Pyridones unsubstituted
at C-3 are customarily obtained through cyclization of
2-Pyridones are of significant interest in current
medicinal chemistry.1 Many syntheses of these hetero-
cycles2 proceed through the regioselective cycloconden-
sation of an acetonitrile derivative (cyanoacetate ester,3
cyanoacetamide,4 or malononitrile5) with an appropriate
carbonyl substrate in a [3 + 3] mode, resulting in overall
formation of 3-cyano-2-pyridones. The efficiency of these
reactions is somewhat variable: good results are obtained
in some cases, but moderate to mediocre yields are not
uncommon. In 1995, we described a technique to effect
the union of various enones and enals 1 with cyano-
acetamide 2 (R4 ) H), leading to 3-cyano-2-pyridones 3
in good to excellent yield, by operating in DMSO and in
the presence of excess t-BuOK under an oxygen atmo-
sphere.6,7 We have recently observed that the conduct of
(4) Representative examples of the principal classes of reactions
leading to pyridones through condensation of cyanoacetamide with the
following. (i) Enones or â-dicarbonyl compounds: (a) Salman, A. S. S.
Pharmazie 1999, 54, 178. (b) Attia, A.; Abdel-Salam, O. I.; Abo-Ghalia,
M. H.; Amr, A. E. Egypt. J . Chem. 1995, 38, 543. (c) Attia, A. M. E.;
Elgemeie, G. E. H. Nucleosides Nucleotides 1995, 14, 1211. (d) Mijin,
D. Z.; Misic-Vukovic, M. M. Indian J . Chem. Sect. B 1995, 34, 348. (e)
Attia, A.; Abo-Ghalia, M. H.; El-Salam, O. I. A. Pharmazie 1995, 50,
455. (f) O’Callaghan, C. N.; McMurry, T. B. H.; Cardin, C. J .; Wilcock,
D. J . J . Chem. Soc., Perkin Trans. 1 1993, 2479. (g) Elgemeie, G. E.
H.; El-Zanate, A. M.; Mansour, A.-K. E. Bull. Chem. Soc. J pn. 1993,
66, 555. (h) Elgemeie, G. E. H.; Ali, H. A.; Eid, M. M. J . Chem. Res.
Miniprint 1993, 7, 1517. (i) Kaiho, T.; San-nohe, K.; Kajiya, S.; Suzuki,
T.; Otsuka, K.; et al. J . Med. Chem. 1989, 32, 351. (j) Paronikyan, E.
G.; Sirakanyan, S. N.; Lindeman, S. V.; Aleksanyan, M. S.; Karapetyan,
A. A.; et al. Chem. Heterocycl. Compd. (Engl. Transl.) 1989, 25, 953.
(k) Hishmat, O. H.; Miky, J . A. A.; Saleh, N. M. Pharmazie 1989, 44,
823. (l) Singh, L. W.; Ila, H.; J unjappa, H. Indian J . Chem. Sect. B
1987, 26, 607. (m) Shestopalov, A. M.; Sharanin, Yu. A. J . Org. Chem.
USSR (Engl. Transl.) 1986, 22, 1163. (n) Al-Hajjar, F. H.; J arrar, A.
A. J . Heterocycl. Chem. 1980, 17, 1521. (ii) Ynones: see ref 4n. See
also ref 2.
(5) Representative examples of the principal classes of reactions
leading to pyridones through condensation of various acceptors with
malononitrile derivatives: (a) Kandeel, K. A.; Vernon, J . M.; Dransfield,
T. A.; Fouli, F. A.; Youssef, A. S. A. J . Chem. Res. Miniprint 1990, 9,
2101. (b) Alberola, A.; Andres, C.; Ortega, A. G.; Pedrosa, R.; Vicente,
M. J . Heterocycl. Chem. 1987, 24, 709. (c) Rodinovskaya, L. A.;
Sharanin, Y. A.; Litvinov, V. P.; Shestopalov, A. M.; Promonenkov, V.
K.; et al. J . Org. Chem. USSR (Engl. Transl.) 1985, 21, 2230. (d)
Nasakin, O. E.; Nikolaev, E. G.; Terent’ev, P. B.; Bulai, A. K.; Zakharov,
V. Y. Chem. Heterocycl. Compd. (Engl. Transl.) 1985, 21, 1019. See
also ref 2.
† Mass spectral facility of the LSMO.
(1) E.g.: Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40, 4073
and references cited therein.
(2) Reviews on the synthesis of pyridones: (a) McKillop, A.; Boulton,
A. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon Press: New York, 1984; Vol. 2, Part 2A, p 67 ff.
(b) J ones, G. In Comprehensive Heterocylic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol. 2, Part
2A, p 395.
(3) Representative examples of the principal classes of reactions
leading to pyridones through condensation of cyanoacetic esters and
ammonium salts (source of ammonia) with: (i) preformed enones or
Knoevenagel adducts, or ketone/aldehyde pairs (in situ formation of
enones or Knoevenagel adducts): (a) Abadi, A.; Al-Deeb, O.; Al-Afify,
A.; El-Kashef, H. Farmaco 1999, 54, 195. (b) El-Emary, T. I.; Bakhite,
E. A. Pharmazie 1999, 54, 106. (c) Grant, N.; Mishriky, N.; Asaad, F.
M.; Fawzy, N. G. Pharmazie 1998, 53, 543. (d) Abadi, A. H.; Al-
Khamees, H. A. Arch. Pharm. 1998, 331, 319. (e) Kamel, M. M.; Omar,
M. T.; Refai, M.; Fahmy, H. H.; Nofal, Z.; Ismail, N. S. Egypt. J . Chem.
1996, 39, 591. (f) Hataba, A. A. Pol. J . Chem. 1996, 70, 41. (g) Latif,
N.; Mishriky, N.; Haggag, B.; Basyouni, W. Indian J . Chem. Sect. B
1995, 24, 1230. (h) Ibrahim, E. S.; Elgemeie, G. E. H.; Abbasi, M. M.;
Abbas, Y. A.; Elbadawi, M. A.; Attia, A. M. E. Nucleosides Nucleotides
1995, 14, 1415. (i) Manna, F.; Chimenti, F.; Bolasco, A.; Filippelli, A.;
Palla, A.; et al.; Eur. J . Med. Chem. Chim. Ther. 1992, 27, 627. (j)
Moustafa, A. H.; Kaddah, A. M.; El-Abbady, S. A.; Gado, S. H. J . Prakt.
Chem. 1982, 324, 1045. (k) Chorvat, R. J .; Desai, B. N. J . Heterocycl.
Chem. 1980, 17, 1313. (ii) â-Enaminones and related substances: (l)
Badr, M. Z. A.; Geies, A. A.; Abbady, M. S.; Dahy, A. A. Can. J . Chem.
1998, 76, 469. (m) Al-Omran, F.; Khalik, M. M. A.; Al-Awadhi, H.;
Elnagdi, M. H. Tetrahedron 1996, 52, 11915. See also ref 2.
(6) (a) J ain, R.; Roschangar, F.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 3307. This work was based on an observation reported by:
(b) Al-Hajjar, F. H.; J arrar, A. A. J . Heterocycl. Chem. 1980, 17, 1521.
(7) This general type of reaction was featured in a total synthesis
of (+)-camptothecin: (a) Ciufolini, M. A.; Roschangar, F. Angew. Chem.
1996, 108, 1789. (b) Ciufolini, M. A.; Roschangar, F. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1692. (c) Ciufolini, M. A.; Roschangar, F.
Tetrahedron 1997, 53, 11049.
10.1021/jo025546d CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/18/2002

Synthesis of Nothapodytine B
Sch em e 1
J . Org. Chem., Vol. 67, No. 12, 2002 4305
Sch em e 2
appropriate acyclic educts,2 whereas their assembly in a
[3 + 3] format is extremely unusual. Limited precedent
for a [3 + 3] de-cyanative aromatization avenue to these
heterocycles from particular substrates may be found in
the work of Eweiss,8 but the literature records only two
methods of sufficient scope that accomplish a similar
construction. In 1957, Thesing and Mu¨ller described a
route involving condensation of R,â-unsaturated ketones
with N-(2-carbamoylmethyl)pyridinium ylide.9 More re-
cently, Katritzky demonstrated a variant of this approach
in which the nucleophilic component is the anion of
decyanative aromatization under conditions of oxygen
starvation and we disclose that formation of either
3-cyano-2-pyridones or 3-unsubstituted-2-pyridones may
be controlled simply by admitting or excluding O2 during
the reaction. We also disclose a new method for the [3 +
3] preparation of 3-alkyl-2-pyridones from enecarbonyl
educts and 2-alkylcyanoacetamides, and we demonstrate
this reaction as the centerpiece of a concise total synthe-
sis of nothapodytine B, an antiviral alkaloid structurally
related to camptothecin.
1-cyanomethyl- or 1-carbamoylmethylbenzotriazole.10
A
conceptually different method that relies on the conden-
sation of maleimide with â-alkylthio-â-enaminones ap-
pears to be more limited in scope.11 It thus seemed that
a useful “dichotomous” synthesis of 2-pyridones would
result if the interaction of cyanoacetamide (2, R4 ) H)
with enecarbonyl compounds could be controlled so as to
produce either 3 or 4. Furthermore, the use of a generic
2-cyanocarboxamide (2, R4 ) alkyl) in this chemistry vis
a` vis an enecarbonyl substrate could produce a 3-alkyl-
2-pyridone 5 in a [3 + 3] mode (Scheme 1). The only
documented example of [3 + 3] assembly of a 3-alkyl-2-
pyridone appears to be Katritzky’s base-promoted con-
densation of 2-(1-benzotriazolyl)propionamide with chal-
cone, leading to 3-methyl-4,6-diphenyl-2-pyridone.10
Experiment revealed that the genesis of 4 is largely
attributable to an insufficient rate of diffusion of molec-
ular oxygen into the reaction solution. We refer to this
phenomenon as “oxygen starvation”. The problem may
become especially significant when larger volumes of
solvent are involved, i.e., when the reaction is scaled up.
In this paper, we describe a solution to the problem of
Discu ssion
A mechanistic hypothesis for the appearance of 4 was
formulated on the basis of our proposal for the formation
of 3.6 The initial interaction of cyanoacetamide and
enecarbonyl substrate in the presence of t-BuOK leads
to an isolable Michael product 6. We had previously
assumed that 6 undergoes base-promoted dehydrative
cyclization to a dihydropyridone, which is rapidly and
irreversibly deprotonated to furnish anion 7 (Scheme 2).
Subsequently, this species would be reversibly converted
to dianion 8, which in the presence of O2 undergoes
oxidative aromatization to 3 via single electron transfer
(SET) and formal loss of a hydrogen atom from the
intervening radical anion 9. It seemed plausible that the
strongly basic medium could induce equilibration of 8
with an isomeric dianion 10, especially if both R1 and R3
were anion-stabilizing substituents such as aryl groups.
The hypothetical intermediate 10 would aromatize through
expulsion of cyanide ion, leading to formation of the anion
of pyridone 4. Compound 4 itself would emerge following
the usual aqueous workup.
(8) Eweiss, N. F. J . Heterocycl. Chem. 1982, 19, 273. This paper
reports that 2-benzylidene-1-indanones combine with cyanoacetamide
under basic conditions to furnish
a mixture of C-3 unsubtituted
2-pyridones and 3,4-dihydro-3-cyano-2-pyridones, while 2-benzylidene-
1,3-indandiones react to provide only 3-descyanopyridones.
(9) (a) Thesing, J .; Mu¨ller, A. Chem. Ber. 1957, 90, 711. Recent
examples: (b) Besidsky, Y.; Luthman, K.; Claesson, A.; Fowler, C. J .;
Csoeregh, I.; Hacksell, U. J . Chem. Soc., Perkin Trans. 1 1995, 465.
Variants of the original Thesing-Mmuller procedure: (c) Grosche, P.;
Hoeltzel, A.; Walk, T. B.; Trautwein, A. W.; J ung, G. Synthesis 1999,
1961. (d) Katoh, A.; Kitamura, Y.; Fujii, H.; Horie, Y.; Satoh, T.;
Ohkanda, J .; Yokomori, Y. Heterocycles 1998, 49, 281.
The foregoing considerations suggest that the extent
of formation of 4 reflects the proportion of dianion 8 that
partitions between the oxidation (cf. koxid, Scheme 2) and
equilibration (kisom) pathways. If the oxygen concentration
in solution were too low to promote rapid oxidation of 8,
then more of 4 would be observed. Likewise, substrates
leading to anions 8 that are more likely to isomerize to
10 would produce more 4, the ease of isomerization being
largely determined by the nature of substituents R1 and
(10) Katritzsky, A. R.; Belayakov, S. A.; Sorochinski, A. E.; Hend-
erson, S. A.; Chen, J . J . Org. Chem. 1997, 62, 6210.
(11) Gupta, A. K.; Ila, H.; J unjappa, H. Synthesis 1988, 284.

4306 J . Org. Chem., Vol. 67, No. 12, 2002
Carles et al.
Sch em e 3a
a
Cyanoacetamide (2, R4 ) H), t-BuOK, DMSO, O2, 55% 3a , 58%
3b.
R3. In any event, a more efficient diffusion of O2 in the
medium should diminish/suppress the side reaction
producing 4.
Enones 1 wherein both R1 and R3 are aryl groups, e.g.,
chalcone, displayed a marked propensity to yield des-
cyanopyridones 4 under our original conditions,6 whereas
enones in which R1 is alkyl and R3 is aryl were signifi-
cantly less susceptible to produce 4. Evidently, the
isomerization of 8 to 10 is more likely to occur when both
R1 and R3 can mesomerically stabilize a negative charge
at C-4 of the pyridone. To illustrate, several benzylide-
neacetone derivatives were readily converted to pyridones
3 under our usual conditions, and without significant
F igu r e 1. J acketed reactor for 3-cyano-2-pyridone synthesis.
The barrel-shaped device is secured to a flask of appropriate
size and charged with a DMSO solution of cyanoacetamide and
R,â-unsaturated carbonyl compound (enone or enal). The
viscosity of DMSO prevents the solution from flowing through
the frit into the flask. t-BuOK is added, oxygen flow is started,
and the device is loosely stoppered to permit venting of the
gas. An exothermic reaction occurs, and significant foaming
is observed. With substrates particularly prone to form the
descyanopyridones, cooling may be applied to moderate the
exothermicity. When the reaction is finished, O2 flow is halted
and vacuum is applied. The reaction mixture is filtered
through the frit (removal of suspended matter) into the
receiver flask and then it is cautiously poured into aqueous 4
N HCl solution, resulting in precipitation of the solid pyridone,
which is recovered by simple filtration.
1
formation of 4 () below detection by H NMR; Scheme
3). On the other hand, chalcone and other substrates
particularly prone to form the descyano products were
best advanced to 3 by ensuring a high O2 flow through
the solution during pyridone synthesis and by controlling
the exothermicity of the reaction by cooling. This is
accomplished by the use of the simple reactor shown in
Figure 1. For instance, reaction of 1d with cyanoacet-
amide in accord with our original procedure (t-BuOK,
DMSO, O2 balloon, no cooling) on scales greater than 300
mg afforded the corresponding cyanopyridone 3 (R1 ) R3
) Ph, R2 ) H) contaminated with 20-80% of 4d depend-
ing on precise conditions (concentration, rate of base
addition and therefore of heat evolution, etc.). The same
reaction run on a 15 g scale in the apparatus of Figure 1
produced 3-cyano-4,6-diphenyl-2-pyridone containing less
than 5% (1H NMR) of 4d . The impurity is easily removed
by recrystallization.
zation of 11 to 12 upon treatment with t-BuOK in DMSO,
in the absence of O2.
Attempts to replace the cyano function in the amide
component with other substituents that may simulta-
neously activate the molecule toward enolate formation,
and act as leaving groups to permit aromatization, were
unfruitful. Thus, the propionyl analogue 13 of the Thes-
ing-Mu¨ller reagent 14 as well as 2-phenylsulfonyl amides
14 and 15 (Scheme 5) failed to give the desired hetero-
cycles in our hands.
As an application of the new method for 3-alkylpyri-
done assembly, we now describe a total synthesis of
nothapodytine B, 16 (Scheme 6), an alkaloid that displays
interesting antiviral properties.15 This substance was
isolated in 1996 from Nothapodytes foetida, a plant native
to the Indian subcontinent.16 The compound is structur-
ally related to mappicine, 17,17 and to camptothecin, 18,
also metabolites of N. foetida.18 Indeed, nothapodytine
B may be obtained by thermolysis of 18.19 Interestingly,
16 was first prepared as a synthetic intermediate toward
The logic of Scheme 2 suggested that rigorous exclusion
of oxygen should result in selective formation of 4.
Indeed, treatment of various enones/enals with cyano-
acetamide or 2-alkyl variants thereof and excess t-BuOK
in degassed DMSO under Ar atmosphere furnished
3-unsubstituted pyridones or 3-alkylpyridones, respec-
tively. Representative examples of the new reaction
appear in Tables 1 and 2. Notice that all substrates
display an aromatic substituent at the conjugate position.
Such a group appears to favor formation of dianion 10
and consequent expulsion of cyanide ion. Indeed, enones
1 in which R3 ) alkyl produced no pyridones of the type
4 under anoxic conditions, but, surprisingly, they were
converted to 3-cyanopyridones 3 (45-50%, unoptimized)
signaling that a pathway for the aromatization of a
presumed intermediate of the type 8 subsists even in the
absence of O2 (Scheme 4). The oxidant in these reactions
may be DMSO itself. Indeed, the literature records
instances of DMSO-promoted dehydrogenation of various
substrates, especially under basic conditions.12 An ex-
ample that is particularly relevant to the present discus-
sion was reported by Massiot,13 who observed aromati-
(13) Massiot, G.; Sousa Oliveira, F.; Levy, J . Tetrahedron Lett. 1982,
23, 177.
(14) Unpublished results from this laborartory.
(15) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.; Kings-
bury, W. D. J . Org. Chem. 1994, 59, 2623. (b) Pendrak, I.; Wittrock,
R.; Kinsbury, W. D. J . Org. Chem. 1995, 60, 2912.
(16) Wu, T. S.; Chan, Y. Y.; Leu, Y. L.; Chern, C. Y.; Chen, C. F.
Phytochemistry 1996, 42, 907.
(17) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan, N. J .
Chem. Soc., Perkin Trans. 1 1974, 1215.
(18) The primary source of 18 is Camptotheca acuminata, a tree
native to the Chinese mainland. N. foetida, earlier known as Mappia
foetida, is native to the Indian subcontinent and represents a secondary
source of 18.
(12) Cf., e.g., the oxidation of compound 10 to 11 in: Grieco, P. A.;
Ferrin˜o, S.; Vidari, G. J . Am. Chem. Soc. 1980, 102, 7586.

Synthesis of Nothapodytine B
J . Org. Chem., Vol. 67, No. 12, 2002 4307
Ta ble 1. P yr id on es 4 Obta in ed fr om En eca r bon yls a n d
Cya n oa ceta m id e in th e Absen ce of O2
Sch em e 4
Sch em e 5
Sch em e 6
furan26 to furnish 22 (Scheme 7). The carbonyl group
connected to the quinoline is particularly electrophilic,
due to the electron-withdrawing character of the quino-
line unit; therefore, we expected that it would effectively
direct 1,4-addition to the π system. This was indeed the
case; however, we also observed that 1,2-diacylethylene
substrates such as 22 are generally intolerant of excess
Ta ble 2. Rep r esen ta tive P yr id on es 5 Obta in ed fr om
En on es a n d 2-Cya n op r oion a m id e in th e Absen ce of O2
(19) (a) Kingsbury, W. D. Tetrahedrom Lett. 1988, 29, 6847. (b)
Fortunak, J . M. D.; Mastrocola, A. R.; Mellinger, M.; Wood, J . L.
Tetrahedron Lett. 1994, 35, 5763. (c) Das, B.; Madhusudhan, P.;
Kashinatham, A. Bioorg. Med. Chem. Lett. 1998, 8, 1403. (d) Das, B.;
Madhusudhan, P.; Kashinatham, A. Tetrahedron Lett. 1998, 39, 431.
See also: (e) Das, B.; Madhusudhan, P.; Venkataiah, B. J . Ind. Chem.
Soc. 1998, 75, 662. This transformation presumably involves thermal
extrusion of CO2 by formal [4 + 2] cycloreversion, followed by
tautomerization of the resulting enol intermediate.
(20) Kametani, T.; Takeda, H.; Nemoto, H.; Fukumoto, K. J . Chem.
Soc., Perkin Trans. 1 1975, 1825, and references cited therein.
(21) (a) J osien, H.; Curran, D. P. Tetrahedron 1997, 53, 8881. (b)
Boger, D. L.; Hong, J . Y. J . Am. Chem. Soc. 1998, 120, 1218. (c) Boger,
D. L. J . Hetercycl. Chem. 1998, 35, 1003. (d) Yadav, J . S.; Sarkar, S.;
Chandrasekhar S. A. Tetrahedron 1999, 55, 5449. Das, B.; Mad-
husudhan P. Tetrahedron 1999, 55, 7875. See also: (e) Takayama, H.;
Kitajima, M.; Aimi, N. J . Synth. Org. Chem. J pn. 1999, 57, 181. (f)
Mekouar, K.; Genisson, Y.; Leue, S.; Greene, A. E. J . Org. Chem. 2000,
65, 5212. (g) Toyota, M.; Komori, C.; Ihara, M. J . Org. Chem. 2000,
65, 7110. (h) Das, B.; Madhusudhan, P. J . Chem. Res., Synopses 2000,
476. (i) Ishibashi, H.; Kato, I.; Takeda, Y.; Tamura, O. Tetrahedron
Lett. 2001, 42, 931. (j) Bowman, W. R.; Bridge, C. F.; Cloonan, M. O.;
Leach, D. C. Synlett 2001, 765.
(22) Comins, D. L.; Saha, J . K. J . Org. Chem. 1996, 61, 9623.
(23) Readily available in two steps from commercial materials:
Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997, 53, 11049.
(24) Thompson, W. J .; Gaudino, J . J . Org. Chem. 1984, 49, 5237.
(25) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(26) cf. Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J .
Org. Chem. 1998, 63, 7505.
17,20 and being an oxidized form thereof, it became known
as “mappicine ketone”. The rarity of Nothapodytes me-
tabolites and the cost of 18 have stimulated substantial
synthetic activity toward mappicine ketone.21 The Comins
synthesis of 16 is especially concise, proceeding in just
six steps from 2-fluoro-3-iodopyridine and 2-bromo-3-
(bromomethyl)quinoline.22 Our pyridone synthesis per-
mits access to 16 in four steps from quinoline 1923 and
boronic acid 20.24 Suzuki coupling25 of these two educts
provided 21, which underwent oxidative cleavage of the

4308 J . Org. Chem., Vol. 67, No. 12, 2002
Carles et al.
Sch em e 7a
Sch em e 9
Furthermore, it was observed that prolonged heating
of the crude Michael product (80 °C, 12 h), which exists
as a mixture of hemiamidals 26 and 27, prior to addi-
tion of acetic anhydride improved the yield of pyridone
and diminished the extent of formation of a byproduct
tentatively assigned as structure 28. Thermal treat-
ment appears to favor accumulation of the six-membered
cyclic species 27 at the expense of the five-membered
tautomer 26 and, therefore, formation of the pyridone.
Reaction of 22 with 2-cyanopropionamide under these
modified conditions provided a mixture of 23 and 24
(variable ratio) in 50% yield. In a like manner, 1,2-
dibenzoylethylene, 1h , afforded 30, mp 117-118 °C, in
48% yield (Scheme 9).
Compounds 23 and 24 are separable by silica gel chro-
matography. However, we found it expedient to per-
form only a rough purification of the crude mixture of
23 and 24, both of which converged to fully synthetic
nothapodytine B upon treatment HBr gas in trifluoro-
ethanol as described by Boger.21b,27 The overall yield of
16 for the 4-step sequence is 34%. The enantioselective
reduction of 16 to 17 has been demonstrated.21b Conse-
quently, a synthesis of mappicine ketone represents also
a formal synthesis of mappicine.
a
Reagents and conditions: (a) cat. Pd(PPh3)4, Ba(OH)2, DME,
86%; (b) NBS, NaHCO3, pyridine, aqueous acetone, 87%; (c) 2 (R4
) Me), pyridine, DBU, 80 °C, 12 h then Ac2O, 80 °C, 50% of 24/
25; (d) HBr, CF3CH2OH, 91%.
Sch em e 8
In summary, the union of cyanoacetamide and an
enone/enal may lead to either 3-cyano-2-pyridones or
3-unsubstituted-2-pyridones, in a [3 + 3] mode, depend-
ing on whether O2 is admitted or excluded during the
reaction, whereas the use of a 2-alkyl cyanoacetamide
results in formation of 3-alkyl-2-pyridones. The new
process has been demonstrated in a concise synthesis of
nothapodytine B.
Ack n ow led gm en t. We thank Aventis Crop Science
(doctoral fellowship to L.C.), the MENRT, the CNRS
(postdoctoral fellowship to K.N.), and the Re´gion Rhoˆne-
Alpes for support of our research program. M.A.C. is
the recipient of a Merck & Co. Academic Development
Award (2000 and 2001).
Su p p or tin g In for m a tion Ava ila ble: Experimental sec-
tion and hardcopy spectra of various nothapodytine B inter-
mediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
t-BuOK, so that their conversion to pyridone required a
modification of the procedure detailed earlier. It was
ultimately determined that pyridone formation proceeds
best through in situ dehydration/decyanidation with
Ac2O/pyridine at 80 °C of a preformed Michael adduct of
a generic 1,2-diacylethylene 25 (Scheme 8) and a substi-
tuted cyanoacetamide. The product thus emerging is
actually the O-acetyl derivative of the expected pyridone
(cf. 29), from which the parent heterocycle may be easily
retrieved by hydrolysis under appropriate conditions.
J O025546D
(27) This procedure represents a variant of a technique the we
devised in connection with the synthesis of camptothecin (ref 7), and
that in its original form would have involved treatment of 23/24 with
hot ethanolic H2SO4. This seemed likely to promote undesirable side
reactions (condensation, etc.) of the free ethyl ketone in 23 and 14;
hence the interest of the Boger method.