2,3-Dihydro-4H-pyran-4-ones and 2,3-dihydro-4-pyridinones by cyclizations of α,β-unsaturated 1,3-diketones

Article abstract of DOI:10.1021/jo901355e

(Chemical Equation Presented) A variety of α,β-unsaturated 1,3-diketones cyclize to 2,3-dihydro-4H-pyran-4-ones in an acidic aqueous medium, with exceptions being α,β-unsaturated 1,3-diketones in which the β carbon is substituted by a phenyl group. Additi

Full text of DOI:10.1021/jo901355e

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2,3-Dihydro-4H-pyran-4-ones and 2,3-Dihydro-4-pyridinones by
Cyclizations of r,β-Unsaturated 1,3-Diketones
Franklyn K. MacDonald and D. Jean Burnell*
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J3
jean.burnell@dal.ca
Received June 25, 2009
A variety of R,β-unsaturated 1,3-diketones cyclize to 2,3-dihydro-4H-pyran-4-ones in an acidic
aqueous medium, with exceptions being R,β-unsaturated 1,3-diketones in which the β carbon is
substituted by a phenyl group. Addition of 1-butanamine to the reaction medium results in the
formation of 2,3-dihydro-4-pyridinones, which appear to arise via an initial 1,4-addition of the amine
to the R,β-unsaturated 1,3-diketones.
Introduction
tone, e.g., 3. However, there are surprisingly few exam-
ples of R,β-unsaturated 1,3-diketones cyclizing to 2,3-
dihydro-4H-pyran-4-ones.4-6 The papers by Gelin5 dealt
with the specific case of acylation of the magnesium
enolate of β-ketoesters with unsaturated acid chlorides
that lead to concomitant cyclization to afford 2,3-dihy-
dro-4H-pyran-4-one-3-carboxylates. The mechanism of
the cyclization of an R,β-unsaturated 1,3-diketone may
Hetero-Diels-Alder cyclizations and stepwise pro-
cesses that are formal [4 þ 2] reactions have emerged as
important methods for the synthesis of molecules con-
taining 2,3-dihydro-4H-pyran-4-one 1,1 but the older
method of acid-mediated cyclization of 5-hydroxy-1,3-
diketones, e.g., 2, continues to have relevance.2,3 In the
latter method, the stereochemistry of the carbinol center
is preserved in the cyclized product,3 and so this cycliza-
tion involves the dehydration of an intermediate hemi-
ketal rather than initial dehydration of the alcohol
followed by cyclization of the R,β-unsaturated 1,3-dike-
(4) (a) Schmitt, J. Liebigs Ann. Chem. 1950, 569, 32–37. (b) Parker, W.;
Raphael, R. A.; Wilkinson, D. I. J. Chem. Soc. 1958, 3871–3875. (c)
Bestmann, H.-J.; Saalfrank, R. W. Chem. Ber. 1976, 109, 403–410. (d)
Sosnovskikh, V. Y. Russ. Chem. Bull. 1997, 46, 2145–2146. (e) Clarke, D.
S.; Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M. Tetrahedron Lett. 2005,
46, 5515–5519.
(1) For example: (a) Danishefsky, S.; Kerwin, J. F. Jr.; Kobayashi, S. J.
Am. Chem. Soc. 1982, 104, 358–360. (b) Danishefsky, S.; Harvey, D. F.;
Quallich, G.; Uang, B. J. J. Org. Chem. 1984, 49, 393–395. (c) Johannsen, M.;
Yao, S.; Jørgensen, K. A. Chem. Commun. 1997, 2169–2170. (d) Zipp, G. G.;
Hilfiker, M. A.; Nelson, S. G. Org. Lett. 2002, 4, 1823–1826. (e) Winkler, J.
D.; Oh, K. Org. Lett. 2005, 7, 2421–2423. (f) Yang, W.; Shang, D.; Liu, Y.;
Du, Y.; Feng, X. J. Org. Chem. 2005, 70, 8533–8537. (g) Mukaiyama, T.;
Kitazawa, T.; Fujisawa, H. Chem. Lett. 2006, 35, 328–329. (h) Denmark, S.
E.; Heemstra, J. R. Jr. J. Org. Chem. 2007, 72, 5668–5688.
(5) (a) Gelin, S.; Gelin, R. Bull Soc. Chim. Fr. 1968, 1, 288–298. (b) Gelin,
R.; Gelin, S.; Dolmazon, R. Tetrahedron Lett. 1970, 42, 3657–3660. (c) Gelin,
S. Tetrahedron Lett. 1975, 48, 4255–4258. (d) Dolmazon, R.; Gelin, S. J. Org.
Chem. 1984, 49, 4003–4007. (e) Dolmazon, R.; Gelin, S. J. Heterocycl. Chem.
1985, 22, 793–795.
(6) Casey, M.; Donnelly, J. A.; Ryan, J. C.; Ushioda, S. ARKIVOC 2003,
310–327.
(7) (a) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005, 105,
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4757–4778. (b) Alajarın, M.; Sanchez-Andrada, P.; Vidal, A.; Tovar, F. J.
(2) (a) Light, R. J.; Hauser, C. R. J. Org. Chem. 1961, 26, 1716–1724. (b)
Zhang, J.; Li, Y.; Wang, W.; She, X.; Pan, X. J. Org. Chem. 2006, 71, 2918–
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Org. Chem. 2005, 70, 1340–1349. (c) Kleinke, A. S.; Li, C.; Rabasso, N.;
Porco, J. A. Jr. Org. Lett. 2006, 8, 2847–2850. (d) Tambar, U. K.; Kano, T.;
Zepernick, J. F.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 345–350. (e) Shoji,
M. Bull. Chem. Soc. Jpn. 2007, 80, 1672–1690. It has been reported that under
basic conditions some R,β-unsaturated 1,3-diketones give carbocyclic pro-
(3) For examples in synthesis, see: (a) Jin, M.; Taylor, R. E. Org. Lett.
ꢀ
2005, 7, 1303–1305. (b) Calad, S. A.; Cirakovic, J.; Woerpel, K. A. J. Org.
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ducts via 6π-electrocyclic reactions: Smith, A. B. III; Kilenyi, S. N.
Chem. 2006, 72, 1027–1030.
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DOI: 10.1021/jo901355e
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Published on Web 08/25/2009
J. Org. Chem. 2009, 74, 6973–6979 6973
2009 American Chemical Society

MacDonald and Burnell
JOCArticle
be via the protonated, enolic form A or by 6π-electro-
cyclization of the fully conjugated enol B.7
SCHEME 1
using Swern oxidation,12 IBX,13 or Dess-Martin period-
inane (DMP).14 Accordingly, most of the R,β-unsaturated
1,3-diketones (Table 1) used in this study were produced in
adequate yield from R,β-unsaturated acid chlorides and
ketones. No O-acylated product was detected. However, a
yield of 24% for the preparation in this way of 6 prompted us
to carry out its synthesis by reaction of the aldehyde with the
enolate, followed by oxidation with DMP; this gave 6 in 54%
yield. Poor reactivity of the enolate of 4-cyanoacetophenone
with R,β-unsaturated acid chlorides necessitated reaction of
the enolate of the R,β-unsaturated ketone with 4-cyanoben-
zoyl chloride to produce 16. It was convenient, due to the
availability of the R,β-unsaturated ketone, also to make 10
via the enolate of this ketone, although the yield of 10 was
only 24%.
Cyclization of r,β-Unsaturated 1,3-Diketones to 2,3-Dihy-
dro-4H-pyran-4-ones. The cyclization of 5 was assessed in
different media (Scheme 2). Under every set of conditions
that was tried (Table 2), the 2,3-dihydro-4H-pyran-4-one 18
was produced, and the yields ranged from 30 to 66%. The use
of methanol as the solvent was problematic because 18 was
contaminated by the product of conjugate addition of the
alcohol 19 in approximately 10% yield and by another
unidentified byproduct that was chromatographically very
similar to 18. NMR analysis of the crude reaction mixtures
suggested that the reaction in DMSO might have produced
18 most quickly. Cyclization was slower in THF/acidic
water, and 24% of 5 was recovered even after 29 h under
reflux, but the ease of workup made this procedure more
attractive to assess a range of R,β-unsaturated 1,3-diketones.
The 2,3-dihydro-4H-pyran-4-one products of heating solu-
tions of the series of R,β-unsaturated 1,3-diketones 6-17 in
acidic 1:1 THF/water are summarized in Table 1. Cycliza-
tions of substrates with methyl substitution R to the central
oxygen (6 f 20 and 8 f 22) were clearly less efficient than the
cyclization of 5. This was likely due to an added difficulty in
attaining a reactive geometry because the cyclic substrate 7
cyclized to 21 more efficiently than 5. Substitution of
the β carbon of the starting alkene was required because 9
gave no detectable (NMR) amount of the corresponding
2,3-dihydro-4H-pyran-4-one, only intractable material was
For the synthesis of a 2,3-dihydro-4-pyridinone ring 4,
hetero-Diels-Alder reactions or stepwise, formal [4 þ 2]
transformations involving imines have been employed usual-
ly.8 Recently, the microwave-assisted formation of 2,3-dihy-
dro-4-pyridinones from an R,β-unsaturated 1,3-diketone
and simple primary amines in the presence of Montmorillo-
nite K-10 was reported, and the mechanism was proposed to
be via a transient imine.9 Additions of Grignard reagents to
1-acyl-4-methoxypyridinium salts have been exploited many
times by Comins.10 Also, although never postulated in the
formation of a 2,3-dihydro-4-pyridinone, aza-6π-electrocy-
clization might be a viable annulation mechanism.11
A study of the efficiencies of cyclization of variously
carbon-substituted analogues of 3 to produce 1 has not
appeared, and neither has a study of the analogous cycliza-
tion to give 4. Herein, we present our findings with respect to
these annulations.
Results and Discussion
Preparation of r,β-Unsaturated 1,3-Diketones. The synthe-
sis of non-2-ene-4,6-dione (5) (Scheme 1) was our test reac-
tion for the formation of the R,β-unsaturated 1,3-diketones.
It was found, based on the procedure by Casey et al.,6 that
R,β-unsaturated acid chloride, trans-crotonoyl chloride,
reacted with the kinetic enolate of the 2-pentanone to give
5 in significantly higher yield than the two-step approach of
the reaction of trans-crotonaldehyde with the same enolate
followed by oxidation of the intermediate β-hydroxy ketone
(8) (a) Kerwin, J. F. Jr.; Danishefsky, S. Tetrahedron Lett. 1982, 23, 3739–
3742. (b) Danishefsky, S.; Vogel, C. J. Org. Chem. 1986, 51, 3915–3916. (c)
Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 1067–1068. (d)
Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444–4451. (e) Huang, Y.;
Rawal, V. H. Org. Lett. 2000, 2, 3321–3323. (f) Alaimo, P. J.; O’Brien, R. III;
Johnson, A. W.; Slauson, S. R.; O’Brien, J. M.; Tyson, E. L.; Marshall, A. L.;
Ottinger, C. E.; Chacon, J. G.; Wallace, L.; Paulino, C.; Connell, S. Org. Lett.
2008, 10, 5111–5114.
(9) Elias, R. S.; Saeed, B. A.; Saour, K. Y.; Al-Masoudi, N. A. Tetra-
hedron Lett. 2008, 49, 3049–3051.
(10) (a) Comins, D. L.; Goehring, R. R.; Joseph, S. P.; O’Connor, S. J.
Org. Chem. 1990, 55, 2574–2576. (b) Comins, D. L.; Hong, H. J. Org. Chem.
1993, 58, 5035–5036. (c) Comins, D. L.; Hong, H. J. Am. Chem. Soc. 1993,
115, 8851–8852. (d) Comins, D. L.; Kuethe, J. T. Org. Lett. 1999, 1, 1031–
1033. (e) Comins, D. L.; Fulp, A. B. Org. Lett. 1999, 1, 1941–1943. (f)
Comins, D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J. J. Am. Chem. Soc.
1999, 121, 2651–2652. (g) Young, D. W.; Comins, D. L. Org. Lett. 2005, 7,
5661–5664. (h) McCall, W. S.; Grillo, T. A.; Comins, D. L. J. Org. Chem.
2008, 73, 9744–9751.
(11) (a) Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995, 60, 1763–
1771. (b) Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611–
2614. (c) Vincze, Z.; Mucsi, Z.; Scheiber, P.; Nemes, P. Eur. J. Org. Chem.
2008, 1092–1100.
(12) Smith, A. B. III; Levenberg, P. A. Synthesis 1981, 7, 567–570.
(13) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125, 10772–
10773.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156–4158.
(15) The predominant enol forms were identified using 1H and 13C NMR
spectra and 2D correlations (HSQC and HMBC). The ratios of enol to keto
forms could be assessed by integration of clearly separated signals in the 1H
NMR spectra.
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MacDonald and Burnell
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TABLE 1. R,β-Unsaturated 1,3-Diketones, Shown in Their Predominant
Tautomeric Forms in CDCl3,15 and Their Cyclization Products in THF/Water
(1:1) with TsOH
SCHEME 2
TABLE 2. Cyclization of 5
solvent,
concn of 5
T (°C),
time (h)
additive
(equiv)
yield of
18 (%)
anhydrous
methanol, 0.02 M
anhydrous
methanol, 0.02 M
anhydrous
reflux, 16
31
reflux, 22
reflux, 16
TsOH, 0.1
NEt3, 1
44
44
methanol, 0.02 M
acetic acid, 0.03 M
DMSO, 0.06 M
THF/water (1:1),
0.03 M
100, 15
95, 18
reflux, 20
30
67
59
THF/water (1:1),
0.05 M
THF, 0.05 M
reflux, 29
reflux, 29
TsOH, 0.1
TsOH, 0.1
66
46
obtained. While substitution of this carbon with tert-butyl (10)
seemed to attenuate the rate of cyclization relative to a methyl
substituent, destruction of the starting compound was not a
competitive process. Relative to the compounds with a single
methyl group on the β carbon of the starting alkene, e.g., 5, 13,
and 14, double methyl substitution of the β carbon, as in 11, 15,
and 16, had no obvious dilatory effect on reactivity, and 24, 27,
and 28, respectively, were obtained in good yield. On the other
hand, substitution of the β carbon with a phenyl group, as in 12
and 17, suppressed cyclization, and 2,3-dihydro-4H-pyran-4-
ones were not detected. A phenyl substituent, or a substituted
phenyl group, R to the first carbonyl, as in 13-16, led to cyclized
products 25-28 with yields equal to, or better than, the yield
of 18 from 5. It should be mentioned that the R,β-unsaturated
1,3-diketone 29, for which enolization to attain the putatively
reactive forms A and B, is blocked but which might cyclize
through the unconjugated enol C, remained unchanged under
the acidic THF/water conditions.
Model Reactions toward Pestaloficiol A. Pestaloficiol A 30
is a recently described natural product with anti-HIV acti-
vity.16 The construction of the 2,3-dihydro-4H-pyran-4-one
moiety onto a bicyclic ketone was explored as a model for the
synthesis of 30. Dulcere17 had reported the formation of
ꢁ
(16) Liu, L.; Tian, R.; Liu, S.; Chen, X.; Guo, L.; Che, Y. Bioorg. Med.
Chem. 2008, 16, 6021–6026.
ꢁ
(17) (a) Dulcere, J.-P.; Rodriguez, J.; Santelli, M.; Zahra, J. P. Tetrahedron
Lett. 1987, 28, 2009–2012. (b) Dulcere, J.-P.; Mihoubi, M. N.; Rodriguez, J.
ꢁ
J. Org. Chem. 1993, 58, 5709–5716.
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MacDonald and Burnell
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However, only the conjugated, O-acylated product 34 was
obtained. A bromine-substituted propargyl alcohol also
added to cyclohexenone, and the resulting dibromo-ether
31c underwent radical cyclization to provide 32c. In contrast
with 32b, this bicyclic compound did not isomerize during
flash chromatography or upon storage at room temperature.
Its kinetic enolate was C-acylated by an R,β-unsaturated acid
chloride to give 35. It was gratifying that when 35 was heated
in 1:1 THF/water with 0.1 equiv of TsOH, cyclization
occurred smoothly to afford the 2,3-dihydro-4H-pyran-4-
one 36 in 78% yield.
the bicyclic ketone 32a in two steps first by reacting propar-
gyl alcohol with cyclohexenone in the presence of NBS and
H2SO4 to give the bromo ether 31a (90-95% yield) and,
second, by effecting radical cyclization of 31a with tri-n-
butyltin hydride to give 32a in 88-92% yield. Acid-induced
isomerization of 32a to 33a took place efficiently. We
investigated this transformation starting with cyclohexenone
and the dimethyl propargyl alcohol, and the bromo ether 31b
was obtained, albeit in a modest yield (Scheme 3). The bromo
ether cyclized in the presence of tri-n-butyltin hydride to give
the bicyclic ketone 32b in 67% yield. The cis ring fusion was
assumed by analogy with related reactions.17,18 Alkene iso-
merization of 32b to 33b occurred upon treatment with acid,
Cyclization of r,β-Unsaturated 1,3-Diketones to 2,3-Dihy-
dro-4-pyridinones. Cyclization of either an enamine derived
from an R,β-unsaturated 1,3-diketone, in the geometry D, or
of the corresponding imine in the geometry E,9 might provide
2,3-dihydro-4-pyridinones by ionic or pericyclic pathways. It
was hypothesized that if an amine could form the enamine or
imine rapidly relative to the rate of cyclization to the 2,3-
dihydro-4H-pyran-4-one, then one might envisage admix-
ture of an R,β-unsaturated 1,3-diketone with an amine in a
suitable medium providing the 2,3-dihydro-4-pyridinone in a
single operation. This idea was tested using the R,β-un-
saturated 1,3-diketone 5 with 1.1 equiv of aniline, cyclohex-
anamine, 1-phenylethanamine, 2-phenylethanamine, 2-pro-
panamine, 1-butanamine, and glycine; under reflux in
methanol and in THF/water (1:1) in the presence of 0.1
equiv of TsOH. Only 2-phenylethanamine and 1-butana-
mine provided any 2,3-dihydro-4-pyridinones, and these
were isolated in very good yield (Scheme 4). Thus, it seems
that the amine must be an unencumbered primary amine.
The remainder of the amines gave mixtures of products that
seemed by NMR to include enamines and some 2,3-dihydro-
4H-pyran-4-one 18.
SCHEME 3
SCHEME 4
Some other R,β-unsaturated 1,3-diketones were heated
with 1-butanamine (5 equiv) in acidic THF/water. The
results are shown in Table 3.19 There is no obvious correla-
tion between the yields of the 2,3-dihydro-4H-pyran-4-ones
versus the yields of the 2,3-dihydro-4-pyridinones. The most
pronounced contrasts were the reactions of 12, 15, and 16.
Diketone 12 had failed to produce any 2,3-dihydro-4H-
pyran-4-one, but 2,3-dihydro-4-pyridinone 43 was obtained,
and even during chromatography or during storage at room
temperature. An attempt was made to C-acylate 33b with an
R,β-unsaturated acid chloride in order to prepare a sub-
strate that might cyclize to a 2,3-dihydro-4H-pyran-4-one.
(19) In addition, neither 10 nor 17 gave any cyclized product. Some
downfield signals in the 1H NMR spectra of the reaction mixtures suggested
that enamines had formed.
(18) Schinzer, D.; Jones, P. G.; Obierey, K. Tetrahedron Lett. 1994, 35,
5853–5856.
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TABLE 3. Cyclization of R,β-Unsaturated 1,3-Diketones to 2,3-Dihy-
dro-4-pyridinones in THF/Water (1:1) with TsOH and 1-Butanamine (5
equiv) with Reaction Times and Isolated Yields
major species in solution. There was a minor amount of the
2,3-dihydro-4H-pyran-4-one 24 but only a trace of 42. Also,
when the 2,3-dihydro-4H-pyran-4-one 18 was heated for 24 h
with 1-butanamine in acidic THF/water the major part of the
product appeared to be a mixture of enamines, but 2,3-
dihydro-4-pyridinone 38 was not detected. Thus, it appeared
that a 2,3-dihydro-4-pyridinone was not derived either from
the enamine or from the 2,3-dihydro-4H-pyran-4-one.
1,3-Diketone 15 failed to provide any 2,3-dihydro-4-pyr-
idinone, but three compounds 48-50 were identified as the
main components of the product mixture. From 16, the
analogous compounds 51-53 were the major components
in the product mixture. Compounds 48 and 51 were enam-
ines related to 45-47, and, given the experiment with 47, it
can be presumed that they could not cyclize in acidic THF/
water. The generation of compounds 49, 50, 52, and 53, with
truncated carbon chains, indicated pathways for the diver-
sion of the R,β-unsaturated 1,3-diketones from the pathway
toward the 2,3-dihydro-4-pyridinones. The acetophenones
49 and 52 might have been derived from a protonated form of
the common intermediate to enamines 48 and 51, i.e., hemi-
aminal 54, by a retro-aldol process. Enamines 50 and 53
could be rationalized by initial 1,4-attack of the amine,
followed by a retro-Mannich reaction, and then by enamine
formation from the resulting truncated 1,3-diketone
(Scheme 5). That 15 and 16 provided no 2,3-dihydro-4-
pyridinones was consistent with the stability of the iminium
ion 55 relative to the less substituted iminium ions that would
have been produced from most of the other R,β-unsaturated
1,3-diketones.
although the yield of 43 was modest. More dramatically,
diketones 15 and 16 had provided some of the best yields of
2,3-dihydro-4H-pyran-4-ones but no 2,3-dihydro-4-pyridi-
nones.
The crude reaction mixtures from 8, 11, 12, and 13
contained material that appeared from the 1H NMR spectra
to include enamine moieties. The major enamines were
isolated from the reaction of 8, and these proved to be a
7:1 mixture of 45 and 46, in a combined yield of 53%.
Enamine 47 was obtained in 18% yield from the reaction
of 11. In order to gain some clues regarding the mechanism
for the formation of the 2,3-dihydro-4-pyridinones, 47 was
reheated in acidic THF/water. After 24 h, 47 was still the
With the suggestion that 1,4-additions of the amine may be
competitive with the formation of enamines, which did not
react further to give 2,3-dihydro-4-pyridinones, the mechan-
ism for the formation of the 2,3-dihydro-4-pyridinones is
therefore postulated to be mainly by initial 1,4-addition of
the amine followed by intramolecular enamine formation
(Scheme 6). Furthermore, it may be suggested that even the
formation of the 2,3-dihydro-4H-pyran-4-ones might be
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MacDonald and Burnell
JOCArticle
SCHEME 5
minimal substitution near the amino-carbon, but yields were
adversely affected by reaction pathways leading to enamines
and to intermediates that were prone to chain-shortening
reactions.
Experimental Section
General Procedure for the Preparation of 2,3-Dihydro-4H-
pyran-4-ones: 2,3-Dihydro-2-methyl-6-propyl-4H-pyran-4-one
(18). A solution of R,β-unsaturated 1,3-diketone 5 (38 mg,
0.25 mmol) and TsOH (5 mg, 0.02 mmol) in THF/H2O (1:1)
(6.0 mL) was heated under reflux for 29 h. The solution was
brought to rt, and H2O and ether were added. The aqueous
phase was extracted thoroughly with ether. The combined
organic layers were dried (MgSO4), and the solvent was removed
under reduced pressure. Flash chromatography of the residue
using pentane containing an increasing proportion of ether
provided 18 (25 mg, 66%) as a liquid, and 9 mg of 5 was
SCHEME 6
recovered. For 18: IR (film) 1726 (m), 1666 (s), 1603 (s) cm-1
;
1H NMR δ 5.32 (1H, s), 4.49 (1H, m), 2.40 (2H, m), 2.21 (2H, m),
1.60 (2H, sextet, J = 7.4 Hz), 1.45 (3H, d, J = 6.4 Hz), 0.95 (3H,
t, J = 7.4 Hz); 13C NMR δ 193.0 (0), 177.6 (0), 104.0 (1), 75.6 (1),
42.7 (2), 36.7 (2), 20.4 (3), 19.8 (2), 13.6 (3); HRMS (ESI)
177.0883, calcd for C9H14O2Naþ 177.0886.
9-(Bromomethylene)-5,6,6a,8,9,9a-hexahydro-2,2,8,8-tetra-
methyl-2H-furo[2,3-h]chromen-4(3H)-one (36). Following the
procedure for 18, 35 gave 36 (78%) after 13 h as a solid: mp
116-118 °C; IR (film) 3058 (w), 1674 (m), 1657 (s), 1609 (s)
1
cm-1; H NMR δ 6.24 (1H, d, J=1.2 Hz), 4.37 (1H, m), 3.64
(1H, m), 2.59 (1H, d, J=16.4 Hz), 2.49 (1H, dd, J=16.1, 5.0 Hz),
2.43 (1H, d, J=16.4 Hz), 2.25 (1H, m), 2.09 (1H, m), 1.52 (1H,
m), 1.46 (3H, s), 1.37 (3H, s), 1.32 (3H, s), 1.24 (3H, s); 13C NMR
δ 192.2 (0), 164.9 (0), 152.0 (0), 110.3 (0), 102.4 (1), 82.4 (0), 79.7
(0), 73.7 (1), 47.7 (1), 47.5 (2), 29.8 (3), 28.2 (3), 27.3 (3), 25.1 (3),
23.8 (2), 14.5 (2); HRMS (ESI) 363.0539, calcd for C16H21BrO3-
Naþ 363.0566.
SCHEME 7
General Procedure for the Preparation of 2,3-Dihydro-4-pyr-
idinones. To a solution of the R,β-unsaturated 1,3-diketone (0.05
M) in THF/water (1:1) was added the amine (for 37 and 38: 1.1
equiv of 2-phenylethanamine and 1-butanamine; for 39-44: 5
equiv of 1-butanamine) followed by TsOH (10 mol %). The mixture
was heated under reflux until TLC indicated the disappearance of
the diketone. The mixture was cooled to rt, and H2O (10 mL) and
Et2O (20 mL) were added. The aqueous phase was re-extracted with
Et2O. The combined organic layers were dried over MgSO4. The
solvent was removed under reduced pressure. Flash chromatogra-
phy was carried out using pentane containing an increasing pro-
portion of ether and then EtOAc containing and increasing propor-
tion of MeOH. For reaction times and yields, see Table 3.
2,3-Dihydro-2-methyl-1-(2-phenylethyl)-6-propyl-4-pyridi-
none (37): viscous liquid; 1H NMR δ 7.33 (2H, m), 7.26 (1H, m),
7.20 (2H, m), 4.92 (1H, s), 3.73 (1H, dt, J=14.6, 7.2 Hz), 3.50
(1H, dp, J=6.7, 2.2 Hz), 3.18 (1H, dt, J=14.6, 7.2 Hz), 2.89 (2H,
t, J=7.2 Hz), 2.67 (1H, dd, J=16.3, 6.8 Hz), 2.16-1.97 (3H, m),
due, at least partly, to an initial 1,4-addition of water to the
R,β-unsaturated 1,3-diketones.
Finally, two examples of double reactions of diamines
were demonstrated (Scheme 7). When 2 equiv of 5 and
1 equiv of 1,3-propanediamine were heated in acidic
THF/water, 1H NMR analysis of the reaction mixture
indicated almost complete conversion to 56 (a mixture of
diastereomers by NMR). This product was difficult to purify
by chromatography on silica gel, and so the isolated yield
was a disappointing 39%. Repeating this process with 7 gave
57, but this was, once again, not well recovered from silica
gel (40%).
In conclusion, the efficiency of cyclization of R,β-unsatu-
rated 1,3-diketones to provide 2,3-dihydro-4H-pyran-4-ones
was viable, except in instances in which the β position of the
alkene was either unsubstituted or substituted by a phenyl
group. The one-pot cyclization of R,β-unsaturated 1,3-dike-
tones and amines was restricted to primary amines with
1.49 (2H, m), 1.18 (3H, d, J=6.7 Hz), 0.94 (3H, t, J=7.3 Hz); 13
C
NMR δ 190.1 (0), 163.0 (0), 138.0 (0), 128.8 (2C, 1), 128.7 (2C,
1), 126.9 (1), 98.3 (1), 54.0 (1), 50.2 (2), 41.6 (2), 36.8 (2), 34.9 (2),
21.2 (2), 14.9 (3), 13.8 (3); HRMS (ESI) 258.1853, calcd for
C17H23NOHþ 258.1852.
1-Butyl-2,3-dihydro-2-methyl-6-propyl-4-pyridinone (38): vis-
cous liquid; IR (film) 1733 (m), 1613 (s), 1530 (s) cm-1; 1H NMR
δ 4.92 (1H, s), 3.62 (1H, dp, J=6.7, 2.2 Hz), 3.45 (1H, ddd, J=
14.8, 8.8, 6.6 Hz), 2.95 (1H, ddd, J=14.6, 9.0, 6.5 Hz), 2.73 (1H,
dd, J=16.2, 6.6 Hz), 2.23 (1H, m), 2.17-2.08 (2H, m), 1.66-1.46
(4H, m) 1.37 (2H, sextet, J=7.4 Hz), 1.20 (3H, d, J = 6.7 Hz),
0.97 (3H, t, J=7.3 Hz), 0.96 (3H, t, J=7.3 Hz); 13C NMR δ 189.9
(0), 163.3 (0), 98.0 (1), 53.5 (1), 48.3 (2), 41.7 (2), 35.2 (2), 32.2 (2),
6978 J. Org. Chem. Vol. 74, No. 18, 2009

MacDonald and Burnell
JOCArticle
21.3 (2), 20.0 (2), 14.9 (3), 13.83 (3), 13.80 (3); HRMS (ESI)
210.1847, calcd for C13H23NOHþ 210.1852.
(2C, 2), 14.6 (2C, 3), 13.6 (2C, 3); HRMS (ESI) 369.2500, calcd
for C21H34N2O2Naþ 369.2512.
Preparation of Three-Carbon-Tethered 2,3-Dihydro-4-pyridi-
nones. To a solution of the R,β-unsaturated 1,3-diketone (0.05
M, 2 equiv) in THF/water (1:1) was added 1,3-propanediamine
(1 equiv) followed by TsOH (10 mol %). The mixture was heated
under reflux until TLC indicated the disappearance of the
diketone (19 h for 5, 11 h for 7). The mixture was cooled to rt,
and H2O (10 mL) and CH2Cl2 (20 mL) were added. The aqueous
phase was re-extracted thoroughly with CH2Cl2. The combined
organic layers were dried over MgSO4. The solvent was removed
under reduced pressure. Flash chromatography was carried out
using a stepwise mobile phase proceeding from 50% Et2O/
pentane to 20% to 40% MeOH/EtOAc.
1,10-(Propane-1,3-diyl)bis(2,3,5,6,7,8-hexahydro-2-methylqui-
nolin-4-one) (57): 1:1 mixture of diastereomers; viscous liquid;
IR (Nujol) 1602 (s), 1537 (s) cm-1; 1H NMR [signal for second
diastereomer where discernible] δ 3.56-3.46 (4H, m), 2.92 [2.89]
(2H, t, J=7.3 Hz), 2.69 [2.66] (2H, dd, J=6.6, 2.7 Hz), 2.36 [2.32]
(2H, t, J=5.2 Hz), 2.29-2.08 (8H, m), 1.88-1.78 (2H, pentet,
J=7.5 Hz), 1.72 (2H, m), 1.65-1.46 (4H, m), 1.37 (2H, m), 1.13
(6H, d, J=6.6 Hz); 13C NMR [second diastereomer] δ 188.89
[188.87] (2C, 0), 156.4 [156.3] (2C, 0), 105.93 [105.87] (2C, 0),
52.9 [52.8] (2C, 1), 45.2 [45.0] (2C, 2), 41.94 [41.92] (2C, 2), 30.3
[30.2] (2), 27.5 (2C, 2), 22.4 (2C, 2), 21.7 (2C, 2), 21.6 (2C, 2),
14.73 [14.70] (2C, 3); HRMS (ESI) 393.2498, calcd for C23H34-
N2O2Naþ 393.2512.
1,10-(Propane-1,3-diyl)bis(2,3-dihydro-2-methyl-6-propyl-4-
pyridinone) (56): 1:1 mixture of diastereomers; viscous liquid; IR
1
(film) 3063 (w), 1709 (w), 1614 (s), 1536 (s) cm-1; H NMR
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada and the Killam Trusts for
funding.
[signal for second diastereomer where discernible] δ 4.92 [4.91]
(2H, br s), 3.60 (2H, br sextet, J=6.8 Hz), 3.55-3.45 (2H, m),
3.05-2.96 (2H, m), 2.67 (2H, dd, J=16.3, 6.6 Hz), 2.22-2.04
(6H, m), 1.90 (2H, m), 1.49 (4H, symmetrical m), 1.17 (6H, d,
J=6.6 Hz), 0.93 (6H, t, J=7.4 Hz); 13C NMR [signal for second
diastereomer where discernible] δ 189.8 (2C, 0), 162.5 [162.4]
(2C, 0), 98.9 [98.8] (2C, 1), 53.6 [53.5] (2C, 1), 45.4 [45.3] (2C, 2),
41.8 (2C, 2), 35.2 [35.1] (2C, 2), 30.4 [30.3] (2), 21.14 [21.11]
Supporting Information Available: Experimental proce-
dures and characterization data for new compounds and H
1
and 13C NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 18, 2009 6979