Total synthesis of the naphthyridine alkaloid jasminine

Article abstract of DOI:10.1016/j.tet.2004.06.027

The synthesis of (±)-jasminine (1), a member of a small group of naphthyridine alkaloids, has been achieved. The synthetic route takes advantage of the reactivity of dihydropyridine intermediates for the preparation of trisubstituted pyridine 4, which giv

Full text of DOI:10.1016/j.tet.2004.06.027

Tetrahedron 60 (2004) 6785–6789
Total synthesis of the naphthyridine alkaloid jasminine
*
M.-Lluısa Bennasar, Tomas Roca, Ester Zulaica and Manuel Monerris
`
¨
Faculty of Pharmacy, Laboratory of Organic Chemistry, University of Barcelona, Avda. Joan XXIII, sn, Barcelona 08028, Spain
Received 14 April 2004; revised 28 May 2004; accepted 7 June 2004
Abstract—The synthesis of (^)-jasminine (1), a member of a small group of naphthyridine alkaloids, has been achieved. The synthetic route
takes advantage of the reactivity of dihydropyridine intermediates for the preparation of trisubstituted pyridine 4, which gives access to the
alkaloid by a reductive amination-lactamization tandem reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Jasminine (1, Fig. 1) is a monoterpene alkaloid isolated in
1968 from Jasminum gracile and other Oleaceae species,1
which is characterized by a pyridine ring fused to a six-
membered lactam moiety. This singular 2,7-naphthyridin-3-
one skeleton is also present in jasminidine (2)2 and
dihydrojasminine (3),3 which co-occur with 1 in Syringa
vulgaris and Osmanthus austrocaledonica, respectively.4
These alkaloids have attracted little synthetic attention: to
our knowledge, only a biomimetic hemisynthesis of
jasminine (1) from related secoiridoids5 has been reported
to date.
The synthesis of the pivotal intermediate 4 through
dihydropyridines 6 and 7 is depicted in Scheme 2. The
benzhydryl group was selected as the nitrogen substituent
for the starting pyridinium salt 5 as it is easily installed in a
3-acylpyridine and can be removed in relatively mild
conditions.8d,9 Based on our own experience, we decided to
use the enolate of methyl a-(methylsulfanyl)acetate10 as the
nucleophilic partner for the introduction of the acetate chain
at the 4-position of the pyridine ring.11 Satisfactorily, the
reaction of this enolate with 5, followed by acylation with
trichloroacetic anhydride gave dihydropyridine 6 (70%
yield, mixture of epimers) along with minor amounts of
regioisomeric 1,2-dihydropyridines (not isolated). 1,4-
Dihydropyridine 6 was subjected to haloform reaction
with sodium methoxide and radical desulfurization with
Ph3SnH–AIBN to give 7 in 75% yield.
As a part of our continuing interest in the chemistry of
dihydropyridines,6 which are useful intermediates for
natural product synthesis,7 we present here a concise, total
synthesis of (^)-jasminine (1). In planning our approach,
we found it logical to close the lactam ring in the last
synthetic step by a reductive amination–lactamization
process from pyridine 4 (Scheme 1), which, in turn, would
be prepared from commercially available 3-acetylpyridine
by the sequential introduction of substituents at the 4- and
5-positions of the ring. To this end, we could take advantage
of our previously reported procedure for the synthesis of
substituted dihydropyridines, based on the addition of
carbon nucleophiles to N-alkylpyridinium substrates, fol-
lowed by acylation of the resultant dihydropyridine
adducts.8 This nucleophilic addition–acylation sequence
would have to be combined with a final oxidative step, with
concomitant or subsequent N-dealkylation.
With 1,4-dihydropyridine 7 in hand, attention was turned to
the oxidative step. We initially tested the oxidative reagent
system (TFA–phenol–Pd/C, 50 8C) we had successfully
used for the tandem N-dealkylation–oxidation of 4-unsub-
stituted N-(benzhydryl)dihydropyridines.9,12 However,
under these conditions the desired pyridine 4 was isolated
in poor yields (15% yield) and pyridine 8,13 lacking the
acetic ester, was the major product (50% yield). As
Keywords: Dihydropyridines; Pyridines; Acylation; Alkaloids.
*
Corresponding author. Tel.: þ34-934024540; fax: þ34-934024539;
e-mail address: bennasar@ub.edu
Figure 1. Jasminine and related alkaloids.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.027

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Scheme 1. Synthetic approach.
formation of 8 is presumably the result of a retroaddition
reaction that occurs from the initially formed N-unsubsti-
tuted dihydropyridine, we reasoned that in order to
minimize this undesired process oxidation should take
place prior to N-dealkylation. We were proved right since
when 7 was treated with Mn(OAc)3 in TFA–acetic acid14
and then with phenol the yield of pyridine 4 increased to
80%, with little or no formation of 8.
Scheme 3. Reagents and conditions: (a) Allylamine or benzylamine,
B10H14, MeOH, rt, 48 h, 9a: 20%, 10a: 40%, 9b: 20%, 10b: 10%; (b)
NaBH4, MeOH, 0 8C, 10 min, 80%; (c) NH3, MeOH, rt, 1 h, 78%.
Having established a functional protocol for the preparation of
pyridine 4, we then proceeded to construct the naphthyridine
ring system of jasminine (1) using a reductive amination–
lactamization tandem reaction sequence.15 We examined first
the behavior in this process of ammonia equivalents such as
allylamine or benzylamine. After recovering the starting
material under standard reaction conditions using
aminolysis of a lactone intermediate, with subsequent
cyclization to the aromatic ester group. This hypothesis
could be confirmed since reduction of 4 with NaBH4 in
methanol gave lactone 11 (80% yield), which upon a short
exposure to a methanolic solution of ammonia afforded
imide 12, the N-unsubstituted derivative of 10, in 78% yield.
Na(CN)BH3 or Na(AcO)3BH15,17 as reducing agents, the
16
desired jasminine lactams 9a and 9b were obtained, although
in low yield (20%), when the reductive amination was effected
inthe presenceofdecaboraneactingasboththe catalystfor the
imine formation and the reducing agent (Scheme 3).18,19
Significantly, bicyclic imides 10a and 10b were also isolated
from the reaction mixtures in 40% and 10% yields,
respectively. These compounds have the 2,7-naphthyridin-
1,3-dione skeleton characteristic of the alkaloid sebasnine,20
which was shown by NMR to be in the highly conjugated
4-alkylidene-1,4-dihydropyridine tautomeric formdepicted in
10. We suspected that formation of 10 involved the initial
reduction of the acetyl carbonyl group of 4, followed by
The low yield of lactams 9 and the need for an additional
N-deprotection step to complete the synthesis21 motivated
us to address the synthesis of jasminine (1) using a reductive
amination with ammonia. Again this seemingly simple task
was complicated by the low reactivity of the acetyl carbonyl
group and the intensive functionalization of our substrate.
Thus, the use of standard protocols such as AcONH4–
Na(CN)BH3 or AcONH4–Na(AcO)3BH resulted, as above,
in the recovery of 4. On the other hand, several noteworthy
results were obtained when the amination reaction was
carried out with more nucleophilic reagents or under more
energetic conditions. Exposure of 4 to MeAl(Cl)NH222,23 at
room temperature in benzene resulted in the formation of a
nearly equimolecular mixture of two fully aromatic
bicycles, 13 and 14, in 60% yield (Scheme 4). Whereas
Scheme 2. Synthesis of pyridine 4. Reagents and conditions: (a)
MeSCH2CO2Me, LDA, THF, 278 8C, 30 min, then 240 8C, 2 h; (b)
(Cl3CCO)2O, triethylamine, rt, 12 h, 70%; (c) MeONa, MeOH, rt, 1 min;
(d) Ph3SnH, AIBN, benzene, reflux, 2 h, 75%; (e) Mn(OAc)3·2H2O, 1:1
TFA–AcOH, 45 8C, 1h, then phenol, 45 8C, 2 h, 80%.
Scheme 4. Synthesis of (^)-jasminine (1). Reagents and conditions: (a)
MeAl(Cl)NH2, C6H6, rt, 5 h, 13: 30%, 14: 30%; (b) Ammonium formate,
150 8C, 10 min, 75%; (c) NH4Cl, Et3N, Ti(i-PrO)4, rt, overnight, then
NaBH4, rt, 2 h, 1: 25%; 13: 40%.

M.-L. Bennasar et al. / Tetrahedron 60 (2004) 6785–6789
6787
dihydroxyisoquinoline 14 is the result of a Claisen
condensation promoted by the basic character of the
reagent, formation of naphthyridinol 13, a didehydro
derivative of the natural product, is striking as it involves
an intramolecular acylation at the imine stage. This
premature lactamization precludes the subsequent reduction
to jasminine as treatment of 4 with ammonium formate
(both an ammonia source and a reducing agent)24 at 150 8C
for a short time (10 min) resulted in the exclusive formation
of 13 in 75% yield. This serious drawback could be partially
countered by the sequential treatment of 4 with ammonia,
generated in situ from NH4Cl and Et3N at room temperature
in the presence of Ti(i-PrO)4, and then with NaBH4.25 Under
these conditions, 13 was still the major product (40% yield),
but the desired lactam 1, (^)-jasminine, was isolated in a
consistent, reproducible 25% yield. Our synthetic product
slowly added to a cooled (278 8C) solution of methyl
(methylsulfanyl)acetate (0.72 mL, 6.60 mmol) in dry THF
(110 mL), and the resulting solution was stirred at 278 8C
for 30 min. Pyridinium salt 5 (2 g, 5.50 mmol) was added in
portions at 278 8C, and the mixture was allowed to rise to
240 8C. After 2 h at this temperature, the mixture was
treated with Et3N (4.60 mL, 33 mmol) and TCAA (6 mL,
33 mmol) and stirred at rt overnight. The reaction mixture
was poured into saturated aqueous Na2CO3 and extracted
with Et2O. The solvent was removed and the crude product
was chromatographed (75:25 hexanes–AcOEt) to give 6
(2.12 g, 70%, mixture of epimers): 1H NMR (CDCl3,
300 MHz) d 2.04 and 2.05 (2s, 3H), 2.20 and 2.27 (2s, 3H),
3.42 and 3.43 (2d, J¼4.8, 5.1 Hz, 1H), 3.62 and 3.69 (2s,
3H), 4.88 and 4.93 (2d, J¼5.1, 4.8 Hz, 1H), 6.10 (s, 1H),
7.20–7.45 (m, 11H), 7.86 and 7.90 (2s, 1H). Anal. Calcd for
C26H24Cl3NO4S: C, 56.48; H, 4.38; N, 2.53. Found: C,
56.12; H, 4.36; N, 2.47.
1
displayed H NMR data identical to those reported for the
natural product,2,3 and its 13C NMR and analytical data were
in full agreement with the proposed structure.
4.1.3. Methyl 3-acetyl-1-benzhydryl-5-(methoxycarbon-
yl)-1,4-dihydropyridine-4-acetate (7). A solution of (tri-
chloroacetyl)-1,4-dihydropyridine 6 (2 g, 3.6 mmol) in THF
(65 mL) was added to a solution of MeONa (10.5 mmol) in
MeOH (35 mL), and the mixture was stirred at rt for 1 min.
The solvent was removed and the resulting residue was
partitioned between Et2O and H2O, and extracted with
Et2O. After concentration of the organic extracts, the resulting
residue was dissolved in C6H6 (100 mL) and treated with
triphenyltin hydride (0.89 mL, 3.5 mmol) and AIBN (58 mg.
0.35 mmol). After stirring at reflux temperature for 1 h,
triphenyltin hydride (0.89 mL, 3.5 mmol) and AIBN (58 mg.
0.35 mmol) were again added and heating was continued for
2 h. The solvent was removed and the resulting residue was
partitioned between Et2O and H2O, and extracted with
Et2O. The organic extracts were concentrated and the residue
was chromatographed (75:25 hexanes–AcOEt) to give 7
(1.13 g; 75%): 1H NMR (300 MHz) d 2.07 (s, 3H), 2.45 and
2.53 (2dd, J¼5.1, 13.8 Hz, 2H), 3.55(s, 3H), 3.67 (s, 3H), 4.36
(t, J¼5.1 Hz, 1H), 5.91 (s, 1H), 7.05 (d, J¼1.2 Hz, 1H), 7.23
(m, 5H), 7.39 (m, 6H); 13C NMR (75.4 MHz) d 24.6, 29.0,
39.9, 51.1, 51.3, 70.7, 107.3, 116.3, 128.2, 128.3, 128.4, 128.5,
128.9, 137.7, 137.8, 138.6, 139.6, 166.8, 172.0, 194.8. Anal.
Calcd for C25H25NO5: C, 71.58; H, 6.01; N, 3.34. Found: C,
71.28; H, 6.16; N, 3.23.
3. Conclusions
In conclusion, the present work provides the first total
synthesis of the naphthyridine alkaloid jasminine, not an
easy target in spite of its apparent structural simplicity. The
strategy employed hinges on the straightforward preparation
of a 3,4,5-trisubstituted pyridine from a 3-substituted
pyridine, emphasizing the well-known utility of 1,4-
dihydropyridines as intermediates for alkaloid synthesis.
4. Experimental
4.1. General
All nonaqueous reactions were performed under an argon
atmosphere. All solvents were dried by standard methods.
Reaction courses and product mixtures were routinely
monitored by TLC on silica gel (precoated F254 Merck plates).
Drying of organic extracts during the workup of reactions was
performed over anhydrous Na2SO4. Evaporation of the
solvents was accomplished under reduced pressure with a
rotatory evaporator. Flash chromatography was carried out on
SiO2 (silica gel 60, SDS, 0.04–0.06 mm). Melting points are
uncorrected. Chemical shifts of NMR spectra are reported in
ppm downfield (d) from Me4Si.
4.1.4. Methyl 3-acetyl-5-(methoxycarbonyl)pyridine-4-
acetate (4). Mn(AcO)3·2H2O (0.54 g, 2 mmol) was added to
a solution of 1,4-dihydropyridine 7 (0.42 g, 1 mmol) in
AcOH–TFA (1:1, 20 mL). After stirring at 45 8C for 1.5 h,
phenol (1.32 g, 14 mmol) was added in 7 portions over 2 h
at 45 8C. The reaction mixture was cooled (ice bath),
basified with saturated aqueous Na2CO3 and extracted with
CH2Cl2. The solvent was removed and the residue was
chromatographed (58:42 hexanes–AcOEt) to give pyridine
4.1.1. 3-Acetyl-1-benzhydrylpyridinium bromide (5). A
solution of 3-acetylpyridine (7 mL, 63.8 mmol) and bromo-
diphenylmethane (18.9 g, 76.6 mmol) in dry acetone
(60 mL) was stirred at rt for a week. The white solid
which appeared was collected by filtration and washed with
Et2O to give pyridinium salt 5 (12.8 g, 55%): mp 145–6 8C;
1H NMR (300 MHz, DMSO-d6) d 2.69 (s, 3H), 7.31 (m,
4H), 7.49 (m, 6H), 7.84 (s, 1H), 8.30 (dd, J¼6, 8.1 Hz, 1H),
9.10 (d, J¼8.1 Hz, 1H), 9.18 (d, J¼6 Hz, 1H), 9.53 (s, 1H);
13C NMR (75.4 MHz) d 27.7, 76.0, 129.0, 129.2, 129.5,
129.7, 135.8, 136.0, 145.1, 145.4, 146.6, 194.1.
1
4 (0.2 g, 80% yield) as a yellow solid: mp 20–22 8C; H
NMR (400 MHz) d 2.67 (s, 3H), 3.72 (s, 3H), 3.95 (s, 3H),
4.39 (s, 2H), 9.05 (s, 1H), 9.20 (s, 1H); 13C NMR
(100.6 MHz) d 30.2, 34.8, 52.5, 53.0, 127.8, 135.0, 144.3,
152.4, 153.9, 166.1, 170.7, 200.1. For the hydrochloride: mp
1
60–61 8C; H NMR (300 MHz, DMSO-d6) d 2.64 (s, 3H),
3.59 (s, 3H), 3.85 (s, 3H), 4.17 (s, 2H), 9.08 (s, 1H), 9.22
(s, 1H). Anal. Calcd for C12H13NO5·HCl: C, 50.10; H, 4.90;
N, 4.87. Found: C, 50.52; H, 4.96; N, 4.91.
4.1.2. Methyl 3-acetyl-1-benzhydryl-a-(methylsulfanyl)-
5-(trichloroacetyl)-1,4-dihydropyridine-4-acetate (6).
LDA (1.5 M in cyclohexane, 4.40 mL, 6.60 mmol) was

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4.2. Tandem reductive amination–lactamization from
pyridine 4 and primary amines
Lactone 11 (0.11 g, 0.50 mmol) in a saturated methanolic
solution of NH3 (4 mL) was stirred at rt for 1 h. The
solvent was removed and the residue was triturated with
Et2O to give 12 (80 mg, 78% yield) as a yellow solid: mp
.300 8C; 1H NMR (300 MHz, DMSO-d6) d 1.28 (d,
J¼6.3 Hz, 3H), 4.63 (q, J¼6 Hz, 1H), 5.07 (s, 1H), 5.20–
5.40 (br s, 1H), 7.43 (s, 1H), 8.23 (s, 1H), 10.55 (s, 1H);
13C NMR (75.4 MHz, DMSO-d6) d 22.5, 63.1, 88.9,
110.2, 128.5, 130.6, 138.3, 143.3, 163.8, 164.9; CI-MS
m/z 207 (MHþ), 189. Anal. Calcd for C10H10N2O3.1/2H2O: C,
55.81; H, 5.15; N, 13.02. Found: C, 55.73; H, 5.06; N,
12.70.
A mixture of pyridine 4 (0.25 g, 1 mmol), the appropriate
amine (10 mmol) and B10H14 (37 mg, 0.30 mmol) in MeOH
(15 mL) was stirred at rt for 48 h. The solvent was removed
and the resulting residue was chromatographed to give
naphthyridines 9 and 10.
4.2.1. Methyl 2-allyl-1,4-dihydro-1-methyl-3-oxo-
2H22,7-naphthyridine-5-carboxylate (9a). Elution with
1
99:1 CH2Cl2–MeOH; yield 20%; H NMR (300 MHz) d
1.46 (d, J¼6.6 Hz, 3H), 3.68 (dd, J¼6.9, 16.2 Hz, 1H), 3.79
and 4.46 (2d, J¼21 Hz, 2H), 3.96 (s, 3H), 4.65 (q,
J¼6.6 Hz, 1H), 4.73 (dddd, J¼1.8, 1.8, 4.8, 16.2 Hz, 1H),
5.20 (m, 2H), 5.78 (dddd, J¼4.8, 6.9, 10.2, 17.1 Hz, 1H),
8.54 (s, 1H), 9.06 (s, 1H); 13C NMR (75.4 MHz) d 22.2,
34.7, 47.2, 52.5, 53.7, 118.0, 123.9, 132.4, 133.5, 142.3,
149.0, 150.4, 165.5, 166.7; HRMS calcd for C14H16N2O3
260.1157, found 260.1151.
4.2.6. Methyl 3-hydroxy-1-methyl-2,7-naphthyridine-5-
carboxylate (13). A mixture of pyridine 4 (0.1 g,
0.40 mmol) and ammonium formate (0.1 g, 1.59 mmol)
was heated at 150 8C for 10 min. The solid residue was
triturated with CH2Cl2 to give 13 (65 mg, 75% yield) as
1
a yellow solid: mp .300 8C; H NMR (200 MHz, DMSO-
d6, major tautomer) d 2.90 (s, 3H), 3.90 (s, 3H), 7.44
(s, 1H), 8.93 (s, 1H), 9.50 (s, 1H), 12.0 (br s, 1H); 13C
NMR (75.4 MHz, DMSO-d6, major tautomer) d 20.3,
52.4, 97.3, 117.2, 140.4, 150.0, 156.6, 161.2, 163.0, 165.9;
CI-MS m/z 219 (MHþ). Anal. Calcd for C11H10N2O3·H2O:
C, 55.93; H, 5.12; N, 11.86. Found: C, 55.81; H, 5.26; N,
11.72.
4.2.2. 2-Allyl-5-(1-hydroxyethyl)-2,7-naphthyridin-1,3-
dione (10a). Elution with 96:4 CH2Cl2–MeOH; yield
40%; yellow solid; mp 205–6 8C; 1H NMR (200 MHz,
DMSO-d6, HSQC and HMBC) d 1.30 (d, J¼6.5 Hz, 3H,
CH3), 4.46 (d, J¼5 Hz, 2H, CH2–CHvCH2), 4.67 (m, 1H,
CH3CH), 4.97 and 5.01 (2m, 2H, CH2¼), 5.23 (s, 1H, 4-H),
5.33 (d, J¼4.5 Hz, 1H, OH), 5.80 (m, 1H, CHv), 7.47 (s,
1H, 6-H), 8.30 (s, 1H, 8-H); 13C NMR (75.4 MHz, DMSO-
d6, HSQC and HMBC) d 22.7 (CH3), 40.8 (CH2–
CHvCH2), 63.2 (CH3CH), 88.6 (C-4), 109.6 (C-8a),
115.7 (CH2¼), 128.6 (C-6), 130.7 (C-5), 133.8 (CHv),
139.1 (C-8), 141.8 (C-4a), 162.9 (C-1), 163.4 (C-3); CI-MS
m/z 247 (MHþ), 229. Anal. Calcd for C13H14N2O3.1/3H2O: C,
61.91; H, 5.86; N, 11.11. Found: C, 61.72; H, 5.82; N, 10.97.
4.2.7. Reaction of pyridine 4 with CH3AlClNH2. A
22
solution of CH3AlClNH2
in C6H6 (0.67 M, 66 ml,
0.044 mmol) was added to a solution of pyridine 4
(10 mg, 0.040 mmol) in C6H6 (0.5 mL) and the mixture
was stirred at rt for 5 h. The solvent was removed and the
resulting residue was partitioned between saturated aqueous
NaHCO3 and AcOEt, and extracted with AcOEt. The
organic extracts were concentrated and the residue was
chromatographed (95:5 CH2Cl2–MeOH). First elution
gave methyl 6,7-dihydroxyisoquinoline-4-carboxylate 14:
2.6 mg (30%); 1H NMR (300 MHz, CD3OD) d 3.96 (s, 3H),
6.56 (d, J¼2.4 Hz, 1H), 7.70 (d, J¼2.4 Hz, 1H), 8.85 (s,
1H), 9.36 (s, 1H); CI-MS m/z 220 (MHþ), 194; HRMS calcd
for C11H9NO4 219.0529, found 219.0522. Further elution
gave 13: 2.6 mg (30%).
4.2.3. Methyl 2-benzyl-1,4-dihydro-1-methyl-3-oxo-2H-
2,7-naphthyridine-5-carboxylate (9b). Elution with 99:1
CH2Cl2–MeOH; yield 20%; 1H NMR (200 MHz) d 1.42 (d,
J¼7 Hz, 3H), 3.84 and 4.55 (2d, J¼20.8 Hz, 2H), 3.97 (s,
3H), 4.17 and 5.44 (2d, J¼15 Hz, 2H), 4.55 (q, J¼7 Hz,
1H), 7.20–7.40 (m, 5H), 8.40 (s, 1H), 9.05 (s, 1H); HRMS
calcd for C18H18N2O3 310.1313, found 310.1324.
4.2.8. (6)-Jasminine (1). A mixture of pyridine 4 (0.1 g,
0.40 mmol), Ti(i-PrO)4 (0.24 mL, 0.80 mmol), NH4Cl
(43 mg, 0.80 mmol) and Et3N (0.11 mL, 0.80 mmol) in
dry MeOH (1 mL) was stirred in a sealed tube at rt
overnight. NaBH4 (23 mg, 0.60 mmol) was then added and
the resulting mixture was stirred at rt for 7 h. The reaction
mixture was poured into a 2 M aqueous solution of NH3
(3 mL), and the precipitate was filtered and washed
successively with CH2Cl2 and 1:1 CH2Cl2–MeOH. Sol-
vents were removed and the resulting residue was
chromatographed. Elution with 97:3 CH2Cl2–MeOH gave
1 (22 mg, 25%) as a pale yellow solid; mp 163–4 8C
4.2.4. 2-Benzyl-5-(1-hydroxyethyl)-2,7-naphthyridin-
1,3-dione (10b). Elution with 96:4 CH2Cl2–MeOH; yield
10%; 1H NMR (200 MHz, DMSO-d6) d 1.30 (d, J¼6.2 Hz,
3H), 4.69 (q, J¼6.2 Hz, 1H), 5.06 (s, 2H), 5.22 (s, 1H),
7.25–7.35 (m, 5H), 7.53 (s, 1H), 8.33 (s, 1H).
4.2.5. 5-(1-Hydroxyethyl)-2,7-naphthyridin-1,3-dione
(12). NaBH4 (15 mg, 0.40 mmol) was added to a solution
of pyridine 4 (0.1 g, 0.40 mmol) in MeOH (4 mL) cooled at
0 8C, and the mixture was stirred at 0 8C for 10 min. The
solvent was removed and the residue was partitioned
between H2O2 and CH2Cl2, and extracted with CH2Cl2.
The organic extracts were concentrated and the residue was
chromatographed (CH2Cl2) to give lactone 11 (70 mg, 80%
yield): 1H NMR (300 MHz) d 1.82 (d, J¼6.9 Hz, 3H), 3.98
(s, 3H), 4.08 and 4.47 (2d, J¼20.1 Hz, 2H), 5.59 (q,
J¼6.9 Hz, 1H), 8.65 (s, 1H), 9.16 (s, 1H); 13C NMR
(75.4 MHz) d 19.8, 33.1, 52.6, 73.9, 123.3, 131.8, 141.6,
147.7, 151.5, 165.1, 168.3.
1
(CH2Cl2); H NMR (400 MHz) d 1.59 (d, J¼6.4 Hz, 3H),
3.96 (s, 3H), 3.99 and 4.15 (2d, J¼21.6 Hz, 2H), 4.80 (br q,
J¼5.6 Hz, 1H), 6.77 (br s, 1H), 8.60 (s, 1H), 9.07 (s, 1H);
13C NMR (100.6 MHz) d 25.0, 34.2, 49.7, 52.8, 124.3,
132.6, 142.1, 149.9, 150.9, 165.9, 169.4. Anal. Calcd for
C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C, 59.50;
H, 5.71; N, 12.61. Elution with 95:5 CH2Cl2–MeOH gave
13: 35 mg (40%).

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6789
11. Several nucleophiles have been tested for this purpose: (a)
Katritzky, A. R.; Zhang, S.; Kurz, T.; Wang, M.; Steel, P. J.
Org. Lett. 2001, 3, 2807–2809, and references cited therein.
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Acknowledgements
Financial support from the ‘Ministerio de Ciencia y
´
Tecnologıa’ (MCYT), Spain (project BQU2000-0785) and
MCYT-FEDER (project BQU2003-04967-C02-02) is grate-
fully acknowledged. We also thank the DURSI (Generalitat
de Catalunya) for Grant 2001SGR00084 and for a fellow-
ship to M.M.
12. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4,
3955–3957.
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