1-alkyl- and (±)-1,2-dialkyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones by a tandem michael-SnAr annulation reaction

Article abstract of DOI:10.1021/jo3018632

A tandem Michael-S_NAr annulation reaction has been developed for the synthesis of 1-alkyl and (±)-1,2-dialkyl-2,3-dihydro-1,8- naphthyridin-4(1H)-ones. Treatment of 1-(2-chloropyridin-3-yl)prop-2-en-1-one (R = H) or (E or Z)-1-(2-chloropyridin-3-yl)but-2-en-1-one (R = CH₃) with R′NH₂ in DMF at 50 C for 24 h provides 2,3-dihydro-1,8-naphthyridin-4(1H)-ones in 65-85% yields. Mechanistic studies suggest that the reaction sequence is initiated by Michael addition to the side chain enone.

Full text of DOI:10.1021/jo3018632

Note
pubs.acs.org/joc
1‑Alkyl- and ( )-1,2-Dialkyl-2,3-dihydro-1,8-naphthyridin-4(1H)‑ones
by a Tandem Michael−SNAr Annulation Reaction
Richard A. Bunce,* Scott T. Squires,† and Baskar Nammalwar
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, United States
S
* Supporting Information
ABSTRACT: A tandem Michael−SNAr annulation reaction has been developed
for the synthesis of 1-alkyl and ( )-1,2-dialkyl-2,3-dihydro-1,8-naphthyridin-4(1H)-
ones. Treatment of 1-(2-chloropyridin-3-yl)prop-2-en-1-one (R = H) or (E or Z)-
1-(2-chloropyridin-3-yl)but-2-en-1-one (R = CH3) with R′NH2 in DMF at 50 °C
for 24 h provides 2,3-dihydro-1,8-naphthyridin-4(1H)-ones in 65−85% yields.
Mechanistic studies suggest that the reaction sequence is initiated by Michael addition to the side chain enone.
Scheme 1. Synthesis of the Annulation Substrates
ur recent research on tandem annulation procedures
involving nucleophilic aromatic substitution (SNAr)
O
reactions has led to the development of numerous syntheses
of nitrogen heterocycles.1,2 These earlier investigations focused
primarily on sequences terminated by addition of an amine
nitrogen to a fluorine-substituted aromatic ring activated by a
C4 nitro group. Very few studies have examined tandem ring
closures involving addition to a 2-chloropyridine in the final
SNAr reaction.3 The current project extends the use of the 2-
chloropyridine moiety as an aromatic acceptor for the tandem
Michael−SNAr reaction and reports a new synthesis of
dihydronaphthyridinones.
Early investigations on the medicinal potential of dihydro-
naphthyridinones, and structures generated from them,
demonstrated modest anaphylaxis inhibitory activity.5 More
recently, however, new derivatives have been reported as
potential β-blockers for the treatment of hypertension.6 These
studies have all focused on heterocycles lacking alkyl
substitution at N1. The current synthesis provides simple
access to this ring system bearing alkyl groups at N1, which
could permit a more thorough examination of this family of
compounds.
The results of our tandem Michael−SNAr annulation
reactions are summarized in Schemes 2 and 3. Since two
Scheme 2. Annulation Results from 4
To date, there has been only one method reported for the
synthesis of 2,3-dihydro-1,8-naphthyridin-4(1H)-ones.4 This
synthesis involved addition of 2-aminopyridine derivatives to
ethyl acrylate, hydrolysis of the ester to the acid and cyclization
to give the ring-fused heterocycle using polyphosphoric acid.
While this approach was scalable, the yields in the final ring-
closure step were generally quite low.
The synthesis of our annulation substrates is shown in
Scheme 1. The required 3-pyridyl vinyl ketones were prepared
in two steps from commercially available 2-chloro-3-pyridine-
carboxaldehyde (1). Treatment of this aldehyde with vinyl-
magnesium bromide or 1-propenylmagnesium bromide in
tetrahydrofuran at −78 °C gave alcohols 2 and 3, respectively.7
These alcohols were then oxidized to the dihydronaphthyr-
idinone precursors 4 and 5 using manganese(IV) oxide,8 which
provided the required ketones without allylic rearrangement9,10
or degradation of the pyridine ring.
Special Issue: Howard Zimmerman Memorial Issue
Received: August 31, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Scheme 3. Annulation Results from 5b
Scheme 4. Reactions with Morpholine
mixture proved inseparable due to the instability of adducts 10
and 11 toward chromatographic separation. Additionally, the
unstable nature of the products and potential reversibility of the
Michael reaction12 could alter the ratio of products observed.
The reaction was, therefore, repeated at 23 °C for 24 h, and this
furnished exclusively the Michael addition product 10 in 87%
yield with only a trace of recovered 5b. Similarly, reaction of 4
with 9 at 23 °C for 12 h afforded 67% of the Michael product
12, along with 9% of recovered 4 and a trace of the double
addition product. Though not unequivocal, these observations,
together with the aromatic amine result, suggest that the
Michael addition is the initiating step of the sequence.
bonds must be formed, the sequence requires the use of a
primary amine. The reactions were performed using a 1:1.5
molar ratio of substrate to amine at 50 °C to afford the
dihydronaphthyridinone products 6a−i in 65−78% from 4 and
7a−i in 72−85% from 5b. The slightly higher yields from 5b
are presumably attributable to the greater stability of the β-
substituted enone side-chain. The dihydronaphthyridinone
products were readily purified by preparative thin layer
chromatography or column chromatography (using a quartz
column) where they were visualized as sky blue bands using UV
detection. The products were generally isolated as yellow oils.
Further work demonstrated that reaction of both the (Z)-
enone 5a and the (E)-enone 5b with benzylamine provided 7f
in nearly the same yield (80 vs 83%, respectively), indicating
that the double bond geometry of the Michael acceptor has a
minimal effect on the reaction outcome. Additionally, the
annulation of 4 with tert-butylamine at 100 °C for 24 h gave 6j
in only 17% yield and did not produce a dihydronaphthyr-
idinone from 5b, illustrating the steric limitations of the
process. Finally, the reaction appears to be restricted to
aliphatic amines since trial reactions of 4 and 5b with aniline
gave complex mixtures at 50 °C and the Michael addition
products 8a (84%) and 8b (87%), respectively, at 23 °C with
no ring formation (see eq 1).
The proposed mechanistic pathway is outlined in Scheme
5.13 Following Michael addition to give 15, the SNAr reaction
Scheme 5. Mechanism of the Ring Closure
occurs at the chlorine-bearing carbon of the pyridine to give
intermediate 16. Rearomatization and loss of a proton, then
affords the dihydronaphthyridinone. The reaction proceeds at
the same temperature as substrates incorporating a fluoroni-
troarene acceptor,1 but requires shorter reaction times
indicating that the 2-chloropyridine ring is more reactive
toward addition by nucleophiles in the SNAr reaction.14 The
electron deficiency of the pyridine ring and the polarization of
the aromatic carbon−nitrogen double bond are known to be
important factors in facilitating this process.15
In conclusion, we have developed a new approach to the
synthesis of 1-alkyl- and ( )-1,2-dialkyl-2,3-dihydro-1,8-naph-
thyridin-4(1H)-ones based on a tandem Michael addition−
SNAr reaction. The required substrates are conveniently
prepared in two steps from commercial 2-chloro-3-pyridine-
carboxaldehyde. The sequence gives good yields of the target
Although the results using aromatic amines suggested that
Michael addition to the side-chain was the initial step of the
sequence, the reaction chronology using more basic aliphatic
amines11 was unclear. Thus, additional reactions with morpho-
line (9) were undertaken to elucidate this aspect of the process
(see Scheme 4). As a secondary amine, 9 can undergo only one
reaction of the sequence but cannot complete the ring closure.
Thus, treatment of 5b with 1.5 equivalents of 9 in DMF at 50
°C for 24 h followed by removal of excess 9 and the solvent
under high vacuum at 23 °C gave 66% of a mixture of the
Michael addition product 10 and the Michael−SNAr double
addition product 11, along with 10% of recovered 5b. This
B
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Note
11.5, 1.4 Hz, 1H), 6.51 (dq, J = 11.5, 6.9 Hz, 1H), 2.20 (dd, J = 7.0, 1.4
Hz, 3H); 13C NMR: δ 191.6, 150.9, 147.5, 146.5, 138.3, 136.4, 127.1,
122.5, 16.4; ms: m/z 181, 183 (ca. 3:1, M+). Anal. Calcd for
C9H8ClNO: C, 59.50; H, 4.41; N, 7.71. Found: C, 59.59; H, 4.47; N,
7.58.
ring system and represents a rare use of the 2-chloropyridine
system as the aromatic acceptor in a tandem reaction. The
reaction proceeds in high yield using primary amines that lack
branching α to the nitrogen. More hindered amines and
aromatic amines give reduced yields or fail to close the final
ring. We are continuing to explore other variants of this
potentially valuable annulation procedure.
E isomer 5b: 1.39 g (52%) as a white solid, mp 53−55 °C; IR: 1660,
1
1624 cm−1; H NMR: δ 8.49 (dd, J = 4.9, 2.2 Hz, 1H), 7.72 (dd, J =
7.7, 2.2 Hz, 1H), 7.34 (dd, J = 7.7, 4.9 Hz, 1H), 6.78 (dq, J = 15.9, 6.9
Hz, 1H), 6.52 (dq, J = 15.9, 1.4 Hz, 1H), 2.00 (dd, J = 6.9, 1.4 Hz,
3H); 13C NMR: δ 192.1, 150.7, 148.6, 147.5, 137.9, 135.2, 131.4,
122.2, 18.6; ms: m/z 181, 183 (ca. 3:1, M+). Anal. Calcd for
C9H8ClNO: C, 59.50; H, 4.41; N, 7.71. Found: C, 59.53; H, 4.41; N,
7.64.
EXPERIMENTAL SECTION
■
General Methods. All reactions were run using anhydrous
solvents under N2 in oven-dried glassware. Preparative separations
were performed using one of the following methods: (1) flash
chromatography16 on silica gel (Davisil, grade 62, 60−200 mesh)
containing 2% UV-active phosphor (Sorbent Technologies, No. UV-
05) packed into quartz columns or (2) preparative thin layer
chromatography (PTLC) on silica gel GF plates (Analtech, No.
02015). Band elution for both methods was monitored using a hand-
held UV lamp. Melting points were uncorrected. FT-IR spectra were
run as thin films on NaCl disks. 1H and 13C NMR spectra were
measured in CDCl3 at 300 and 75 MHz, respectively, using (CH3)4Si
as the internal standard. Unless otherwise indicated, low-resolution
mass spectra (EI/DP) were obtained at 70 eV.
Representative Procedure for the Tandem Michael−SNAr
Reaction: 1-Cyclopropyl-2,3-dihydro-1,8-naphthyridin-4(1H)-
one (6a). To a solution of 67 mg (0.40 mmol) of 4 in 2 mL of
DMF was added 34 mg (42 μL, 0.60 mmol) of cyclopropylamine, and
the reaction was heated at 50 °C for 24 h. The reaction mixture was
then cooled, added to 25 mL of saturated NaCl and extracted three
times with ether. The combined ether extracts were washed with water
and saturated NaCl, dried over MgSO4, filtered, and concentrated
under vacuum to afford a yellow oil. The product was purified on a 20-
cm × 20-cm PTLC plate eluted with 4:1 hexanes:ether to give 50 mg
(66%) of 6a as a yellow oil, which crystallized on standing, mp 67−68
Representative Procedure for Grignard Reactions: 1-(2-
Chloropyridin-3-yl)-2-propen-1-ol (2). To a −78 °C solution of
2.12 g (15.0 mmol) of 2-chloro-3-pyridinecarboxaldehyde (1) in 75
mL of THF was added 22.5 mL of 1.0 M vinylmagnesium bromide in
THF (22.5 mmol).7 The reaction mixture was stirred for 3.5 h at −78
°C, then quenched by addition of 50 mL of 10% NH4Cl and extracted
three times with ether. The combined ether extracts were washed with
H2O and saturated NaCl, dried over MgSO4, filtered, and concentrated
under vacuum to give 2.02 g (79%) of 2 as a viscous yellow oil. This
product was spectroscopically pure and was used directly in the next
1
°C. IR: 1682 cm−1; H NMR: δ 8.43 (dd, J = 4.9, 2.2 Hz, 1H), 8.09
(dd, J = 7.7, 2.2 Hz, 1H), 6.75 (dd, J = 7.7, 4.9 Hz, 1H), 3.63 (t, J = 7.1
Hz, 2H), 2.68 (t, J = 7.1 Hz, 2H), 2.67 (m, 1H), 0.96 (m, 2H), 0.73
(m, 2H); 13C NMR: δ 193.9, 161.4, 154.3, 136.1, 115.1, 114.1, 47.6,
38.2, 31.2, 8.3; ms: m/z 188 (M+). Anal. Calcd for C11H12N2O: C,
70.21; H, 6.38; N, 14.89. Found: C, 70.25; H, 6.39; N, 14.83.
1-Cyclohexyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (6b):
1
65 mg (71%) as a yellow oil; IR: 1682 cm−1; H NMR: δ 8.31 (dd,
J = 4.9, 2.2 Hz, 1H), 8.07 (dd, J = 7.7, 2.2 Hz, 1H), 6.59 (dd, J = 7.7,
4.9 Hz, 1H), 4.84 (m, 1H), 3.49 (t, J = 7.1 Hz, 2H), 2.63 (t, J = 7.1 Hz,
2H), 1.86−1.68 (complex m, 5H), 1.49 (m, 4H), 1.16 (m, 1H); 13C
NMR: δ 193.7, 159.3, 154.4, 136.5, 114.3, 112.3, 52.8, 39.7, 37.4, 30.0,
25.9, 25.7; ms: m/z 230 (M+). Anal. Calcd for C14H18N2O: C, 73.04;
H, 7.83; N, 12.17. Found: C, 73.13; H, 7.86; N, 12.05.
1-Hexyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (6c): 69 mg
(74%) as a yellow oil; IR: 1682 cm−1; 1H NMR: δ 8.30 (dd, J = 4.9, 2.2
Hz, 1H), 8.04 (dd, J = 7.7, 2.2 Hz, 1H), 6.59 (dd, J = 7.7, 4.9 Hz, 1H),
3.67 (t, J = 7.7 Hz, 2H), 3.56 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.1 Hz,
2H), 1.62 (distorted quintet, J = 7.1 Hz, 2H), 1.33 (m, 6H), 0.89
(distorted t, J = 6.8 Hz, 3H); 13C NMR: δ 193.6, 159.5, 154.6, 136.2,
114.0, 112.4, 48.6, 46.0, 37.1, 31.6, 27.2, 26.7, 22.6, 14.0; ms: m/z 161
(M+ − C5H11). Anal. Calcd for C14H20N2O: C, 72.41; H, 8.62; N,
12.07. Found: C, 72.55; H, 8.64; N, 11.96.
1
step. IR: 3334 cm−1; H NMR: δ 8.26 (dd, J = 4.9, 2.2 Hz, 1H), 7.95
(dd, J = 7.7, 2.2 Hz 1H), 7.28 (dd, J = 7.7, 4.9 Hz, 1H), 5.98 (ddd, J =
17.2, 10.4, 5.5 Hz, 1H), 5.57 (br d, J = 5.5 Hz, 1H), 5.40 (d, J = 17.2
Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 3.50 (br s, 1H); 13C NMR: δ
149.1, 148.2, 137.5, 137.0, 136.7, 122.9, 116.3, 70.6; ms (30 eV): m/z
169, 171 (ca 3:1, M+). Anal. Calcd for C8H8ClNO: C, 56.64; H, 4.72;
N, 8.26. Found: C, 56.89; H, 4.79; N, 8.07.
(Z)- and (E)-1-(2-Chloropyridin-3-yl)-2-buten-1-ol (3): 2.31 g
(84%) as a yellow oil; IR: 3337 cm−1; 1H NMR (Z and E): δ 8.26 (m,
1H), 7.98 (2 dd, J = 7.7, 2.2 Hz, 1H), 7.28 (m, 1H), 5.89−5.39
(complex m, 3H), 2.84 (br s, 0.5H), 2.76 (br s, 0.5H), 1.85 (dd, J =
6.6, 1.4 Hz, 1.5H), 1.71 (d, J = 6.6 Hz, 1.5H); 13C NMR (Z and E): δ
148.9, 147.96, 147.92, 137.9, 137.7, 136.5, 130.8, 130.2, 128.7, 128.5,
122.8, 70.6, 65.7, 17.6, 13.6; ms (30 eV): m/z 183, 185 (ca. 3:1, M+).
Anal. Calcd for C9H10ClNO: C, 58.86; H, 5.45: N, 7.63. Found: C,
59.04; H, 5.53; N, 7.44.
2,3-Dihydro-1-isobutyl-1,8-naphthyridin-4(1H)-one (6d): 61
1
mg (75%) as a yellow oil; IR: 1682 cm−1; H NMR: δ 8.29 (dd, J =
4.9, 2.2 Hz, 1H), 8.05 (dd, J = 7.7, 2.2 Hz, 1H), 6.59 (dd, J = 7.7, 4.9
Hz, 1H), 3.57 (t, J = 7.1 Hz, 2H), 3.49 (d, J = 7.7 Hz, 2H), 2.69 (t, J =
7.1 Hz, 2H), 2.11 (nonet, J = 7.1 Hz, 1H), 0.97 (d, J = 7.1 Hz, 6H);
13C NMR: δ 193.6, 159.7, 154.5, 136.2, 113.8, 112.4, 55.7, 46.6, 37.1,
Representative Procedure for Oxidation with Manganese
Dioxide: 1-(2-Chloropyridin-3-yl)-2-propen-1-one (4). To a
solution of 2.00 g (11.8 mmol) of 2 in 50 mL of CH2Cl2 was added
20.0 g of manganese(IV) oxide.8 The reaction was stirred vigorously
for 12 h at 23 °C and then filtered through a plug of Celite. The Celite
was washed thoroughly with CH2Cl2 and the solvent was removed
under vacuum to give a yellow oil. The product was purified by flash
chromatography on a 30-cm × 2.5-cm silica gel column eluted with
increasing concentrations of ether in hexanes to give 1.42 g (72%) of
enone 4. This compound was stored in the dark at −20 °C as a dilute
27.3, 20.2; ms: m/z 161 (M+ − C3H7). Anal. Calcd for C12H16N2O: C,
70.59; H, 7.84; N, 13.73. Found: C, 70.64; H, 7.87; N, 13.62.
2,3-Dihydro-1-(2-phenylethyl)-1,8-naphthyridin-4(1H)-one
(6e): 75 mg (74%) as a yellow solid, mp 36−37 °C; IR: 1682 cm−1; 1H
NMR: δ 8.35 (dd, J = 4.9, 2.2 Hz, 1H) 8.05 (dd, J = 7.7, 2.2 Hz, 1H),
7.34−7.18 (m, 5H), 6.63 (dd, J = 7.7, 4.9 Hz, 1H), 3.91 (t, J = 7.1 Hz,
2H), 3.39 (t, J = 7.1 Hz, 2H), 2.95 (t, J = 7.1 Hz, 2H), 2.55 (t, J = 7.1
Hz, 2H); 13C NMR: δ 193.6, 159.1, 154.6, 139.6, 136.2, 128.9, 128.4,
126.3, 114.1, 112.7, 50.9, 46.8, 37.0, 33.7; ms: m/z 161 (M+ − C7H7).
Anal. Calcd for C16H16N2O: C, 76.19; H, 6.35; N, 11.11. Found: C,
76.12; H, 6.34; N, 11.19.
1
solution in pentane. IR: 1671, 1609 cm−1; H NMR: δ 8.64 (dd, J =
4.9, 2.2 Hz, 1H), 7.91 (dd, J = 7.7, 2.2 Hz, 1H), 7.50 (dd, J = 7.7, 4.9
Hz, 1H), 6.94 (dd, J = 17.2, 10.4 Hz, 1H), 6.33 (d, J = 17.2 Hz, 1H),
6.25 (d, J = 10.4 Hz, 1H); 13C NMR: δ 192.3, 151.1, 147.7, 138.2,
135.4, 134.4, 132.6, 122.3; ms: m/z 167, 169 (ca. 3:1, M+). Anal. Calcd
for C8H6ClNO: C, 57.31; H, 3.58; N, 8.36. Found: C, 57.55; H, 3.69;
N, 8.13.
(Z)- and (E)-1-(2-Chloropyridin-3-yl)-2-buten-1-one (5a and
5b). Z isomer 5a: 745 mg (27%) as a light-yellow solid, mp 40−42 °C;
IR: 1679, 1610 cm−1; 1H NMR: δ 8.48 (dd, J = 4.9, 2.2 Hz, 1H), 7.84
(dd, J = 7.7, 2.2 Hz, 1H), 7.35 (dd, J = 7.7, 4.9 Hz, 1H), 6.62 (dq, J =
1-Benzyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (6f): 74 mg
(77%) as a yellow oil; IR: 1682 cm−1; 1H NMR: δ 8.34 (dd, J = 4.4, 2.2
Hz, 1H), 8.09 (dd, J = 7.7, 2.2 Hz, 1H), 7.38−7.22 (complex m, 5H),
6.67 (dd, J = 7.7, 4.4 Hz, 1H), 4.96 (s, 2H), 3.49 (t, J = 7.1 Hz, 2H),
2.68 (t, J = 7.1 Hz, 2H); 13C NMR: δ 193.4, 159.5, 154.5, 137.7, 136.4,
128.6, 127.7, 127.3, 114.2, 113.2, 51.1, 45.2, 37.1; ms: m/z 147 (M+ −
C
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Note
C7H7). Anal. Calcd for C15H14N2O: C, 75.63; H, 5.88; N, 11.76.
Found: C, 75.72; H, 5.93; N, 11.61.
1-(4-Chlorobenzyl)-2,3-dihydro-1,8-naphthyridin-4(1H)-one
(6g): 85 mg (78%) as a yellow solid, mp 75−77 °C; IR: 1681 cm−1;
1H NMR: δ 8.33 (dd, J = 4.4, 2.2 Hz, 1H), 8.09 (dd, J = 7.7, 2.2 Hz,
1H), 7.30 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 6.69 (dd, J =
7.7, 4.4 Hz, 1H), 4.91 (s, 2H), 3.48 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.1
Hz, 2H); 13C NMR: δ 193.2, 159.4, 154.5, 136.4, 136.3, 133.1, 129.1,
128.7, 114.3, 113.4, 50.6, 45.4, 37.1; ms: m/z 147 (M+ − C7H6Cl).
Anal. Calcd for C15H13ClN2O: C, 66.06; H, 4.77; N, 10.28. Found: C,
66.12; H, 4.79; N, 10.19.
8.28 (dd, J = 4.9, 2.2 Hz, 1H), 8.03 (dd, J = 7.7, 2.2 Hz, 1H), 6.75 (dd,
J = 7.7, 4.9 Hz, 1H), 4.20 (dd, J = 13.2, 6.6 Hz, 1H), 3.79 (quintet d, J
= 6.6, 2.2 Hz, 1H), 2.95 (dd, J = 15.9, 6.0 Hz, 1H), 2.61 (dd, J = 13.2,
7.7 Hz, 1H), 2.52 (dd, J = 15.9, 2.2 Hz, 1H), 2.11 (nonet, J = 7.1 Hz,
1H), 1.15 (d, J = 6.6 Hz, 3H), 1.02 (dd, J = 6.6 Hz, 3H), 0.97 (d, J =
6.6 Hz, 3H); 13C NMR: δ 193.4, 157.7, 154.9, 135.6, 113.4, 112.0,
53.9, 52.4, 43.3, 27.5, 20.3, 20.1, 15.2; ms: m/z 175 (M+ − C3H7).
Anal. Calcd for C13H18N2O: C, 71.56; H, 8.26; N, 12.84. Found: C,
71.68; H, 8.29; N, 12.69.
2,3-Dihydro-2-methyl-1-(2-phenylethyl)-1,8-naphthyridin-
1
4(1H)-one (7e): 79 mg (74%) as a yellow oil; IR: 1680 cm−1; H
NMR: δ 8.36 (dd, J = 4.9, 2.2 Hz, 1H), 8.03 (dd, J = 7.7, 2.2 Hz, 1H),
7.35−7.17 (complex m, 5H), 6.61 (dd, J = 7.7, 4.9 Hz, 1H), 4.49 (ddd,
J = 13.2, 7.1, 5.5 Hz, 1H), 3.41 (quintet d, J = 6.6, 2.7 Hz, 1H), 3.17
(dt, J = 13.2, 7.7 Hz, 1H), 3.01 (td, J = 7.7, 2.7 Hz, 2H), 2.67 (dd, J =
15.9, 6.0 Hz, 1H), 2.32 (dd, J = 15.9, 2.7 Hz, 1H), 1.10 (d, J = 6.6 Hz,
3H); 13C NMR: δ 193.4, 157.2, 155.0, 139.8, 135.6, 128.9, 128.4,
126.3, 113.5, 112.2, 52.6, 49.1, 43.2, 34.7, 16.0; ms: m/z 175 (M+ −
C7H7). Anal. Calcd for C17H18N2O: C, 76.69; H, 6.77; N, 10.53.
Found: C, 76.58; H, 6.74; N, 10.57
2,3-Dihydro-1-(4-methoxybenzyl)-1,8-naphthyridin-4(1H)-
1
one (6h): 82 mg (76%) as a yellow oil; IR: 2838, 1682 cm−1; H
NMR: δ 8.34 (dd, J = 4.9, 2.2 Hz, 1H), 8.08 (dd, J = 7.7, 2.2 Hz, 1H),
7.24 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.66 (dd, J = 7.7, 4.9
Hz, 1H), 4.89 (s, 2H), 3.79 (s, 3H), 3.46 (t, J = 7.1 Hz, 2H), 2.68 (t, J
= 7.1 Hz, 2H); 13C NMR: δ 193.5, 159.5, 158.9, 154.5, 136.4, 129.6,
129.1, 114.2, 113.9, 113.1, 55.2, 50.5, 45.0, 37.1; ms: m/z 147 (M+ −
C8H9O). Anal. Calcd for C16H16N2O2: C, 71.64; H, 5.97; N, 10.45.
Found: C, 71.73; H, 5.99; N, 10.34.
2,3-Dihydro-1-(4-trifluoromethylbenzyl)-1,8-naphthyridin-
4(1H)-one (6i): 88 mg (72%) as a yellow solid, mp 37−39 °C; IR:
1682, 1324 cm−1; 1H NMR: δ 8.34 (dd, J = 4.9, 2.2 Hz, 1H), 8.11 (dd,
J = 7.7, 2.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H),
6.71 (dd, J = 7.7, 4.9 Hz, 1H), 5.01 (s, 2H), 3.52 (t, J = 7.1 Hz, 2H),
2.72 (t, J = 7.1 Hz, 2H); 13C NMR: δ 193.1, 159.3, 154.5, 148.5, 142.0,
136.5, 127.9, 125.5 (q, J = 3.7 Hz), 124.1 (q, J = 271.6 Hz), 114.4,
113.7, 51.0, 45.7, 37.1; ms: m/z 147 (M+ − C8H6F3). Anal. Calcd for
C16H13F3N2O: C, 62.75; H, 4.25; N, 9.15. Found: C, 62.91; H, 4.48;
N, 9.04.
1-tert-Butyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (6j): 16
mg (17%) as a yellow solid, mp 31−32 °C; IR: 1686 cm−1; 1H NMR:
δ 8.32 (dd, J = 4.9, 2.2 Hz, 1H), 8.09 (dd, J = 7.7, 2.2 Hz, 1H), 6.64
(dd, J = 7.7, 4.9 Hz, 1H), 3.60 (t, J = 6.6 Hz, 2H), 2.63 (t, J = 6.6 Hz,
2H), 1.60 (s, 9H); 13C NMR: δ 194.8, 161.0, 152.7, 136.2, 115.9,
112.8, 57.6, 42.5, 38.7, 29.0; ms: m/z 189 (M+ − CH3). Anal. Calcd
for C12H16N2O: C, 70.59; H, 7.84; N, 13.73. Found: C, 70.66; H, 7.87
N, 13.57.
1-Benzyl-2,3-dihydro-2-methyl-1,8-naphthyridin-4(1H)-one
1
(7f): 84 mg (83%) as a yellow oil; IR: 1682 cm−1; H NMR: δ 8.33
(dd, J = 4.9, 2.2 Hz, 1H), 8.08 (dd, J = 7.7, 2.2 Hz, 1H), 7.41−7.22
(complex m, 5H), 6.64 (dd, J = 7.7, 4.9 Hz, 1H), 5.72 (d, J = 15.4 Hz,
1H), 4.18 (d, J = 15.4 Hz, 1H), 3.77 (quintet d, J = 6.6, 3.3 Hz, 1H),
2.89 (dd, J = 15.9, 6.0 Hz, 1H), 2.48 (dd, J = 15.9, 3.3 Hz, 1H), 1.17
(d, J = 6.6 Hz, 3H); 13C NMR: δ 193.3, 157.6, 154.9, 138.5, 135.8,
128.6, 127.4, 127.2, 113.5, 112.7, 50.4, 48.6, 43.5, 15.5; ms: m/z 237
(M+ − CH3). Anal. Calcd for C16H16N2O: C, 76.19; H, 6.35; N, 11.11.
Found: C, 76.25; H, 6.39; N, 10.98. When the Z isomer 5a was used in
this reaction, 81 mg (80%) of 7f was isolated from the reaction.
1-(4-Chlorobenzyl)-2,3-dihydro-2-methyl-1,8-naphthyridin-
1
4(1H)-one (7g): 88 mg (77%) as a yellow oil; IR: 1684 cm−1; H
NMR: δ 8.32 (dd, J = 4.9, 2.2 Hz, 1H), 8.08 (dd, J = 7.7, 2.2 Hz, 1H),
7.31 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.66 (dd, J = 7.7, 4.9
Hz, 1H), 5.62 (d, J = 15.9 Hz, 1H), 4.19 (d, J = 15.9 Hz, 1H), 3.76
(quintet d, J = 6.6, 3.3 Hz, 1H), 2.88 (dd, J = 15.9, 6.0 Hz, 1H), 2.50
(dd, J = 15.9, 3.3 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H); 13C NMR: δ
193.1, 157.5, 154.8, 137.1, 135.9, 133.0, 128.8, 128.7, 113.6, 113.0,
50.7, 48.2, 43.6, 15.6; ms: m/z 273, 271 (ca 3:1, M+ − CH3). Anal.
Calcd for C16H15ClN2O: C, 67.02; H, 5.24; N, 9.77. Found: C, 67.15;
H, 5.26; N, 9.69.
2,3-Dihydro-1-(4-methoxybenzyl)-2-methyl-1,8-naphthyri-
din-4(1H)-one (7h): 94 mg (83%) as a yellow oil; IR: 1682 cm−1; 1H
NMR: δ 8.33 (dd, J = 4.9, 2.2 Hz, 1H), 8.06 (dd, J = 7.7, 2.2 Hz, 1H),
7.28 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.63 (dd, J = 7.7, 4.9
Hz, 1H), 5.62 (d, J = 15.4 Hz, 1H), 4.13 (d, J = 15.4 Hz, 1H), 3.80 (s,
3H), 3.77 (quintet d, J = 6.6, 3.3 Hz, 1H), 2.85 (dd, J = 15.9, 6.0 Hz,
1H), 2.46 (dd, J = 15.9, 3.3 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H); 13C
NMR: δ 193.4, 158.9, 157.6, 154.9, 135.8, 130.4, 128.8, 114.0, 113.5,
112.6, 55.2, 50.2, 48.1, 43.5, 15.4; ms: m/z 267 (M+ − CH3). Anal.
Calcd for C17H18N2O2: C, 72.34; H, 6.38; N, 9.93. Found: C, 72.49;
H, 6.43; N 9.78.
2,3-Dihydro-1-(4-trifluoromethylbenzyl)-2-methyl-1,8-naph-
thyridin-4(1H)-one (7i): 96 mg (75%) as a yellow oil; IR: 1684, 1325
cm−1; 1H NMR: δ 8.32 (dd, J = 4.9, 2.2 Hz, 1H), 8.10 (dd, J = 7.7, 2.2
Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.68 (dd, J
= 7.7, 4.9 Hz, 1H), 5.71 (d, J = 15.9 Hz, 1H), 4.29 (d, J = 15.9 Hz,
1H), 3.78 (quintet d, J = 6.6, 3.3 Hz, 1H), 2.92 (dd, J = 15.9, 6.0 Hz,
1H), 2.53 (dd, J = 15.9, 3.3 Hz, 1H), 1.20 (d, J = 6.6 Hz, 3H); 13C
NMR: δ 193.0, 157.5, 154.8, 142.9, 135.9, 127.6 (2C), 125.4 (q, J = 3.7
Hz), 124.1 (q, J = 272.0 Hz), 113.7, 113.2, 51.1, 48.6, 43.6, 15.7; ms:
m/z 305 (M+ − CH3). Anal. Calcd for C17H15F3N2O: C, 63.75; H,
4.69; N, 8.75. Found: C, 63.93; H, 4.74; N, 8.53.
1-Cyclopropyl-2,3-dihydro-2-methyl-1,8-naphthyridin-
1
4(1H)-one (7a): 58 mg (72%) as a yellow oil; IR: 1683 cm−1; H
NMR: δ 8.43 (dd, J = 4.9, 2.2 Hz, 1H), 8.06 (dd, J = 7.7, 2.2 Hz, 1H),
6.71 (dd, J = 7.7, 4.9 Hz, 1H), 3.98 (quintet d, J = 6.6, 2.2 Hz, 1H),
2.88 (dd, J = 16.5, 6.0 Hz, 1H), 2.69 (m, 2H), 2.54 (dd, J = 16.5, 2.2
Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.17 (m, 1H), 0.87−0.64 (m, 3H);
13C NMR: δ 193.7, 159.2, 154.6, 135.4, 114.6, 113.6, 53.2, 44.3, 29.5,
15.2, 10.5, 6.2; ms: m/z 187 (M+ − CH3). Anal. Calcd for C12H14N2O:
C, 71.29; H, 6.93; N, 13.86. Found: C, 71.36; H, 6.93; N, 13.77.
1-Cyclohexyl-2,3-dihydro-2-methyl-1,8-naphthyridin-4(1H)-
1
one (7b): 72 mg (74%) as a yellow oil; IR: 1682 cm−1; H NMR: δ
8.30 (dd, J = 4.9, 2.2 Hz, 1H), 8.03 (dd, J = 7.7, 2.2 Hz, 1H), 6.84 (dd,
J = 7.7, 4.9 Hz, 1H), 4.83 (tt, J = 11.5, 3.3 Hz, 1H), 4.00 (quintet d, J =
6.6, 2.2 Hz, 1H), 2.78 (dd, J = 15.9, 5.5 Hz, 1H), 2.44 (dd, J = 15.9, 2.2
Hz, 1H), 1.94−1.67 (complex m, 6H), 1.66−1.40 (complex m, 4H),
1.20 (d, J = 6.6 Hz, 3H); 13C NMR: δ 193.6, 156.9, 154.7, 135.8,
113.6, 111.6, 53.7, 45.4, 43.7, 31.6, 30.7, 26.04, 25.99, 25.7, 18.1; ms:
m/z 229 (M+ − CH3). Anal. Calcd for C15H20N2O: C, 73.77; H, 8.20;
N, 11.48. Found: C, 73.83; H, 8.24; N, 11.40.
1-Hexyl-2,3-dihydro-2-methyl-1,8-naphthyridin-4(1H)-one
1
(7c): 84 mg (85%) as a yellow oil; IR: 1682 cm−1; H NMR: δ 8.30
(dd, J = 4.9, 2.2 Hz, 1H), 8.02 (dd, J = 7.7, 2.2 Hz, 1H), 6.56 (dd, J =
7.7, 4.9 Hz, 1H), 4.22 (dt, J = 14.0, 7.1 Hz, 1H), 3.81 (quintet d, J =
6.6, 2.7 Hz, 1H), 3.00 (dt, J = 14.0, 7.1 Hz, 1H), 2.91 (dd, J = 15.9, 6.0
Hz, 1H), 2.51 (dd, J = 15.9, 2.7 Hz, 1H), 1.68 (quintet, J = 7.7 Hz,
2H), 1.44−1.28 (complex m, 6H), 1.18 (d, J = 6.6 Hz, 3H), 0.90
(distorted t, J = 7.1 Hz, 3H); 13C NMR: δ 193.4, 157.5, 154.9, 135.6,
113.4, 111.9, 51.6, 46.5, 43.5, 31.7, 28.4, 26.7, 22.6, 15.9, 14.0; ms: m/z
175 (M+ − C5H11). Anal. Calcd for C15H22N2O: C, 73.17; H, 8.94; N,
11.38. Found: C, 73.21; H, 8.96; N, 11.33.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectral data are provided for 2, 3, 4,
5a−b, 6a−j, 7a−i, 8a−b, 10 and 12. Experimental is also
2,3-Dihydro-1-isobutyl-2-methyl-1,8-naphthyridin-4(1H)-
1
one (7d): 74 mg (85%) as a yellow oil; IR: 1684 cm−1; H NMR: δ
D
dx.doi.org/10.1021/jo3018632 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(11) In water, morpholine is ca. 5000 times more basic than aniline,
see: (a) Perrins, D. D. Dissociation Constants of Organic Bases in
Aqueous Solution; Butterworths: London, 1965; Supplement, 1972
(aniline: entry 4256; morpholine: entry 5517). See also: (b) Solomons,
T. W. G.; Fryhle, C. B. Organic Chemistry, 10th ed.; Wiley: New York,
2011; pp 915−918.
(12) (a) Smith, M. B.; March, J. March's Advanced Organic Chemistry:
Reactions, Mechanisms and Structure, 6th ed.; Wiley-Interscience: New
York, 2007; p 1009. (b) Heathcock, C. H.; Oare, D. A. Top.
Stereochem.1989, 19, 227−407; see in particular p 232.
(13) Joule, J. A; Mills, K. Heterocyclic Chemistry at a Glance; Blackwell
Publishing, Oxford, UK, 2007; p 18.
(14) Strong activation of α-halo nitrogen heterocycles: (a) Smith, M.
B.; March, J. March's Advanced Organic Chemistry: Reactions,
Mechanisms and Structure, 6th ed.; Wiley-Interscience: New York,
2007; p 864. (b) Miller, J.; Parker, A. J. Aust. J. Chem. 1958, 11, 302−
308.
provided for the mechanistic experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: rab@okstate.edu
■
Notes
The authors declare no competing financial interest.
†Undergraduate Research Participant, Spring 2011.
ACKNOWLEDGMENTS
■
Funding for the 300 MHz NMR spectrometer of the Oklahoma
Statewide Shared NMR Facility was provided by NSF (BIR-
9512269), the Oklahoma State Regents for Higher Education,
the W. M. Keck Foundation, and Conoco, Inc. Finally, the
authors wish to thank the OSU College of Arts and Sciences for
funds to upgrade our departmental FT-IR and GC-MS
instruments.
(15) Uff, B. C. in Comprehensive Heterocyclic Chemistry, Boulton, A. J.;
McKillop, A., eds.; Pergamon Press: Oxford, UK, 1984; Vol 2, Part 2A,
p 315, see in particular pp 359−360.
(16) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923−
2925.
DEDICATION
■
This work is dedicated to the memory of Professor Howard E.
Zimmerman.
REFERENCES
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E
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