1-Alkyl-2,3-dihydro-4(1H)-quinolinones by a tandem Michael-SNAr annulation reaction

Article abstract of DOI:10.1002/jhet.70

(Chemical Equation Presented) A tandem Michael-S_NAr annulation reaction has been developed for the synthesis of 1-alkyl-2,3-dihydro-4(1H)- quinolinones. Success in the reaction followed expected electronic effects for the final S_NAr

Full text of DOI:10.1002/jhet.70

July 2009
1-Alkyl-2,3-dihydro-4(1H)-quinolinones by a Tandem
Michael-SNAr Annulation Reaction
623
Richard A. Bunce* and Takahiro Nago [1]
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
*E-mail: rab@okstate.edu
Received October 15, 2008
DOI 10.1002/jhet.70
Published online 2 July 2009 in Wiley InterScience (www.interscience.wiley.com).
A tandem Michael-SNAr annulation reaction has been developed for the synthesis of 1-alkyl-2,3-dihy-
dro-4(1H)-quinolinones. Success in the reaction followed expected electronic effects for the final SNAr
ring closure. Treatment of doubly activated 1-(2-fluoro-5-nitrophenyl)-2-propen-1-one with primary
amines in N,N-dimethylformamide at 50ꢀC for 24 h provided 2,3-dihydro-4(1H)-quinolinones in 67–
78% yields. Singly activated 1-(2-fluorophenyl)-2-propen-1-one reacted similarly, but failed to undergo
the final ring closure with hindered or aromatic amines. Finally, 1-(2-fluoro-5-methoxyphenyl)-2-
propen-1-one, with one activating and one deactivating group on the ring, gave only simple 1,4-addition
products.
J. Heterocyclic Chem., 46, 623 (2009).
INTRODUCTION
methoxybenzaldehyde (3). Treatment of these aldehydes
with vinylmagnesium bromide in tetrahydrofuran at
ꢁ78ꢀC gave alcohols 4, 5, and 6, respectively. These
alcohols were carried on directly to dihydroquinolinone
precursors 7, 8, and 9 by Jones oxidation in 34–39%
overall yields after chromatography [12].
Over the past several years, our work has led to a
number of tandem cyclizations terminated by nucleo-
philic aromatic substitution reactions [2]. The current
work extends these previous results to the preparation of
1-alkyl-2,3-dihydro-4(1H)-quinolinones by a sequential
Michael-SNAr process. Earlier approaches to these ring
systems have involved Friedel-Crafts cyclizations of N-
phenyl-b-alanine derivatives [3]; acid mediated ring open-
ing-Friedel-Crafts reactions of 1-aryl-2-azetidinones [4];
acid or base promoted cyclizations of 2-aminochalcone
derivatives [5]; or reaction of aromatic amines with imi-
nium salts derived from reaction of N,N-dimethylacryla-
mide with trifluoromethanesulfonic anhydride [6]. These
protocols gave modest to good yields, but generally sub-
jected substrates to strongly acidic reagents. The current
reaction provides a straightforward route to the title com-
pounds in good yields under very mild reaction condi-
tions. The target dihydroquinolinones are valuable build-
ing blocks for the synthesis of drugs used to treat pain
[7], psychosis [8], and Alzheimer’s disease [9] as well as
several other medical afflictions [10].
Scheme 1
In the planning stages, we anticipated that 1,4-addition
to the unhindered side chain enone would precede nucleo-
philic attack on the aromatic ring. Because of this, how-
ever, bulky amines could pose a problem in the final
SNAr ring closure. Thus, precursor 7 was selected as our
initial test case because this compound possessed two
electron-withdrawing substituents positioned to facilitate
the final ring-closing step. If the annulation proceeded
RESULTS AND DISCUSSION
The synthesis of our cyclization substrates is shown
in Scheme 1. The requisite aryl vinyl ketones were eas-
ily prepared in two steps from 2-fluoro-5-nitrobenzalde-
hyde (1) [11], 2-fluorobenzaldehyde (2), and 2-fluoro-5-
C
V
2009 HeteroCorporation

624
R. A. Bunce and T. Nago
Vol 46
Table 1
Michael-SNAr reaction of a doubly activated substrate.
Table 2
Michael-SNAr reaction of a singly activated substrate.
R
Yield (%)
R
Yield (%)
61
a
C6H5CH2
C6H5CH2CH2
n-C6H13
i-C3H7OCH2CH2CH2
i-C4H9
c-C6H11
t-C4H9
C6H5
69
78
67
75
72
77
71
72
a
b
c
d
e
f
C6H5CH2
C6H5CH2CH2
n-C6H13
i-C3H7OCH2CH2CH2
i-C4H9
c-C6H11
t-C4H9
C6H5
b
c
d
e
f
58
74
70
75
54
0a
g
h
g
h
0b
a This reaction gave 3-(tert-butylamino)-1-(2-fluorophenyl)-1-propa-
none (12a) as the only product in 52% yield.
b This reaction gave 1-(2-fluorophenyl)-3-(phenylamino)-1-propanone
(12b) as the only product in 65% yield.
smoothly for 7, we planned to further explore the scope
of the reaction by studying compounds 8 and 9, which
vary the electronic nature of the aromatic moiety. Sub-
strate 8 has a single activating group for the final SNAr
reaction; 9 has one activating and one deactivating group.
Experimentally, the Michael-SNAr reaction was carried
out by dissolving 1.00 equivalent of the aryl vinyl ketone
in dry N,N-dimethylformamide, adding 1.25 equivalents
of the amine and heating for 24 h at 50ꢀC. Following
workup, the products were easily isolated and purified by
chromatography to give the target heterocycles in good
yields. The use of N,N-dimethylformamide as the solvent
was critical to the success of the reaction; methanol gave
complex product mixtures and was not useful.
relative stereochemistry places both aryl moieties in
equatorial positions and allows hydrogen bonding
between the C1 alcohol and the side chain carbonyl.
Thus, for success in the two-reaction sequence, the sub-
strate must possess at least one electron-withdrawing
group ortho or para to fluorine on the aromatic ring. Sub-
strates incorporating an electron-donating group on the
ring (even in the presence of a second withdrawing
The results of our cyclization studies are summarized
in Tables 1 and 2. Doubly activated substrate 7 reacted
with a-branched as well as unbranched and aryl primary
amines to give dihydroquinolinones in 67–78% yields.
Singly activated precursor 8 was successful in most
cases, but failed to cyclize with sterically hindered
amines such as tert-butylamine and deactivated amines
Scheme 2
such as aniline. The methoxy-bearing substrate
9
afforded products derived only from 1,4-addition with-
out the subsequent ring closure. Thus, under our stand-
ard conditions with benzylamine, 9 gave the expected
1:1 Michael adduct 13 in 12% yield (Scheme 2). More
surprisingly, however, the reaction also produced piperi-
dinol 15 in 42% yield. This product presumably arose
from silica gel-promoted aldol ring closure of the 2:1
1
Michael adduct 14 during chromatography. Indeed, H
NMR analysis of the crude reaction mixture revealed
that 14 was present before purification. The structure of
15 was deduced from spectral analysis and by compari-
1
son to calculated H and 13C NMR spectra [13], but the
stereochemical assignment is tentative. The indicated
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
1-Alkyl-2,3-dihydro-4(1H)-quinolinones by a Tandem Michael-SNAr Annulation Reaction
625
of 1 [11] in 75 mL of anhydrous tetrahydrofuran was added
35.6 mL of 1M vinylmagnesium bromide in tetrahydrofuran
(35.6 mmoles). The reaction mixture was stirred for 3.5 h at
ꢁ78ꢀC, then quenched by addition of 50 mL of 0.5M hydro-
chloric acid and ether extracted (three times). The combined
ether extracts were washed with water (three times), saturated
sodium chloride (one time), dried (magnesium sulfate), and
concentrated under vacuum to give 3.09 g (66%) of 4 as a
brown oil. This product was spectroscopically pure and was
used without further purification. IR: 3382, 1530, 1353, 1254
substituent) fail to undergo the final ring closure. Addi-
tionally, the reacting partner must be an alkyl or aryl pri-
mary amine. Secondary amines give only complex prod-
uct mixtures containing low yields of the 1,4-adduct.
The mechanism of dihydroquinolinone formation
involves sequential Michael addition to the side chain
enone followed by SNAr ring closure. The fact that hin-
dered and deactivated amines react with 8 to afford only
the simple 1,4-addition product confirms this reaction
sequence. Uncyclized structures resulting from an initial
SNAr reaction with the aromatic ring are not observed,
nor are products resulting from attack at the carbonyl.
1
cmꢁ1; H NMR: d 8.44 (dd, 1H, J ¼ 6.1, 2.9), 8.18 (ddd, 1H,
J ¼ 9.0, 4.4, 2.9), 7.18 (t, 1H, J ¼ 9.0), 6.02 (ddd, 1H, J ¼
17.2, 10.3, 6.0), 5.55 (d, 1H, J ¼ 6.0), 5.43 (d, 1H, J ¼ 17.2),
5.28 (d, 1H, J ¼ 10.3), 2.53 (br s, 1H); 13C NMR: d 163.1 (d,
J ¼ 257.9), 144.7, 137.7, 131.8 (d, J ¼ 16.0), 125.0 (d, J ¼
10.3), 123.8 (d, J ¼ 6.6), 116.7, 116.4 (d, J ¼ 24.6), 68.5 (d, J
¼ 2.3); ms (30 eV): m/z 197 (Mþ). Anal. Calcd. for
C9H8FNO3: C, 54.82; H, 4.06; N, 7.11. Found: C, 54.89; H,
4.10; N, 7.02.
CONCLUSION
We have developed a new approach to the synthesis of
1-alkyl-2,3-dihydro-4(1H)-quinolinones based on a novel
tandem Michael addition-SNAr reaction. The required sub-
strates are easily prepared in two steps from readily avail-
able precursors. The sequence gives good yields of the
target ring system from substrates having either one or
two electron withdrawing groups ortho or para to fluorine
on the aromatic ring. Systems having one activating group
are slightly less reactive while those incorporating an elec-
tron donating group give only Michael adducts and fail to
close the final ring. We are pursuing further studies of
this annulation procedure in systems bearing alkyl groups
at the b-carbon of the Michael acceptor.
(ꢃ)-1-Phenyl-2-propen-1-ol (5). This compound (3.10 g,
69%) was prepared as above from 3.66 g (29.6 mmoles) of 2
and 30 mL of 1M vinylmagnesium bromide (30.0 mmoles). It
was used without further purification. IR: 3363, 1228 cmꢁ1
;
1H NMR: d 7.43 (td, 1H, J ¼ 7.4, 1.6), 7.25 (m, 1H), 7.14 (td,
1H, J ¼ 7.6, 1.0), 7.02 (ddd, 1H, J ¼ 10.3, 8.2, 1.0), 6.06
(ddd, 1H, J ¼ 17.2, 10.3, 5.5), 5.50 (d, 1H, J ¼ 5.5), 5.34 (d,
1H, J ¼ 17.2), 5.19 (dd, 1H, J ¼ 10.3, 1.2), 2.47 (br s, 1H);
13C NMR: d 159.9 (d, J ¼ 246.6), 138.8, 129.6, (d, J ¼ 13.3),
129.2, (d, J ¼ 8.1), 127.6 (d, J ¼ 3.7), 124.3 (d, J ¼ 3.7),
115.3 (d, J ¼ 22.1), 115.3, 69.1 (d, J ¼ 2.9); ms (30 eV): m/z
152 (Mþ). Anal. Calcd. for C9H9FO: C, 71.05; H, 5.92. Found:
C, 71.08; H, 5.93.
EXPERIMENTAL
(ꢃ)-1-(2-Fluoro-5-methoxyphenyl)-2-propen-1-ol (6). This
compound (2.21 g, 75%) was prepared as above from 2.50 g
(16.2 mmoles) of 3 and 24.5 mL of 1M vinylmagnesium bro-
mide (24.5 mmoles). It was used without further purification.
All reactions were run under dry nitrogen. Vinylmagnesium
bromide (1M in tetrahydrofuran) was purchased from Aldrich
Chemical Company. N,N-Dimethylformamide from a freshly
1
IR: 3402, 2839, 1272 cmꢁ1; H NMR: d 6.97 (m, 1H), 6.95 (t,
˚
opened bottle was stored over 4 A molecular sieves and syringed
1H, J ¼ 9.0), 6.76 (ddd, 1H, J ¼ 9.0, 3.8, 3.3), 6.05 (ddd, 1H,
J ¼ 16.4, 10.0, 5.5), 5.48 (d, 1H, J ¼ 5.5), 5.35 (dd, 1H, J ¼
17.3, 0.8), 5.20 (dt, 1H, J ¼ 1.0, 1.1), 3.78 (s, 3H), 2.27 (br s,
1H); 13C NMR: d 155.8, 154.3 (d, J ¼ 238.8), 138.7, 130.3 (d,
J ¼ 14.9), 115.9 (d, J ¼ 23.5), 115.4, 114.2 (d, J ¼ 8.3),
112.2 (d, J ¼ 4.0), 69.2, 55.7; ms (30 eV): m/z 182 (Mþ).
Anal. Calcd. for C10H11FO2: C, 65.93; H, 6.04. Found: C,
66.01; H, 6.10.
into reactions where it was used. Reactions were monitored by
thin layer chromatography on silica gel GF plates (Analtech
21521) with ultraviolet detection. The 0.5M hydrochloric acid,
saturated sodium bisulfite, saturated sodium chloride, and 0.1M
sodium hydroxide used in workup procedures were aqueous solu-
tions. Preparative separations were performed by one of the fol-
lowing methods: (1) flash column chromatography [14] on silica
gel (grade 62, 60–200 mesh) containing ultraviolet-active phos-
phor (Sorbent Technologies UV-5) packed into quartz columns or
(2) preparative thin layer chromatography on 20-cm ꢂ 20-cm
silica gel GF plates (Analtech 02015). Band elution for both
methods was monitored using a hand-held ultraviolet lamp. Hex-
anes used in chromatography had a boiling range of 65–70ꢀC.
Melting points were uncorrected. Infrared spectra were run as
thin films on sodium chloride disks and referenced to polystyrene.
1H and 13C Nuclear magnetic resonance spectra were measured
in deuteriochloroform at 300 MHz and 75 MHz, respectively,
using tetramethylsilane as the internal standard; coupling con-
stants (J) are given in Hertz. Unless otherwise indicated, mass
spectra (electron impact/direct probe) were obtained at 70 eV.
Representative procedure for the addition of vinylmagne-
sium bromide: (ꢃ)-1-(2-Fluoro-5-nitrophenyl)-2-propen-1-ol
(4). The general procedure of Danishefsky and coworkers
was used [11]. To a ꢁ78ꢀC solution of 4.00 g (23.7 mmoles)
Representative procedure for oxidation to the enone:
1-(2-Fluoro-5-nitrophenyl)-2-propen-1-one (7). The general
procedure of Danishefsky and coworkers was used [12]. To a
solution of 3.09 g (15.7 mmoles) of 4 in 30 mL of acetone
was added 8.10 mL of freshly prepared Jones reagent (ca.,
2.9M, 23.5 mmoles) [15]. After 15 min, 37.5 mL of ice water
was added followed by 7.5 mL of saturated sodium bisulfite
and the resulting mixture was extracted with ether (four times).
The combined ether extracts were washed with water (three
times), saturated sodium chloride (one time), dried (magne-
sium sulfate), and concentrated under vacuum. The resulting
yellow oil was flash chromatographed on a 40 cm ꢂ 2.5 cm
silica gel column eluted with 5–15% ether in hexanes to give
1.57 g (51%) of 7 as a light yellow oil that crystallized on
1
standing, mp 50–52ꢀC. IR: 1673, 1530, 1349, 1251 cmꢁ1; H
NMR: d 8.65 (dd, 1H, J ¼ 6.1, 2.9), 8.42 (ddd, 1H, J ¼ 9.0,
4.1, 2.9), 7.35 (t, 1H, J ¼ 9.0), 7.01 (ddd, 1H, J ¼ 17.2, 10.3,
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DOI 10.1002/jhet

626
R. A. Bunce and T. Nago
Vol 46
3.0), 6.45 (dt, 1H, J ¼ 17.2, 1.2), 6.06 (dd, 1H, J ¼ 10.3, 1.2);
13C NMR: d 187.1 (d, J ¼ 2.9), 164.1 (d, J ¼ 264.3), 144.4,
134.4 (d, J ¼ 5.9), 132.2, 129.0 (d, J ¼ 11.0), 127.0 (d, J ¼
16.2), 127.0 (d, J ¼ 5.2), 118.0 (d, J ¼ 25.8); ms (30 eV): m/z
195. Anal. Calcd. for C9H6FNO3: C, 55.38; H, 3.08; N, 7.18.
Found: C, 55.44; H, 3.11; N, 7.15.
1-Phenyl-2-propen-1-one (8). This compound was prepared
as a colorless oil from 3.10 g (20.3 mmoles) of 5 and 10.5 mL
of freshly prepared Jones reagent (ca., 2.9M, 30.4 mmoles)
[15]. The crude product was flash chromatographed on a 40
cm ꢂ 2.5 cm silica gel column eluted with 5% ether in hex-
anes to give 1.64 g (54%) of 8 as a colorless oil. IR: 1673,
112.5, 53.8, 49.2, 36.7, 33.2; ms: m/z 205 (Mþ-C7H7). Anal.
Calcd. for C17H16N2O3: C, 68.91; H, 5.41; N, 9.46. Found: C,
68.94; H, 5.40; N, 9.49.
1-Hexyl-6-nitro-4(1H)-quinolinone (10c). This compound
(74 mg, 67%) was isolated as a yellow oil. IR: 1688, 1515,
1
1317 cmꢁ1; H NMR: d 8.73 (d, 1H, J ¼ 2.7), 8.17 (dd, 1H, J
¼ 9.4, 2.7), 6.71 (d, 1H, J ¼ 9.4), 3.68 (t, 2H, J ¼ 7.0), 3.48
(t, 2H, J ¼ 7.4), 2.76 (t, 2H, J ¼ 7.0), 1.68 (quintet, 2H, J ¼
7.4), 1.41–1.33 (complex, 6H), 0.91 (t, 3H, J ¼ 6.8); 13C
NMR: d 191.3, 154.1, 137.4, 129.9, 125.3, 117.8, 112.6, 52.1,
48.7, 36.9, 31.5, 26.6 (2C), 22.5, 13.9; ms: m/z 205 (Mþ-
C5H11). Anal. Calcd. for C15H20N2O3: C, 65.21; H, 7.25; N,
10.14. Found: 65.34; 7.29; N, 10.06.
1276 cmꢁ1
;
1H NMR: 7.75 (td, 1H, J ¼ 7.4, 1.8), 7.51 (m,
1H), 7.24 (td, 1H, J ¼ 7.6, 1.0), 7.14 (ddd, 1H, J ¼ 10.7, 8.4,
1.0), 7.02 (ddd, 1H, J ¼ 17.2, 10.4, 3.1), 6.39 (dt, 1H, J ¼
17.2, 1.6), 5.92 (dd, 1H, J ¼ 10.4, 1.6); 13C NMR: d 189.6,
161.2 (d, J ¼ 254.0), 135.5 (d, J ¼ 5.9), 134.1 (d, J ¼ 8.8),
130.9 (d, J ¼ 2.9), 130.2, 128.3, 124.4 (d, J ¼ 2.9), 116.5 (d,
J ¼ 22.8); ms (30 eV): m/z 150 (Mþ). Anal. Calcd. for
C9H7FO: C, 72.00; H, 4.67. Found: C, 72.04; H, 4.69.
1-(3-Isopropoxypropyl)-6-nitro-4(1H)-quinolinone (10d). This
compound (88 mg, 75%) was isolated as a yellow oil. IR:
1687, 1516, 1317 cmꢁ1
;
1H NMR: d 8.70 (d, 1H, J ¼ 2.7),
8.14 (dd, 1H, J ¼ 9.4, 2.7), 6.84 (d, 1H, J ¼ 9.4), 3.71 (t, 2H,
J ¼ 7.0), 3.63 (t, 2H, J ¼ 7.1), 3.57 (septet, 1H, J ¼ 6.1),
3.50 (t, 2H, J ¼ 6.0), 2.75 (t, 2H, J ¼ 7.0), 1.92 (quintet, 2H,
J ¼ 7.0), 1.18 (d, 6H, J ¼ 6.1); 13C NMR: d 191.4, 154.3,
137.4, 129.8, 125.2, 117.7, 112.9, 71.8, 64.4, 48.9, 48.5, 36.9,
27.4, 22.0 (2C); ms: m/z 205 (Mþ-C5H11O). Anal. Calcd. for
C15H20N2O4; C, 61.64; H, 6.85; N, 9.59. Found: C, 61.76; H,
6.89; N, 9.53.
1-(2-Fluoro-5-methoxyphenyl)-2-propen-1-one (9). This
compound was prepared from 2.21 g (12.1 mmoles) of 6 and
6.86 mL of freshly prepared Jones reagent (ca., 2.9M, 19.9
mmoles) [15]. The crude product was flash chromatographed
on a 40 cm ꢂ 2.5 cm silica gel column eluted with 5% ether
in hexanes to give 1.14 g (52%) of 9 as a colorless oil. IR:
1-Isobutyl-6-nitro-4(1H)-quinolinone (10e). This com-
pound (72 mg, 72%) was isolated as a yellow solid, mp 102–
1
1
2840, 1671, 1273 cmꢁ1; H NMR: d 7.24 (m, 1H), 7.10–6.99
104ꢀC. IR: 1686, 1520, 1315 cmꢁ1; H NMR: d 8.73 (d, 1H, J
(complex, 3H), 6.41 (dt, 1H, J ¼ 17.0, 1.6), 5.91 (dd, 1H, J ¼
10.4, 1.6), 3.82 (s, 3H); 13C NMR: d 189.2, 155.9 (d, J ¼
246.8), 155.8, 135.4 (d, J ¼ 7.2), 130.1, 126.3 (d, J ¼ 15.9),
120.8 (d, J ¼ 8.6), 117.4 (d, J ¼ 25.4), 113.6 (d, J ¼ 2.9),
55.9; ms (30 eV): m/z 180 (Mþ). Anal. Calcd. for C10H9FO2:
C, 66.67; H, 5.00. Found: C, 66.71; H, 5.03.
¼ 2.7), 8.14 (dd, 1H, J ¼ 9.4, 2.7), 6.71 (d, 1H, J ¼ 9.4), 3.71
(t, 2H, J ¼ 7.0), 3.28 (d, 2H, J ¼ 7.4), 2.76 (t, 2H, J ¼ 7.0),
2.13 (nonet, 1H, J ¼ 6.6), 1.04 (d, 6H, J ¼ 6.6); 13C NMR: d
191.3, 154.4, 137.3, 129.8, 125.3, 117.6, 112.7, 59.6, 49.5,
36.8, 27.4, 20.3, 20.2; ms: m/z 205 (Mþ-C3H7). Anal. Calcd.
for C13H16N2O3: C, 62.90; H, 6.45; N, 11.29. Found: C,
62.94; H, 6.45; N, 11.26.
Representative procedure for the tandem Michael-SNAr
reaction using 7: 1-Benzyl-6-nitro-4(1H)-quinolinone
(10a). To a solution of 78 mg (0.4 mmoles) of 5 in 3 mL
of anhydrous N,N-dimethylformamide was added 53.5 mg
(0.055 mL, 0.5 mmoles) of benzylamine and the solution was
heated at 50ꢀC for 22 h. The reaction mixture was cooled and
added to 25 mL of saturated sodium chloride and extracted
with ether (three times). The combined ether extracts were
washed with water (one time), saturated sodium chloride (one
time), dried (magnesium sulfate), and concentrated under vac-
uum to afford a dark yellow oil. The product was purified on a
20-cm ꢂ 20-cm preparative thin layer chromatography plate
using 50–70% ether in hexanes to afford 78 mg (69%) of ꢁ71a
1-Cyclohexyl-6-nitro-4(1H)-quinolinone (10f). This com-
pound (84 mg, 77%) was isolated as a yellow solid, mp 174–
1
177ꢀC. IR: 1688, 1504, 1316 cmꢁ1; H NMR: d 8.77 (d, 1H
J ¼ 2.5), 8.16 (dd, 1H, J ¼ 9.5, 2.5), 6.86 (d, 1H, J ¼ 9.5),
3.81 (tt, 1H, J ¼ 11.5, 3.3), 3.60 (d, 2H, J ¼ 7.0), 2.70 (d,
2H, J ¼ 7.0), 1.91 (m, 4H), 1.78 (m, 1H), 1.58 (m, 2H), 1.45
(m, 2H), 1.21 (m, 1H); 13C NMR: d 191.6, 154.3, 137.4,
129.9, 12.57, 118.5, 112.6, 57.4, 41.2, 37.3, 30.0 (2C), 25.8
(2C), 25.4; ms: m/z 274 (Mþ). Anal. Calcd. for C15H18N2O3:
C, 65.69; H, 6.57; N, 10.22. Found: C, 65.70; H, 6.56; N,
10.20.
1-tert-Butyl-6-nitro-4(1H)-quinolinone (10g). This com-
pound (70 mg, 71%) was isolated as a yellow solid, mp 132–
as a yellow solid, mp 118–121ꢀC. IR: 1686, 1513, 1314 cm
;
1H NMR: d 8.77 (d, 1H, J ¼ 2.7), 8.11 (dd, 1H, J ¼ 9.5, 2.7),
7.43–7.28 (complex, 3H), 7.25 (d, 2H, J ¼ 7.0), 6.74 (d, 1H, J
¼ 9.5), 4.72 (s, 2H), 3.77 (t, 2H, J ¼ 7.1), 2.83 (t, 2H, J ¼
7.1); 13C NMR: d 191.2, 154.5, 138.3, 135.2, 130.0, 129.2,
128.0, 126.5, 125.1, 118.1, 113.3, 55.4, 49.0, 37.1; ms: m/z
191 (Mþ-C7H7). Anal. Calcd. for C16H14N2O3: C, 68.09; H,
4.96; N, 9.93. Found: C, 68.05; H, 4.95; N, 9.96.
134ꢀC. IR: 1688, 1499, 1317 cmꢁ1; H NMR: d 8.81 (d, 1H, J
1
¼ 2.9), 8.13 (dd, 1H, J ¼ 9.6, 2.9), 7.19 (d, 1H, 9.6), 3.73 (t,
2H, J ¼ 6.6), 2.70 (t, 2H, J ¼ 6.6), 1.61 (s, 9H); 13C NMR: d
192.5, 155.2, 137.9, 127.9, 125.5, 121.2, 117.5, 57.7, 44.2,
38.9, 29.6 (3C); ms: m/z 233 (Mþ-CH3). Anal. Calcd. for
C13H16N2O3: C, 62.90; H, 6.45; N, 11.29. Found: C, 62.93; H,
6.44; N, 11.27.
6-Nitro-1-(2-phenylethyl)-4(1H)-quinolinone (10b). This
compound (92 mg, 78%) was isolated as a yellow solid, mp
6-Nitro-1-phenyl-4(1H)-quinolinone (10h). This compound
(77 mg, 72%) was isolated as a yellow solid, mp 126–128ꢀC.
96–99ꢀC. IR: 1687, 1517, 1317 cmꢁ1
;
1H NMR: d 8.74 (s,
IR: 1688, 1498, 1314 cmꢁ1
;
1H NMR: d 8.80 (d, 1H, J ¼
1H), 8.17 (d, 1H, J ¼ 9.2), 7.38–7.18 (complex, 5H), 6.73 (d,
1H, J ¼ 9.2), 3.76 (t, 2H, J ¼ 6.8), 3.49 (t, 2H, J ¼ 7.0), 2.98
(t, 2H, J ¼ 7.0), 2.59 (t, 2H, J ¼ 7.0); 13C NMR: d 191.3,
153.7, 137.9, 137.6, 129.9, 128.9, 128.7, 127.1, 125.4, 117.9,
2.7), 8.00 (dd, 1H, J ¼ 9.4, 2.7), 7.54 (t, 2H, J ¼ 7.5), 7.41 (t,
1H, J ¼ 7.4), 7.30 (d, 2H, J ¼ 7.4), 6.59 (d, 1H, J ¼ 9.4),
4.03 (t, 2H, J ¼ 6.9), 2.93 (t, 2H, J ¼ 7.0); 13C NMR: d
191.1, 154.5, 144.0, 138.9, 130.5, 129.3, 127.9, 126.1, 125.0,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
1-Alkyl-2,3-dihydro-4(1H)-quinolinones by a Tandem Michael-SNAr Annulation Reaction
627
118.4, 115.4, 50.6, 37.4; ms: m/z 268 (Mþ). Anal. Calcd. for
C15H12N2O3: C, 67.16; H, 4.48; N, 10.45. Found: C, 67.18; H,
4.47; N, 10.42.
13C NMR: d 193.9, 151.6, 135.3, 128.6, 120.1, 116.1, 112.7,
56.0, 41.5, 38.3, 29.8 (2C), 26.1 (2C), 25.7; ms: m/z 229
(Mþ). Anal. Calcd for C15H19NO: C, 78.60; H, 8.30; N, 6.11.
Found: C, 78.54; H, 8.34; N, 6.04.
3-(tert-Butylamino)-1-(2-fluorophenyl)-1-propanone (12a). This
compound (58 mg, 52%) from tert-butylamine and 8 was
isolated as a yellow oil. To prevent extraction of the product
into the aqueous layer during workup, the reaction was
diluted with water and made slightly basic with 0.1M NaOH
before extraction with ether. Attempts to purify this material
by chromatography resulted in extensive decomposition, and
thus, characterization was carried out on the crude product.
Representative procedure for the tandem Michael-SNAr
reaction using 8: 1-Benzyl-4(1H)-quinolinone (11a). This
reaction was run using 75 mg (0.50 mmoles) of 8 and the gen-
eral procedure given above for the preparation of 10a. This
compound (72 mg, 61%) was isolated as a light yellow solid,
1
mp 111–114ꢀC [16]. IR: 1673 cmꢁ1; H NMR d 7.93 (dd, 1H,
J ¼ 7.8, 1.8), 7.39–7.24 (complex, 6H), 6.72 (t, 1H, J ¼ 8.0),
6.70 (d, 1H, J ¼ 8.4), 4.57 (s, 2H), 3.60 (t, 2H, J ¼ 7.0), 2.75
(t, 2H, J ¼ 7.0); 13C NMR: d 193.5, 151.7, 137.2, 135.5,
128.8, 128.2, 127.4, 126.7, 119.8, 117.0, 113.4, 55.2, 49.4,
38.0; ms: m/z 146 (Mþ-C7H7). Anal. Calcd. for C16H15NO: C,
81.01; H, 6.33; N, 5.91. Found: C, 80.97; H, 6.35; N, 5.89.
1-(2-Phenylethyl)-4(1H)-quinolinone (11b). This com-
pound (73 mg, 58%) was isolated as a yellow oil. IR: 1673
IR: 3454, 1685, 1269 cmꢁ1
;
1H NMR: d 7.87 (td, 1H, J ¼
7.6, 1.8), 7.50 (m, 1H), 7.22 (t, 1H, J ¼ 7.8), 7.12 (dd, 1H, J
¼ 11.2, 8.0), 3.20 (td, 2H, J ¼ 6.2, 3.3), 2.96 (t, 2H, J ¼
6.2), 1.71 (br s, 1H), 1.13 (s, 9H); 13C NMR: d 198.1, 162.0
(d, J ¼ 254.7), 134.5 (d, J ¼ 8.8), 130.5 (d, J ¼ 2.9), 130.4,
124.4 (d, J ¼ 3.4), 116.7 (d, J ¼ 24.2), 50.5, 44.7 (d, J ¼
7.4), 37.3 (d, J ¼ 2.2), 28.9 (3C); ms: m/z 123 (Mþ-
C6H14N).
1
cmꢁ1; H NMR d 7.91 (dd, 1H, J ¼ 7.8, 1.8), 7.39 (ddd, 1H,
J ¼ 8.6, 7.2, 1.8), 7.36–7.18 (complex, 5H), 6.78 (d, 1H, J ¼
8.6), 6.71 (t, 1H, J ¼ 7.2), 3.61 (t, 2H, J ¼ 7.5), 3.41 (t, 2H, J
¼ 7.0), 2.91 (t, 2H, J ¼ 7.5), 2.59 (t, 2H, J ¼ 7.0); 13C NMR:
d 193.5, 150.8, 138.9, 135.4, 128.7, 128.6, 128.4, 126.5, 119.6,
116.4, 112.7, 53.3, 49.4, 37.7, 32.7; ms: m/z 160 (Mþ-C7H7).
Anal. Calcd. for C17H17NO: C, 81.27; H, 6.77; N, 5.58. Found:
C, 81.21; H, 6.74; N, 5.62.
1-(2-Fluorophenyl)-3-(phenylamino)-1-propanone (12b). This
compound (79 mg, 65%) from aniline and 8 was isolated as a
yellow solid, mp 69–71ꢀC. IR: 3405, 1683, 1264 cmꢁ1 1H
;
NMR: d 7.88 (td, 1H, J ¼7.8, 1.8), 7.50 (m, 1H), 7.25–7.08
(complex, 5H), 6.70 (t, 1H, J ¼ 7.2), 6.64 (dd, 1H, J ¼ 7.6,
1.0), 4.09 (br s, 1H), 3.58 (t, 2H, J ¼ 6.1), 3.28 (m, 2H); 13C
NMR: d 197.4, 162.1 (d, J ¼ 254.7), 147.7, 134.8 (d, J ¼
8.8), 130.5 (d, J ¼ 2.2), 129.3, 124.5 (d, J ¼ 3.7), 117.5,
116.8, 116.6 (d, J ¼ 11.8), 112.9, 42.8, 38.5; ms: m/z 123
(Mþ-C8H10N). Anal. Calcd. for C15H14FNO: C, 74.07; H,
5.76; N, 5.76. Found: C, 73.98; H, 5.79; N, 5.70.
1-Hexyl-4(1H)-quinolinone (11c). This compound (90 mg,
1
78%) was isolated as a yellow oil. IR: 1677 cmꢁ1; H NMR:
d 7.89 (dd, 1H, J ¼ 7.8, 1.8), 7.35 (ddd, 1H, J ¼ 8.6, 7.0,
1.8), 6.70 (d, 1H, J ¼ 8.6), 6.67 (t, 1H, J ¼ 7.8), 3.51 (t, 2H,
J ¼ 7.0), 3.34 (t, 2H, J ¼ 7.6), 2.68 (t, 2H, J ¼ 7.0), 1.61
(quintet, 2H, J ¼ 7.6), 1.34 (m, 6H), 0.90 (distorted t, 3H, J ¼
6.8); 13C NMR: d 193.5, 151.4, 135.3, 128.3, 119.5, 116.1,
112.8, 51.5, 49.0, 37.8, 31.6, 26.8, 26.1, 22.6, 14.0; ms: m/z
160 (Mþ-C5H11). Anal. Calcd. for C15H21NO: C, 77.92; H,
9.09; N, 6.06. Found: C, 77.81; H, 9.04; N, 6.12.
Representative procedure for the tandem Michael-SNAr
reaction using 9: 1-(2-Fluoro-5-methoxyphenyl)-3-(benzyl-
amino)-1-propanone (13) and (ꢃ)-(3S*,4R*)-1-benzyl-3-(2-
fluoro-5-methoxybenzoyl)-4-(2-fluoro-5-methoxyphenyl)-4-
piperidinol (15). This reaction was run using 75 mg (0.42
mmoles) of 9 and the general procedure given above for the
preparation of 10a. The reaction did not yield the dihydroqui-
nolinone but yielded only products resulting from the initial
conjugate addition without subsequent SNAr ring closure. The
1:1 Michael addition product 13 (14 mg, 12%) was isolated as
1-(3-Isopropoxypropyl)-4(1H)-quinolinone
compound (86 mg, 70%) was isolated as a yellow oil. IR:
(11d). This
1674 cmꢁ1
;
1H NMR: d 7.89 (dd, 1H, J ¼ 7.8, 1.8), 7.35
(ddd, 1H, J ¼ 8.5, 7.0, 1.8), 6.78 (d, 1H, J ¼ 8.5), 6.67 (ddd,
1H, J ¼ 7.8, 7.0, 1.8), 3.61–3.45 (complex, 7H), 2.68 (t, 2H, J
¼ 7.0), 1.86 (quintet, 2H, J ¼ 6.1), 1.17 (d, 6H, J ¼ 6.1); 13C
NMR: d 193.5, 151.4, 135.3, 128.2, 119.5, 116.2, 113.0, 71.6,
65.0, 49.1, 48.4, 37.8, 27.2, 22.1 (2C); ms: m/z 160 (Mþ-
C5H11O). Anal. Calcd for C15H21NO2: C, 72.87; H, 8.50; N,
5.67. Found: C, 72.96; H, 8.54; N, 5.64.
a yellow oil. IR: 3333, 2815, 1685, 1271 cmꢁ1 1H NMR: d
;
7.32 (m, 5H), 7.25 (m, 1H), 7.04 (m, 2H), 3.83 (s, 2H), 3.81
(s, 3H), 3.22 (td, 2H, J ¼ 6.2, 3.3), 3.02 (t, 2H, J ¼ 6.2), 1.77
(br s, 1H); 13C NMR: d 197.7 (d, J ¼ 4.4), 156.6 (d, J ¼
247.4), 155.7, 140.2, 128.4, 128.1, 126.9, 125.5 (d, J ¼ 14.7),
121.5 (d, J ¼ 8.8), 117.7 (d, J ¼ 26.5), 112.7 (d, J ¼ 2.9),
55.9, 54.0, 43.9, 43.8 (d, J ¼ 7.4); ms: m/z 153 (Mþ-C9H12N).
Anal. Calcd. for C17H18FNO2: C, 71.08; H, 6.27; N, 4.88.
Found: C, 71.12; H, 6.29; N, 4.82.
1-Isobutyl-4(1H)-quinolinone (11e). This compound (76
mg, 75%) was isolated as a yellow oil. IR: 1677 cmꢁ1 1H
;
NMR d 7.89 (dd, 1H, J ¼ 7.8, 1.8), 7.34 (ddd, 1H, J ¼ 8.6,
7.0, 1.8), 6.68 (d, 1H, J ¼ 8.8), 6.67 (t, 1H, J ¼ 7.8), 3.54 (t,
2H, J ¼ 7.0), 3.10 (d, 2H, J ¼ 7.4), 2.68 (t, 2H, J ¼ 7.0),
2.07 (nonet 1H, J ¼ 6.8), 1.01 (d, 6H, J ¼ 6.6); 13C NMR: d
193.5, 151.7, 135.3, 128.3, 119.2, 116.0, 112.7, 59.6, 50.0,
37.8, 27.4, 20.4 (2C); ms: m/z 160 (Mþ-C3H7). Anal. Calcd.
for C13H17NO: C, 76.85; H, 8.37; N, 6.90. Found: C, 76.90;
H, 8.40; N, 6.83.
1-Cyclohexyl-4(1H)-quinolinone (11f). This compound (62
;
mg, 54%) was isolated as a yellow oil. IR: 1674 cmꢁ1 1H
NMR d 7.92 (dd, 1H, J ¼ 7.8, 1.8), 7.35 (ddd, 1H, J ¼ 8.6,
7.0, 1.8), 6.83 (d, 1H, J ¼ 8.8), 6.67 (t, 1H, J ¼ 7.8), 3.68 (tt,
1H, J ¼ 11.1, 3.1), 3.43 (t, 2H, J ¼ 7.0), 2.62 (t, 2H, J ¼
7.0), 1.85 (m, 4H), 1.74 (m, 1H), 1.45 (m, 4H), 1.15 (m, 1H);
This reaction also yielded piperidinol 15, which results from
the silica gel-promoted aldol ring closure of the 2:1 Michael
addition product 14. Compound 15 (82 mg, 42%) was isolated
1
as a viscous yellow oil. IR: 3462, 2830, 1663 cmꢁ1; H NMR:
d 7.39 (d, 2H, J ¼ 7.4), 7.32 (t, 2H, J ¼ 7.4), 7.25 (m, 2H),
6.97 (m, 2H), 6.91 (m, 1H), 6.77 (dd, 1H, J ¼ 11.5, 8.9), 6.63
(dt, 1H, J ¼ 8.9, 3.5), 4.89 (d, 1H, J ¼ 2.3), 4.71 (dd, 1H, J
¼ 11.1, 3.5), 3.76 (s, 3H), 3.69 (s, 3H), 3.68 (s, 2H), 3.03 (dd,
1H, J ¼ 11.1, 3.5), 2.75 (complex, 3H), 2.72 (m, 1H), 1.65 (d,
1H, J ¼ 13.7); 13C NMR: d 203.2 (d, J ¼ 3.7), 156.1 (d, J ¼
250.3), 155.6, 155.5, 153.2 (d, J ¼ 237.8), 138.3, 134.1 (d, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

628
R. A. Bunce and T. Nago
Vol 46
P.; Lee, C.-H.; Schmidt, R. G. Chem Abstr 2008, 149, 104611; (c)
Glamkowski, E. J.; Hamer, R. R. L. U.S. Pat. 4,786,644 (1988), 14;
(d) Glamkowski, E. J.; Hamer, R. R. L. Chem Abstr 1989, 110,
135097.
¼ 14.0), 128.8, 128.2, 127.0, 125.3 (d, J ¼ 13.9), 121.9 (d, J
¼ 8.8), 117.7 (d, J ¼ 25.8), 116.6 (d, J ¼ 26.5), 113.9 (d, J ¼
8.8), 112.9 (d, J ¼ 4.4), 112.6 (d, J ¼ 2.2), 72.3 (d, J ¼ 5.9),
62.0, 55.7, 55.6, 53.1 (t, J ¼ 7.4), 51.4, 48.5, 36.2 (d, J ¼
2.9); ms (30 eV): m/z 467 (Mþ). Anal. Calcd for
C27H27F2NO4: C, 69.38; H, 5.78; N, 3.00. Found: C, 69.44; H,
5.81; N, 2.93. The 1H and 13C NMR spectra compare well
with calculated spectra [12], but the stereochemical assignment
is tentative.
[8] Bagolini, C.; de Witt, P.; Pacifici, L.; Ramacci, M. T. J
Med Chem 1978, 21, 476.
[9] (a) Hom, R.; Tucker, J.; Varghese, J.; Shah, N. World Pat-
ent WO 2005095326 (2005), 365; (b) Hom, R.; Tucker, J.; Varghese,
J.; Shah, N. Chem Abstr 2005, 143, 386930. (c) Varghese, J.; Maillard,
M.; Fang, L; Tucker, J.; Brogley, L.; Aquino, J.; Bowers, S.; Probst,
G.; Tung, J. World Patent WO 2005087714 (1995), 428; (d) Varghe-
seJ.; Maillard, M.; Fang, L; Tucker, J.; Brogley, L.; Aquino, J.;
Bowers, S.; Probst, G.; Tung, J. Chem Abstr 2005, 143, 326226.
[10] These compounds are also currently being evaluated for
the treatment of: (a) Central nervous system disorders: Galley, G.;
Groebke Zbinden, K. G.; Norcross, R.; Stalder, H. World Patent WO
2007085558 (2007), 85; (b) Galley, G.; Groebke Zbinden, K. G.; Nor-
cross, R.; Stalder, H. Chem Abstr 2007, 147, 841292; (c) Potassium
channel blockers: Gerlach, U.; Brendel, J.; Lang, H. J.; Weidmann, K.
Eur. Pat. EP 857,724 (1998), 23; (d) Gerlach, U.; Brendel, J.; Lang, H.
J.; Weidmann, K. Chem Abstr 1998, 129, 175447. (e) Cancer: Vicker,
N.; Day, J. M.; Bailey, H. V.; Heaton, W.; Gonzalez, A. M. R.; Shar-
land, C. M.; Reed, M. J.; Purohit, A.; Potter, B. V. L. World Patent
2007003934 (2007), 266; (f) Vicker, N.; Day, J. M.; Bailey, H. V.;
Heaton, W.; Gonzalez, A. M. R.; Sharland, C. M.; Reed, M. J.; Puro-
hit, A.; Potter, B. V. L. Chem Abstr 2007, 146, 142281.
Acknowledgment. T. N. thanks Oklahoma State University for
a Niblack Scholarship and the Department of Chemistry for a
Moore Scholarship. Funding for the 400 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 FTIR and GC-MS
instruments.
REFERENCES AND NOTES
[1] Undergraduate research participant, 2006–2009.
[2] (a) Bunce, R. A.; Rogers, D.; Nago, T.; Bryant, S. A. J Het-
erocyclic Chem 2008, 45, 547; (b) Bunce, R. A.; Nago, T.; Sonobe,
N.; Slaughter, L. M. J Heterocyclic Chem 2008, 45, 551; (c) Bunce,
R. A.; Nago, T. J Heterocyclic Chem 2008, 45, 1155.
[11] Gale, D. J.; Wilshire, J. F. K. Aust J Chem 1970, 23, 1063.
[12] Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky,
S. J. J Org Chem 1993, 58, 611.
[13] The calculated 1H and 13C nmr spectra were obtained using
ACD HNMR and CNMR software from Advanced Chemistry Devel-
opment, Inc. Toronto, Canada, 2007.
[3] See for example (a) Johnson, W. S.; Woroch, E. L.; Buell,
B. G. J Am Chem Soc 1949, 71, 1901; (b) Hurd, C. D.; Hayao, S. J
Am Chem Soc 1954, 76, 5065; (c) Allison, J. A. C.; Braunholtz, J. T.;
Mann, F. G. J Chem Soc 1954, 403.
[4] (a) Kano, S.; Ebata, T.; Shibuya, S. J Chem Soc Perkin
Trans 1, 1980, 2105; (b) Anderson, K. W.; Tepe, J. J. Tetrahedron
2002, 58, 8475.
[14] Still, W. C.; Kahn, M.; Mitra, A. J Org Chem 1978, 43,
2923.
[5] Donnelly, J. A.; Farrell, D. F. J Org Chem 1990, 55, 1757.
[6] Baraznenok, I. L.; Nenaidenko, V. G.; Balenkova, E. S.
Chem Heterocyclic Compd 1997, 33, 429.
[15] Eisenbraun, E. J. Organic Syntheses; Wiley: New York,
NY, 1973; Vol. V, pp 310–314.
[16] This is a known compound, but it is reported with only a
boiling point (175–177ꢀC, 0.2 mmHg), see Atwal, M. S.; Bauer, L.;
Dixit, S. N.; Gearien, J. E.; Morris, R. W. J Med Chem 1965, 8, 566.
Reference 8a also reports this compound without a melting point.
[7] (a) Bayburt, E. K.; Daanen, J. F.; Gomtsyan, A. R.; Lat-
shaw, S. P.; Lee, C.-H.; Schmidt, R. G. U.S. Pat. 20080153871 (2008),
45; (b) Bayburt, E. K.; Daanen, J. F.; Gomtsyan, A. R.; Latshaw, S.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet