Steric and Electronic Requirements in the Synthesis of 2,3-Dihydro-4(1H)-quinolinones by the Tandem Michael-SNAr Reaction

Article abstract of DOI:10.1002/jhet.2142

The steric and electronic requirements have been investigated for the synthesis of 2,3-dihydro-4(1H)-quinolinones by the tandem Michael-S_NAr reaction. Substrates bearing a single methyl group at the β-enone carbon gave excellent yields of the title compounds from both the E and Z isomers with X=H or NO₂. Substrates with β,β-dimethyl substitution at the Michael terminus gave low yields of heterocyclic products in molecules having monoactivated S_NAr aromatic acceptor rings (X=H) and very good yields for diactivated systems (X=NO₂). For these hindered substrates, success in the final cyclization hinges on the ability of the aromatic acceptor to capture the pendant nitrogen nucleophile of the initial Michael adduct before this intermediate can revert to starting materials.

Full text of DOI:10.1002/jhet.2142

Month 2014 Steric and Electronic Requirements in the Synthesis of 2,3-Dihydro-4(1H)-
quinolinones by the Tandem Michael-SNAr Reaction
*
Richard A. Bunce, Takahiro Nago, and Suaad Abuskhuna
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, USA
*
E-mail: rab@okstate.edu
Received September 3, 2013
DOI 10.1002/jhet.2142
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The steric and electronic requirements have been investigated for the synthesis of 2,3-dihydro-4(1H)-
quinolinones by the tandem Michael-SNAr reaction. Substrates bearing a single methyl group at the
β-enone carbon gave excellent yields of the title compounds from both the E and Z isomers with X═H or
NO2. Substrates with β,β-dimethyl substitution at the Michael terminus gave low yields of heterocyclic
products in molecules having monoactivated SNAr aromatic acceptor rings (X═H) and very good yields
for diactivated systems (X═NO2). For these hindered substrates, success in the final cyclization hinges on
the ability of the aromatic acceptor to capture the pendant nitrogen nucleophile of the initial Michael adduct
before this intermediate can revert to starting materials.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
nitrobenzaldehyde [13] (2) with vinylmagnesium bromides
3 and 4 afforded the allylic alcohols 5–8 in 86–88% yields.
However, conversion of these alcohols to the corresponding
ketones 9–12 using chromic acid [14] in aqueous acetone, as
in our original report [1,15], proved troublesome. Under
these conditions, oxidation of 5 afforded the 1,3-carbonyl
transposition product 13 in 58% yield, along with only 9%
of the desired ketone 9 [16]. Fortunately, this difficulty
could be circumvented by using activated manganese(IV)
dioxide [17] as the oxidizing agent. This method gave clean
conversion to the desired products 9–12 in 65–84% yields
with no rearrangement.
Our results, from reactions of 9 and 10 with amines a–c,
are shown in Figure 2. These substrates each possess one
alkyl group at the β-enone carbon and differ only in the
number of activating (electron-withdrawing) substituents
at C2 and C4 relative to the fluoro substituent on the SNAr
aromatic acceptor ring. Based on the yields of 14 and 15, it
can be seen that the reaction proceeds well for compounds
having both one and two activating groups, with the
diactivated substrate 10 providing slightly higher yields
of the heterocyclic products. As previously described, the
mechanism of this reaction is consistent with an initial
Michael reaction followed by an SNAr ring closure [1].
Substrates 11 and 12 (Fig. 3) have increased steric
demand for the initial Michael reaction because of the
presence of a second methyl group at the Michael
terminus. Reaction of monoactivated substrate 11 with
amines a–c furnished only meager yields of the Michael-
SNAr products 20a–c, along with recovered starting material.
We have recently described several synthetic approaches
to substituted 2,3-dihydro-4(1H)-quinolines [1–3].
Additionally, numerous schemes have been developed by
others for the preparation of these heterocycles and many
are cited in our earlier reports [1–3]. The 2,3-dihydro-4
(1H)-quinoline scaffold is a common structural component
in many biologically active compounds. Members of this
compound family are valuable building blocks for the con-
struction of drugs to treat pain [4], Alzheimer’s disease [5],
cancer [6], and central nervous system disorders [7].
Other derivatives have demonstrated activity as potassium
channel blockers [8], steroid receptor modulators [9],
cholesterol ester transfer protein inhibitors [10], and agents
for the treatment of inflammation-based diseases such as
asthma [11]. The current work is an extension of a previous
study from our laboratory [1], which disclosed a tandem
Michael-SNAr strategy for the preparation of simple
derivatives of this ring system and delineated the steric
requirements of the starting amine for successful ring
closure [12]. The current project sought to further define
the steric and electronic demands of this reaction with
respect to the acceptor substrate.
RESULTS AND DISCUSSION
Reactive substrates for the current study were prepared
by a modification of our earlier synthesis [1] (Fig. 1).
Treatment of 2-fluorobenzaldehyde (1) and 2-fluoro-5-
© 2014 HeteroCorporation

R. A. Bunce, T. Nago, and S. Abuskhuna
Vol 000
Figure 1. Synthesis of cyclization substrates.
Figure 3. Cyclizations with 11 and 12.
toward nucleophilic attack. In our earlier study [1], which
explored this transformation using substrates lacking
β-enone substitution, the Michael addition was relatively
fast and less reversible, leading to adducts that cyclized
even with weakly activated rings. The intramolecular
nature of the final SNAr ring closure through a chair-like
conformation [19], aided in the current case by the
Thorpe–Ingold effect [20], appears to be important for
cyclizations of minimally activated systems [21] (Fig. 4).
By using substrate 12, which has two activating
substituents on the SNAr acceptor ring, the reaction
proceeded smoothly to give very good yields of the target
heterocycles. The cyclized products most likely resulted
from the normal Michael-SNAr process via 22, with the
ring being sufficiently active to capture the initial Michael
adduct before it could revert to starting materials (Fig. 4
and Scheme 1). The additional formation of 19 from 12
could conceivably arise from an alternative pathway
initiated by an SNAr reaction to give 17’ [22]. This
pathway should occur competitively with Michael addition
for 12, due to the β-enone disubstitution, resulting in partial
reordering of the reaction sequence. Once addition to the
aromatic acceptor occurs to give 17’, steric interaction
between the added amine and the side chain would cause
rotation of the enone moiety away from the amine to give
the six-centered, hydrogen bond-stabilized rotamer 17 [23],
which cannot undergo cyclization. Subsequent Michael
addition of excess amine to 17 would then give 23, and
Figure 2. Cyclizations with 9 and 10.
Other possible products, such as 16 from a simple SNAr
addition and 18 from an SNAr-Michael-reverse aldol
sequence (vide infra), were not observed. On the other hand,
doubly activated substrate 12 afforded three products
from each amine including the SNAr adduct 17, the SNAr-
Michael-retro-aldol acetophenone 19, and the desired
heterocycle 21 as the major product.
The β,β-dimethyl substitution on the side chain enone in
11 and 12 resulted in a noticeable decrease in yield of the
desired heterocycle. Reaction of substrate 11, with a single
activating group on the SNAr acceptor ring, led to
significant recovery of starting material. In this system,
the Michael addition would be slow and reversible due to
steric crowding at the β-enone carbon [18], and thus, the
adduct produced could revert to starting material or cyclize
to product. For compound 11, the reverse reaction
predominated because the ring was not strongly activated
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Month 2014
2,3-dihydro-4(1H)-quinolinones by the Tandem Michael-SNAr Reaction
step correlated predictably with the electronics of the SNAr
acceptor moiety. In monoactivated substrates, the reverse
Michael pathway predominated and significant quantities
of starting materials were recovered. For diactivated
substrates, however, capture of the tethered nitrogen
nucleophile by the aromatic ring was more efficient, and
ring closures were observed. Moreover, the increased steric
bulk at the Michael terminus resulted in perturbation of the
normal reaction sequence to yield simple SNAr adducts,
which assumed a six-centered, hydrogen bond-stabilized
conformation that could not cyclize. Further addition to
the enone in these products then led to 2-alkylamino-
5-nitroacetophenone derivatives via a retro-aldol process.
Figure 4. Chair-like conformation for cyclization of 11 (X═H) and 12
(X═NO2). [R═PhCH2, n-C6H13 or i-C4H9].
Scheme 1. Proposed mechanisms.
EXPERIMENTAL
All reactions were run under dry nitrogen in oven-dried
glassware. Grignards 3 and 4 in THF as well as anhydrous
DMF were purchased from Sigma-Aldrich. Reactions were
monitored by thin layer chromatography on silica gel GF plates
(Analtech, No. 21521). Preparative separations were performed
by one of the following methods: (1) column chromatography
on silica gel (grade 62, 60–200 mesh) containing UV-active
phosphor (Sorbent Technologies, No. UV-05) packed into quartz
columns or (2) preparative thin layer chromatography (PTLC) on
20 cm × 20 cm silica gel GF plates (Analtech, No. 02015). Band
elution for all chromatographic methods was monitored using a
hand-held UV lamp. Melting points were uncorrected. IR spectra
1
were run as thin films on NaCl disks. H-NMR and 13C-NMR
spectra were measured in CDCl3 using (CH3)4Si as the internal
standard; coupling constants (J) are given in Hertz. Unless
otherwise indicated, low-resolution mass spectra (electron
impact/direct probe) were obtained at 70 eV.
Representative Grignard addition procedure
( )-(E)- and ( )-(Z)-1-(2-Fluorophenyl)-2-buten-1-ol (5). The
general procedure of Danishefsky and co-workers was used [14]. To
a À78°C solution of 1.86 g (15.0 mmol) of 2-fluorobenzaldehyde (1)
in 75 mL of anhydrous THF was added 45 mL of 0.5 M 1-
propenylmagnesium bromide (3, 22.5 mmol) in THF. The
reaction mixture was stirred for 3.5 h at À78°C, then quenched
by addition of 50 mL of saturated aqueous NH4Cl and extracted
with ether (3× 50mL). The combined ether extracts were washed
with water (three times), saturated aqueous NaCl (one time), dried
(MgSO4), filtered, and concentrated under vacuum to give 2.19 g
(88%) of 5 (ca. 3:1 E/Z) as a viscous yellow oil. Product 5
decomposed slightly on attempted chromatography and was
used without further purification. The spectral data for the
mixture were IR: 3347, 1616, 1242 cmÀ1; 1H-NMR (300 MHz):
δ 7.49 (overlapping td, 1H, J = 7.4, 1.6 Hz), 7.24 (m, 1H), 7.14
(td, 1H, J = 7.4, 1.6 Hz), 7.01 (ddd, 1H, J = 10.4, 9.3, 1.1 Hz),
5.83 and 5.63 (2d, 1H, J = 7.1, 5.0 Hz), 5.73 (m, ~0.5H), 5.61
(m, ~1.5H), 2.18 (br s, 1H), 1.77 and 1.70 (2d, 3H, J = 4.9 and
5.4 Hz); 13C-NMR (75 MHz): δ 159.9 (d, J = 246.2 Hz), 132.1,
131.4, 130.6 (d, J = 13.2 Hz), 129.0 (d, J = 8.3 Hz), 128.4
(d, J = 8.3 Hz), 127.6, 127.4 (d, J = 4.3 Hz), 126.9, 124.3 (d,
J = 3.4 Hz), 115.3 (d, J = 21.8 Hz), 69.2 (d, J = 2.2 Hz), 64.1
(d, J = 3.4 Hz), 17.6, 13.2; ms: m/z 123 (M+ À C3H7).
reverse aldol reaction would finally produce the acetophenone
derivative 19, via enol 24, along with imine 25. This imine
would presumably hydrolyze to acetone and the amine during
workup and be lost from the product mixture.
CONCLUSIONS
We have explored the steric and electronic requirements
for the synthesis of 2,3-dihydro-4(1H)-quinolinones by
the tandem Michael-SNAr reaction. The current work
demonstrates that the steric environment at the β carbon
of the Michael acceptor and the activation of SNAr
acceptor ring have a major impact on the reaction outcome.
With a single alkyl substituent at the Michael terminus, the
reaction proceeded cleanly and in high yield from both
the E and the Z isomers for all cases. Additional substitu-
tion at this site, however, slowed addition to the enone
and generated an adduct that could partition between two
reaction pathways: (1) a reverse Michael reaction or (2)
ring closure to the heterocycle. Success in the cyclization
( )-(E)- and ( )-(Z)-1-(2-Fluoro-5-nitrophenyl)-2-buten-1-ol
(6). This compound (1.81 g, ca. 3:1 E/Z, 86%) was prepared from
Journal of Heterocyclic Chemistry
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R. A. Bunce, T. Nago, and S. Abuskhuna
Vol 000
1.69 g (10.0mmol) of 2-fluoro-5-nitrobenzaldehye (2) [13] and
30mL of 0.5 M 1-propenylmagnesium bromide (3) in THF
(3, 15.0 mmol), and was isolated as viscous yellow oil. Product 6
decomposed slightly on attempted chromatography and was used
without further purification. IR: 3378, 1629, 1530, 1350,
(d, J = 3.4Hz), 116.5 (d, J = 23.5 Hz), 16.4; ms: m/z 123
(M+ À C3H5). Anal. Calcd for C10H9FO: C, 73.17; H, 5.49.
Found: C, 73.12; H, 5.51.
Band 2 gave 516 mg (52%) of (E)-9 as a viscous yellow oil. IR:
1667, 1619, 1215 cmÀ1 1H-NMR (300 MHz): δ 7.70 (td, 1H,
;
1247cmÀ1 1H-NMR (300 MHz): δ 8.49 and 8.46 (dd, 1H,
;
J = 7.7, 1.6 Hz), 7.48 (m, 1H), 7.22 (t, 1H J = 7.7 Hz), 7.12 (dd,
1H, J = 11.0, 8.2 Hz), 6.99 (m, 1H), 6.76 (dq, 1H, J = 15.4,
1.1 Hz), 1.98 (dd, 3H, J = 6.6, 1.1 Hz); 13C-NMR (75 MHz): δ
189.5, 160.9 (d, J = 253.1 Hz), 145.6, 135.5 (d, J = 8.6 Hz),
131.1 (d, J = 5.7 Hz), 130.7 (d, J = 2.9 Hz), 127.0 (d,
J = 13.5 Hz), 124.3 (d, J = 3.4 Hz), 116.4 (d, J = 23.2 Hz), 18.5;
ms: m/z 123 (M+ À C3H5). Anal. Calcd for C10H9FO: C, 73.17;
H, 5.49. Found: C, 73.15; H, 5.47.
J = 6.1, 2.7 Hz), 8.16 (m, 1H), 7.16 (t, 1H, J = 9.2 Hz), 5.84
(m, 1H), 5.68 (m, 1H), 5.51 (m, 1H), 2.55 (br s, 1H), 1.82
(dm, ~1.5H, J= 6.8 Hz), 1.72 (dd, ~1.5H, J= 6.4, 0.8 Hz); 13C-
NMR (75 MHz): δ 163.2 (d, J= 262.8 Hz), 163.1 (d, J=262.8Hz),
144.8, 132.6 (d, J= 15.5 Hz), 132.4 (d, J= 15.5 Hz), 131.0, 130.2,
129.1, 128.5, 124.7 (d, J= 3.7 Hz), 124.6 (d, J= 3.7 Hz), 123.6
(d, J= 6.6 Hz), 116.3 (d, J= 25.0 Hz), 68.4, 63.3, 17.6, 13.2; ms:
m/z 168 (M+ À C3H7).
Attempts to oxidize 5 with chromic acid [1,14,15] on the same
scale led to a mixture of 90 mg (9%) of (E)-9 and 572 mg (58%)
of the 1,3-carbonyl transposition [16] product (E)-4-(2-
fluorophenyl)-3-buten-1-one (13) as a light yellow solid, mp
42–43°C. The spectral data for 13 were IR: 1672, 1612, 1221,
( )-1-(2-Fluorophenyl)-3-methyl-2-buten-1-ol (7).
This
compound (2.35 g, 87%) was prepared from 1.86 g (15.0 mmol)
of and 45 mL of 0.5 M 2-methyl-1-propenylmagnesium
1
bromide (4, 22.5 mmol) in THF, and was isolated as a light
yellow solid, mp 37–39°C. Product 7 was pure by 1H-NMR
analysis and was used without further purification. IR: 3353,
1618, 1224 cm-1; 1H-NMR (300 MHz): δ 7.50 (td, 1H, J = 7.7,
1.6 Hz), 7.22 (m, 1H), 7.14 (td, 1H, J = 7.1, 1.1 Hz), 7.01
(m, 1H), 5.73 (dd, 1H, J = 8.8, 3.3 Hz), 5.40 (dq, 1H, J = 8.8,
1.1 Hz), 1.95 (d, 1H, J = 3.3 Hz), 1.80 (s, 3H), 1.74 (s, 3H);
13C-NMR (75 MHz): δ 159.9 (d, J = 245.9 Hz), 135.9, 131.1
(d, J = 13.2 Hz), 128.7 (d, J = 8.0 Hz), 127.3 (d, J = 4.6 Hz),
126.2, 124.2 (d, J = 3.4 Hz), 115.3 (d, J = 21.8 Hz), 65.4
(d, J = 3.1 Hz), 25.8, 18.2; ms: m/z 123 (M+ À C4H9). Anal.
Calcd for C11H13FO: C, 73.33; H, 7.22. Found: C, 73.57;
H, 7.24.
980 cmÀ1 1H-NMR (400 MHz): δ 7.67 (d, 1H, J = 16.6 Hz),
;
7.57 (t, 1H, J = 7.4 Hz), 7.37 (m, 1H), 7.17 (t, 1H, J = 7.4 Hz),
7.11 (dd, 1H, J = 9.9, 9.1 Hz), 6.78 (d, 1H, J = 16.6 Hz), 2.40 (s,
3H); 13C-NMR (100 MHz): δ 198.3, 161.2 (d, J = 254.0 Hz),
135.5 (d, J = 3.7 Hz), 131.9 (d, J = 8.8 Hz), 129.1 (d, J = 5.2 Hz),
128.6 (d, J = 2.9 Hz), 124.5 (d, J = 3.7 Hz), 122.4 (d,
J = 11.8 Hz), 116.1 (d, J = 22.1 Hz), 27.4; ms: m/z 164 (M+). Anal.
Calcd for C10H9FO: C, 73.17; H, 5.49. Found: C, 73.13; H, 5.51.
(E)- and (Z)-1-(2-Fluoro-5-nitrophenyl)-2-buten-1-one (10). These
compounds (0.67 g, ca. 3:1 E:Z mixture, 68%) were prepared
from 1.00g (4.74 mmol) of E/Z-6 and 10.0 g of manganese(IV)
oxide in 25mL of dichloromethane. The products were purified
on a 40 cm× 2.0 cm silica gel column eluted with increasing
concentrations of ether in hexanes to give 2 bands. Band 1 gave
138 mg (14%) of (Z)-10 as a light yellow solid, mp 43–45°C. IR:
1675, 1621, 1532, 1355, 1246cmÀ1; 1H-NMR (300 MHz): δ 8.69
(dd, 1H, J = 6.0, 2.7 Hz), 8.38 (dt, 1H, J = 9.3, 3.8 Hz), 7.31
(t, 1H, J = 9.3 Hz), 6.74 (dq, 1H, J= 11.5, 1.6 Hz), 6.57 (dq, 1H,
J= 11.5, 7.1 Hz), 2.24 (d, 3H, J=7.1Hz); 13C-NMR (75 MHz): δ
186.8, 163.9 (d, J= 264.0 Hz), 147.5, 144.5, 128.7 (d, J=10.9 Hz),
128.6 (d, obscured), 127.1 (d, J= 4.9 Hz), 126.8 (d, J=6.3Hz),
118.0 (d, J= 26.1 Hz), 16.7; ms: m/z 168 (M+ À C3H5). Anal.
Calcd for C10H8FNO3: C, 57.42; H, 3.83; N, 6.70. Found: C,
57.49; H, 3.86; N, 6.64.
( )-1-(2-Fluoro-5-nitrophenyl)-3-methyl-2-buten-1-ol (8). This
compound (1.98g, 88%) was prepared from 1.69g (10.0mmol)
of 2 and 30 mL of 0.5 M 2-methyl-1-propenylmagnesium bromide
(4, 15.0mmol) in THF, and was isolated as a viscous yellow oil.
1
Product 8 was pure by H-NMR analysis and was used without
1
further purification. IR: 3372, 1626, 1531, 1350, 1248 cmÀ1; H-
NMR (400 MHz): δ 8.49 (dd, 1H, J = 6.2, 2.9 Hz), 8.15 (ddd, 1H,
J = 9.0, 4.3, 2.9 Hz), 7.15 (t, 1H, J = 9.0 Hz), 5.77 (d, 1H,
J = 9.0 Hz), 5.30 (d, 1H, J = 9.0 Hz), 2.13 (br s, 1H), 1.84 (s, 3H),
1.76 (s, 3H); 13C-NMR (100 MHz): δ 163.1 (d, J = 257.7Hz),
144.5, 137.7, 133.1 (d, J = 14.7Hz), 125.1, 124.5 (d, J = 10.3Hz),
123.6 (d, J = 7.4Hz), 116.3 (d, J = 24.2 Hz), 64.7 (d, J = 2.9 Hz),
25.8, 18.2 (d, J = 1.5 Hz); ms: m/z 168 (M+ À C4H9). Anal. Calcd
for C11H12FNO3: C, 58.67; H, 5.33; N, 6.22. Found: C, 58.78; H,
5.45; N, 6.08.
Band 2 gave 555 mg (56%) of (E)-10 as a light yellow solid,
mp 43–45°C. IR: 1674, 1623, 1532, 1350, 1246 cmÀ1 1H-
;
NMR (400 MHz): δ 8.60 (dd, 1H, J = 6.0, 2.7 Hz), 8.37
(ddd, 1H, J = 9.3, 3.8, 2.7 Hz), 7.32 (t, 1H, J = 9.3 Hz), 7.07
(m, 1H), 6.74 (dq, 1H, J = 15.4, 1.6 Hz), 2.03 (dd, 3H, J = 7.1,
1.6 Hz); 13C-NMR (100 MHz): δ 186.8, 163.8 (d, J = 263.4 Hz),
148.0, 144.3, 130.1 (d, J = 5.1 Hz), 128.5 (d, J = 10.9 Hz), 127.9
(d, J = 16.6 Hz), 126.9 (d, J = 4.9 Hz), 117.9 (d, J = 25.8 Hz),
18.7; ms: m/z 168 (M+ À C3H5). Anal. Calcd for C10H8FNO3:
C, 57.42; H, 3.83; N, 6.70. Found: C, 57.46; H, 3.85; N, 6.65.
Representative oxidation using manganese(IV) oxide
(E)- and (Z)-1-(2-Fluorophenyl)-2-buten-1-one (9). To a solution
of 1.00g (6.02 mmol) of E/Z-5 in 25 mL of dichloromethane was
added 10.0 g of manganese(IV) oxide [17]. The reaction was
stirred vigorously for 4–8 h at 23°C, then filtered through a plug
of Celite®. The Celite® was washed thoroughly with
dichloromethane, and the solvent was removed to give 620 mg of
a mixture of the E and Z enones. The products were purified on a
40cm× 2.0 cm silica gel column eluted with increasing
concentrations of ether in hexanes to give two bands. Band 1 gave
127 mg (13%) of (Z)-9 as a viscous yellow oil. IR: 1669, 1614,
1-(2-Fluorophenyl)-3-methyl-2-buten-1-one (11).
This
compound was prepared from 1.00 g (5.56 mmol) of 7 and
10.0 g of manganese(IV) oxide in 25 mL of dichloromethane.
The product was purified on a 25 cm × 2.0 cm silica gel column
eluted with increasing concentrations of ether in hexanes to give
1
1215cmÀ1; H-NMR (400 MHz): δ 7.78 (td, 1H, J = 7.7, 1.6 Hz),
0.83 g (84%) of 11 as a yellow oil. IR: 1667, 1614, 1228 cmÀ1
;
7.49 (m, 1H), 7.22 (t, 1H, J = 7.7 Hz), 7.11 (dd, 1H, J = 11.0,
8.2 Hz), 6.75 (dq, 1H, J = 11.2, 1.6Hz), 6.44 (dq, 1H, J = 11.2,
7.1 Hz), 2.19 (dd, 3H, J = 7.1, 1.6 Hz); 13C-NMR (100 MHz): δ
189.8, 161.1 (d, J = 253.9 Hz), 144.5, 133.8 (d, J = 8.9 Hz), 130.8
(d, J = 2.6 Hz), 128.2 (d, J = 6.0 Hz), 127.7 (d, J = 13.2Hz), 124.4
1H-NMR (300 MHz): δ 7.74 (td, 1H, J = 7.7, 1.6 Hz), 7.44
(m, 1H), 7.20 (td, 1H, J = 8.2, 1.1 Hz), 7.09 (dd, 1H,
J = 11.0, 8.2 Hz), 6.64 (m, 1H), 2.25 (s, 3H), 2.00 (s, 3H);
13C-NMR (75 MHz): δ 189.1, 160.8 (d, J = 252.8 Hz), 157.5,
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2,3-dihydro-4(1H)-quinolinones by the Tandem Michael-SNAr Reaction
133.3 (d, J = 8.9 Hz), 130.7 (d, J = 2.9 Hz), 128.5 (d, J = 13.2Hz),
124.4 (d, J = 6.6 Hz), 124.2 (d, J = 3.7 Hz), 116.3 (d, J = 23.5Hz),
28.0, 21.4; ms: m/z 123 (M+ À C4H7). Anal. Calcd for C11H11FO:
C, 74.16; H, 6.18. Found: C, 74.22; H, 6.21.
J = 8.6 Hz), 3.70 (quintet of d, 1H, J = 6.6, 2.3 Hz), 3.44 (dd,
1H, J = 14.4, 5.1 Hz), 2.99 (dd, 1H, J = 15.9, 6.1 Hz), 2.64
(dd, 1H, J = 14.4, 9.6 Hz), 2.48 (dd, 1H, J = 15.9, 2.3 Hz),
2.04 (m, 1H), 1.13 (d, 3H, J = 6.6 Hz), 1.04 (d, 3H,
J = 6.6 Hz), 0.99 (d, 3H, J = 6.8 Hz); 13C-NMR (100 MHz): δ
193.2, 149.1, 135.6, 127.7, 118.6, 115.4, 112.7, 57.7, 55.5,
43.7, 27.3, 20.4, 20.0, 14.6; ms: m/z 174 (M+ À C3H7). Anal.
Calcd for C14H19NO: C, 77.42; H, 8.76; H, 6.45. Found: C,
77.45; H, 8.78; N, 6.38.
1-(2-Fluoro-5-nitrophenyl)-3-methyl-2-buten-1-one (12). This
compound was prepared from 1.00 g (4.39 mmol) of 8 and 10.0 g
of manganese(IV) oxide in 25mL of dichloromethane. The
product was purified on a 25cm× 2.0 cm silica gel column eluted
with increasing concentrations of ether in hexanes to give 0.80 g
(81%) of 12 as a light yellow solid, mp 54–55°C. IR: 1667, 1624,
( )-1-Benzyl-2,3-dihydro-2-methyl-6-nitro-4(1H)-quinolinone
1532, 1350, 1252cmÀ1
;
1H-NMR (300 MHz): δ 8.64 (dd, 1H,
(15a).
This compound was prepared, as described for 14a,
J = 6.0, 2.7 Hz), 8.35 (ddd, 1H, J = 9.3, 3.8, 2.7 Hz), 7.29 (t, 1H,
J = 9.3 Hz), 6.62 (q, 1H, J = 1.1 Hz), 2.30 (s, 3H), 2.06 (s, 3H);
13C-NMR (75MHz): δ 186.1, 163.9 (d, J = 263.4 Hz), 161.1,
144.4, 129.4, 128.2 (d, J = 10.9Hz), 127.0 (d, J = 5.2 Hz), 123.1
(d, J = 5.7 Hz), 117.9 (d, J = 26.3 Hz), 28.3, 21.8; ms: m/z 168
(M+ À C4H7). Anal. Calcd for C11H10FNO3: C, 59.19; H, 4.48; N,
6.28. Found: C, 59.22; H, 4.49; N, 6.25.
from 84 mg (0.40 mmol) of (E)-10 and 51 mg (0.052 mL,
0.48 mmol) of benzylamine. Following purification by PTLC,
115 mg (97%) of 15a was isolated as a light yellow solid,
mp 118–120°C. IR: 1688, 1506, 1317 cmÀ1
;
1H-NMR
(300 MHz): δ 8.75 (d, 1H, J = 2.7 Hz), 8.09 (dd, 1H, J = 9.3,
2.7 Hz), 7.44–7.26 (complex, 5H), 6.64 (d, 1H, J = 9.3 Hz),
4.84 (d, 1H, J = 16.8 Hz), 4.55 (d, 1H, J = 16.8 Hz), 3.98
(quintet of d, 1H, J = 6.4, 2.7 Hz), 3.08 (dd, 1H, J = 15.9,
6.0 Hz), 2.64 (dd, 1H, J = 15.9, 2.7 Hz), 1.28 (d, 3H,
J = 6.9 Hz); 13C-NMR (75 MHz): δ 191.1, 152.5, 137.6, 135.7,
130.2, 129.1, 128.0, 126.2, 124.5, 117.5, 113.4, 55.0, 53.6,
43.3, 16.2; ms: m/z 205 (M+ À C7H7). Anal. Calcd for
C17H16N2O3: C, 68.92; H, 5.41; N, 9.46. Found: C, 68.88; H,
5.42; N, 9.43.
Representative procedure for the tandem Michael-SNAr reaction
( )-1-Benzyl-2,3-dihydro-2-methyl-4(1H)-quinolinone (14a). To
a solution of 66 mg (0.40 mmol) of (E)-9 in 3 mL of anhydrous
DMF was added 51mg (0.052 mL, 0.48 mmol) of benzylamine,
and the solution was heated at 50°C for 24h. The reaction
mixture was cooled, added to 25mL of saturated aqueous NaCl
and extracted with ether (3× 50mL). The combined ether extracts
were washed with water (one time), saturated aqueous NaCl
(one time), dried (MgSO4), filtered, and concentrated under
vacuum to afford a yellow oil. The product was purified on a
20cm× 20cm PTLC plate using 50–70% ether in hexanes to
afford 78 mg (80%) of 14a as a light yellow solid, mp 88–90°C.
( )-1-Hexyl-2,3-dihydro-2-methyl-6-nitro-4(1H)-quinolinone
(15b).
This compound was prepared, as described for 14a,
from 84mg (0.40mmol) of (E)-10 and 49 mg (0.063mL,
0.48mmol) of hexylamine. Following purification by PTLC,
114 mg (98%) of 15b was isolated as a viscous yellow oil. IR:
1688, 1510, 1315 cmÀ1 1H-NMR (400 MHz): δ 8.72 (d, 1H,
;
IR: 1673cmÀ1 1H-NMR (400 MHz): δ 7.90 (dd, 1H, J = 7.9,
;
J = 2.8Hz), 8.17 (dd, 1H, J = 9.6, 2.8 Hz), 6.67 (d, 1H, J = 9.6Hz),
3.88 (quintet of d, 1H, J = 6.6, 2.4 Hz), 3.63 (dt, 1H, J = 14.7,
7.2 Hz), 3.23 (dt, 1H, J = 14.7, 7.6 Hz), 2.98 (dd, 1H, J = 16.0,
6.2 Hz), 2.59 (dd, 1H, J = 16.0, 2.5 Hz), 1.73 (quintet, 2H,
J = 7.4Hz), 1.46–1.32 (complex, 6H), 1.23 (d, 3H, J = 6.8 Hz),
0.91 (distorted t, 3H, J = 6.9 Hz); 13C-NMR (100 MHz): δ 191.2,
152.0, 136.9, 130.2, 124.8, 117.0, 112.5, 54.9, 50.4, 43.2, 31.4,
27.8, 26.6, 22.5, 16.2, 13.9; ms: m/z 219 (M+ À C5H11). Anal.
Calcd for C16H22N2O3: C, 66.21; H, 7.59; N, 9.66. Found: C,
66.26; H, 7.62; N, 9.58.
1.7 Hz), 7.39–7.25 (complex, 6H), 6.69 (apparent t, 1H,
J = 7.4 Hz), 6.57 (d, 1H, J = 8.6 Hz), 4.69 (d, 1H, J = 16.6 Hz),
4.37 (d, 1H, J = 16.6Hz), 3.83 (m, 1H), 3.06 (dd, 1H, J = 16.0,
6.1 Hz), 2.55 (dd, 1H, J = 16.0, 3.3 Hz), 1.22 (d, 3H, J = 6.6 Hz);
13C-NMR (100 MHz): δ 193.3, 149.4, 137.7, 135.7, 128.8, 127.6,
127.4, 126.4, 119.2, 116.4, 113.5, 54.7, 53.3, 44.3, 15.4; ms:
m/z 160 (M+ À C7H7). Anal. Calcd for C17H17NO: C, 81.27; H,
6.77; N, 5.58. Found: C, 81.28; H, 6.77; N, 5.59. This same
reaction, using, (Z)-9, gave 14a in 82% yield.
( )-1-Hexyl-2,3-dihydro-2-methyl-4(1H)-quinolinone (14b). This
compound was prepared, as described for 14a, from 66 mg (0.40 mmol)
of (E)-9 and 49mg (0.063 mL, 0.48 mmol) of hexylamine.
Following purification by PTLC, 0.84mg (86%) of 14b was
( )-2,3-Dihydro-1-isobutyl-2-methyl-6-nitro-4(1H)-quinolinone
(15c). This compound was prepared, as described for 14a, from
84 mg (0.40 mmol) of (E)-10 and 29 mg (0.040 mL, 0.48 mmol)
of isobutylamine. Following purification by PTLC, 96 mg
(92%) of 15c was isolated as a light yellow solid, mp
isolated as a viscous yellow oil. IR: 1674cmÀ1 1H-NMR
;
(400MHz): δ 7.86 (dd, 1H, J = 8.2, 1.7 Hz), 7.35 (ddd, 1H,
J = 8.8, 7.2, 1.7 Hz), 6.63 (d, 1H, J = 8.8 Hz), 6.62 (t, 1H,
J = 7.2 Hz), 3.72 (m, 1H), 3.49 (dt, 1H, J = 14.8, 7.2 Hz), 3.07
(dt, 1H, J= 15.0, 7.4 Hz), 2.93 (dd, 1H, J= 15.8, 6.1 Hz), 2.47
(dd, 1H, J= 16.0, 3.1 Hz), 1.67 (quintet, 2H, J= 7.2 Hz), 1.45–1.29
(complex, 6H), 1.16 (d, 3H, J= 6.6 Hz), 0.91 (distorted t, 3H,
J=6.8Hz); 13C-NMR (100 MHz): δ 193.2, 149.1, 135.6, 127.7,
118.6, 115.3, 112.6, 54.5, 49.6, 44.0, 31.6, 27.9, 26.8, 22.6 15.6,
14.0; ms: m/z 174 (M+ À C5H11). Anal. Calcd for C16H23NO: C,
78.37; H, 9.39; N, 5.71. Found: C, 78.41; H, 9.42; N, 5.67.
1
120–121 °C. IR: 1687, 1511, 1316 cmÀ1; H-NMR (400 MHz):
δ 8.74 (d, 1H, J = 2.8 Hz), 8.16 (dd, 1H, J = 9.4, 2.8 Hz), 6.66
(d, 1H, J = 9.4 Hz), 3.85 (quintet of d, 1H, J = 6.6, 2.1 Hz), 3.59
(dd, 1H, J = 14.5, 5.3 Hz), 3.01 (dd, 1H, J = 16.0, 6.1 Hz), 2.84
(dd, 1H, J = 14.5, 9.6 Hz), 2.60 (dd, 1H, J = 16.0, 2.0 Hz), 2.10
(m, 1H), 1.20 (d, 3H, J = 6.8 Hz), 1.08 (d, 3H, J = 6.6 Hz), 1.04
(d, 3H, J = 6.6 Hz); 13C-NMR (100 MHz): δ 191.1, 152.2,
137.0, 130.1, 124.9, 117.1, 112.7, 57.8, 55.7, 42.9, 27.5, 20.2,
20.0, 15.5; ms: m/z 219 (M+ À C3H7). Anal. Calcd for
C14H18N2O3: C, 64.12; H, 6.87; N, 10.69. Found: C, 64.15; H,
6.89; N, 10.64.
( )-2,3-Dihydro-1-isobutyl-2-methyl-4(1H)-quinolinone (14c). This
compound was prepared, as described for 14a, from 66 mg
(0.40 mmol) of (E)-9 and 29 mg (0.040 mL, 0.48 mmol) of
isobutylamine. Following purification by PTLC, 68mg (78%) of 14c
Cyclizations of 11.
By using the procedure given for the
preparation of 14a, a solution of 71 mg (0.40 mmol) of 11 and
0.48 mmol of the amine in 2.5 mL of dry DMF was heated at
50°C for 48 h. Workup and purification by PTLC showed two
major bands.
was isolated as a viscous yellow oil. IR: 1674 cmÀ1 1H-NMR
;
(400 MHz): δ 7.87 (dd, 1H, J= 7.8, 1.8 Hz), 7.34 (ddd, 1H, J=8.6,
7.0, 1.8 Hz), 6.63 (apparent t, 1H, J= 7.8 Hz), 6.59 (d, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. A. Bunce, T. Nago, and S. Abuskhuna
Vol 000
With benzylamine.
Band 1 gave 48 mg of recovered 11
Band 3 gave 81 mg (65%) of 1-benzyl-2,3-dihydro-2,2-di-
(67%) as a light yellow oil. Band 2 gave 5 mg (5%) of 1-
methyl-6-nitro-4(1H)-quinolinone (21a) as a light yellow solid,
benzyl-2,3-dihydro-2,2-dimethyl-4(1H)-quinolinone (20a) as a
mp 137–138°C. IR: 1691, 1506, 1323 cmÀ1 1H-NMR
;
light yellow solid, mp 114–115°C. IR 1676, 1605, 1364 cmÀ1
;
(300 MHz): δ 8.77 (d, 1H, J = 2.7 Hz), 8.08 (dd, 1H, J = 9.4,
2.7 Hz), 7.44–7.26 (complex, 5H), 6.57 (d, 1H, J = 9.4 Hz), 4.71
(s, 2H), 2.83 (s, 2H), 1.40 (s, 6H); 13C-NMR (75 MHz): δ 191.7,
153.9, 137.9, 136.7, 130.1, 129.1, 127.6, 125.5, 124.0, 118.2,
114.4, 59.2, 51.1, 49.5, 25.1 (2C); ms: m/z 295 (M+ À CH3). Anal.
Calcd for C18H18N2O3: C, 69.68; H, 5.81; N, 9.03. Found: C,
69.72; H, 5.79; N, 9.01.
1H-NMR (300 MHz): δ 7.90 (dd, 1H, J = 7.7, 1.6 Hz), 7.36
(apparent d, 3H, J = 4.4 Hz), 7.27 (m, 3H), 6.70 (t, 1H,
J = 7.7 Hz), 6.50 (d, 1H, J = 8.2 Hz), 4.54 (s, 2H), 2.77 (s, 2H),
1.34 (s, 6H); 13C-NMR (75 MHz): δ 193.8, 150.7, 138.9, 135.7,
128.8, 127.1, 127.0, 125.8, 119.5, 116.5, 114.3, 58.4, 51.8,
49.5, 29.7, 24.8 (2C); ms: m/z 250 (M+ À CH3). Anal Calcd
C18H19NO: C, 81.51; H, 7.17; N, 5.28. Found: C, 81.45; H,
7.15; N, 5.33.
With hexylamine.
Band 1 gave 23 mg (19%) of 1-(2-
hexylamino-5-nitrophenyl)-3-methyl-2-buten-1-one (17b) as a
yellow oil that crystallized on standing, mp 44–46°C. IR: 3262,
With hexylamine. Band 1 gave 37mg of recovered 11 (52%)
as a light yellow oil. Band 2 gave 12mg (12%) of 1-hexyl-2,3-
1
1644, 1610, 1505, 1327 cmÀ1; H-NMR (300 MHz): δ 9.72 (br
dihydro-2,2-dimethyl-4(1H)-quinolinone (20b) as
a
viscous
s, 1H), 8.74 (d, 1H J = 2.7 Hz), 8.18 (dd, 1H, J = 9.4, 2.7 Hz),
6.69 (d, 1H, J = 9.4 Hz), 6.69 (s, 1H), 3.30 (dt, 2H, J = 7.1,
5.5 Hz), 2.12 (d, 3H, J = 1.1 Hz), 2.04 (s, 3H), 1.73 (quintet, 2H,
J = 7.1 Hz), 1.50–1.22 (complex, 6H), 0.91 (distorted t, 3H,
J = 6.8 Hz); 13C-NMR (75 MHz): δ 194.0, 155.2, 155.1, 135.0,
129.6, 129.4, 121.8, 117.1, 111.2, 43.1, 31.4, 28.8, 27.7, 26.7,
22.5, 21.0, 14.0; ms: m/z 233 (M+ À C5H11). Anal. Calcd for
C17H24N2O3: 67.11; H, 7.89; N, 9.21. Found: C, 67.15; H,
7.93; N, 9.16.
yellow oil. IR 1680, 1604, 1361cmÀ1 1H-NMR (300 MHz): δ
;
7.87 (dd, 1H, J = 7.7, 1.6 Hz), 7.38 (ddd, 1H, J = 8.8, 7.1, 1.6 Hz),
6.67 (t, 1H, J = 7.1 Hz), 6.66 (d, 1H, J = 8.4 Hz), 3.24 (t, 2H,
J = 7.7 Hz), 2.60 (s, 2H), 1.66 (m, 2H), 1.37 (m, 6H), 1.30 (s, 6H),
0.93 (distorted t, 3H, J = 6.6 Hz); 13C-NMR (75 MHz): δ 193.9,
150.4, 135.6, 127.4, 119.2, 115.6, 113.2, 57.9, 51.8, 45.6, 31.6,
29.5, 26.7, 24.9 (2C), 22.7, 14.0; ms: m/z 188 (M+ À C5H11). Anal
Calcd C17H25NO: C, 78.76; H, 9.65; N, 5.41. Found: C, 78.90; H,
9.67; N, 5.32.
Band 2 gave 4 mg (4%) of 2-hexylamino-5-nitroacetophenone
(19b) as a yellow oil that crystallized on standing, mp 46–48°C.
With isobutylamine.
Band 1 gave 40mg of recovered 11
1
IR: 3276, 1648, 1502, 1329 cmÀ1; H-NMR (300 MHz): δ 9.66
(56%) as a light yellow oil. Band 2 gave 6 mg (7%) of 1-isobutyl-
2,3-dihydro-2,2-dimethyl-4(1H)-quinolinone (20c) as a viscous
(br s, 1H), 8.73 (d, 1H, J = 2.7 Hz), 8.20 (dd, 1H, J = 9.4,
2.7 Hz), 6.71 (d, 1H, J = 9.4 Hz), 3.30 (dt, 2H, J = 7.1, 5.5 Hz),
2.67 (s, 3H), 1.72 (quintet, 2H, J = 7.1 Hz), 1.51–1.24 (complex,
6H), 0.91 (distorted t, 3H, J = 6.6 Hz); 13C-NMR (75 MHz): δ
200.4, 154.7, 135.0, 130.1, 130.0, 115.6, 111.5, 43.0, 31.4,
28.7, 27.8, 26.7, 22.5, 14.0; ms: m/z 193 (M+ À C5H11). Anal.
Calcd for C14H20N2O3: C, 63.64; H, 7.58; N, 10.61. Found: C,
63.71; H, 7.62; N, 10.54.
yellow oil. IR 1679, 1604, 1366cmÀ1 1H-NMR (300 MHz): δ
;
7.91 (dd, 1H, J = 7.7, 1.6 Hz), 7.37 (ddd, 1H J = 8.8, 7.1, 1.6 Hz),
6.71 (d, 1H, J = 8.4 Hz), 6.71 (t, 1H, J = 7.1 Hz), 3.04 (d, 2H,
J = 7.7 Hz), 2.64 (s, 2H), 2.07 (nonet, 1H, J = 7.1 Hz), 1.28
(s, 6H), 1.02 (d, 6H, J = 6.6 Hz); 13C-NMR (75MHz): δ 194.0,
151.3, 135.4, 127.5, 120.0, 116.2, 114.4, 58.6, 52.2, 52.1, 27.7,
25.1 (br, 2C), 20.5 (2C); ms: m/z 188 (M+ À C3H7). Anal Calcd
C15H21NO: C, 77.92; H, 9.09; N, 6.06. Found: C, 77.99; H, 9.12;
N, 5.97.
Band 3 gave 83 mg (68%) of 1-hexyl-2,3-dihydro-2,2-di-
methyl-6-nitro-4(1H)-quinolinone (21b) as a light yellow solid,
mp: 78–79°C. IR: 1691, 1503, 1322 cmÀ1
;
1H-NMR
Cyclizations of 12.
By using the procedure given for the
(300 MHz): δ 8.74 (d, 1H, J = 2.8 Hz), 8.19 (dd, 1H, J = 9.4,
2.8 Hz), 6.70 (d, 1H, J = 9.4 Hz), 3.39 (distorted t, 2H,
J = 8.2 Hz), 2.68 (s, 2H), 1.71 (quintet, 2H, J = 7.7 Hz), 1.48–
1.34 (complex, 6H), 1.38 (s, 6H), 0.94 (distorted t, 3H,
J = 6.8 Hz); 13C-NMR (75 MHz): δ 191.7, 153.3, 137.2, 130.1,
124.4, 117.8, 113.2, 58.7, 51.5, 45.9, 31.4, 29.1, 26.6, 25.3
(2C), 22.6, 13.9; ms: m/z 289 (M+ À CH3). Anal. Calcd for
C17H24N2O3: C, 67.11; H, 7.89; N, 9.21. Found: C, 67.16; H,
7.92; N, 9.13.
preparation of 14a, a solution of 89 mg (0.40 mmol) of 12 and
0.48 mmol of the amine in 2.5 mL of dry DMF was heated at
50°C for 24 h. Workup and purification by PTLC showed three
major bands.
With benzylamine.
Band 1 gave 35 mg (28%) of 1-(2-
benzylamino-5-nitrophenyl)-3-methyl-2-buten-1-one (17a) as a light
yellow solid, mp 92–94°C. IR: 3265, 1644, 1609, 1505,
1328 cmÀ1 1H-NMR (300 MHz): δ 10.1 (br s, 1H), 8.77
;
(d, 1H, J = 2.7 Hz), 8.13 (dd, 1H, J = 9.4, 2.7 Hz), 7.42–7.28
(complex, 5H), 6.73 (s, 1H), 6.68 (d, 1H, J = 9.4 Hz), 4.55
(d, 2H, J = 5.5 Hz), 2.13 (s, 3H), 2.05 (s, 3H); 13C-NMR
(75 MHz): δ 193.9, 155.9, 154.9, 136.8, 135.6, 129.5, 129.1,
128.9, 127.7, 127.0, 121.6, 117.4, 111.8, 47.0, 27.8, 21.1; ms:
m/z 219 (M+ À C7H7). Anal. Calcd for C18H18N2O3: C, 69.68;
H, 5.81; N, 9.03. Found: C, 69.77; H, 5.80; N, 8.96.
With isobutylamine.
Band 1 gave 20 mg (18%) of 1-(2-
isobutylamino-5-nitrophenyl)-3-methyl-2-buten-1-one (17c) as a
light yellow solid, mp 75–77°C. IR: 3258, 1643, 1610, 1506,
1
1327 cmÀ1; H-NMR (300 MHz): δ 9.85 (br s, 1H), 8.74 (d, 1H,
J = 2.7 Hz), 8.17 (dd, 1H, J = 9.3, 2.7 Hz), 6.70 (s, 1H), 6.68 (d,
1H, J = 9.3 Hz), 3.13 (t, 2H, J = 6.6 Hz), 2.12 (s, 3H), 2.04 (s,
3H), 2.03 (septet, 1H, J = 6.6 Hz), 1.06 (d, 6H, J = 6.6 Hz); 13C-
NMR (75 MHz): δ 194.1, 155.3, 155.2, 134.9, 129.5, 129.4,
121.8, 117.1, 111.2, 50.7, 28.0, 27.7, 21.0, 20.4 (2C); ms: m/z
233 (M+ À C3H7). Anal. Calcd for C15H20N2O3: C, 65.22; H,
7.25; N, 10.14. Found: C, 65.19; H, 7.23; N, 10.15.
Band 2 gave 3 mg (3%) of 2-benzylamino-5-nitroacetophenone
(19a) as a light yellow solid, mp 85–88°C. IR: 3282, 1648,
1
1504, 1328 cmÀ1; H-NMR (300 MHz): δ 10.0 (br s, 1H), 8.76
(d, 1H, J = 2.7 Hz), 8.16 (dd, 1H, J = 9.3, 2.7 Hz), 7.42–7.27
(complex, 5H), 6.69 (d, 1H, J = 9.3 Hz), 4.55 (d, 2H,
J = 6.0 Hz), 2.69 (s, 3H); 13C-NMR (75 MHz): δ 200.6, 154.5,
136.6, 130.0, 129.8, 129.0, 127.8, 127.0, 116.2, 112.0, 47.0,
29.7, 27.9; ms: m/z 179 (M+ À C7H7). Anal. Calcd for
C15H14N2O3: C, 66.67; H, 5.19; N, 10.37. Found: C, 66.70; H,
5.21; N, 10.32.
Band 2 gave 6 mg (6%) of 2-isobutylamino-5-nitroacetophenone
(19c) as a yellow oil that crystallized on standing, mp 44–45°C. IR:
3273, 1652, 1509, 1328 cmÀ1 1H-NMR (300MHz): δ 9.78
;
(br s, 1H), 8.74 (d, 1H, J = 2.7 Hz), 8.20 (dd, 1H, J = 9.4, 2.7 Hz),
6.70 (d, 1H, J = 9.4 Hz), 3.13 (t, 2H, J = 6.6Hz), 2.67 (s, 3H), 2.01
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
2,3-dihydro-4(1H)-quinolinones by the Tandem Michael-SNAr Reaction
(septet, 1H, J = 6.6 Hz), 1.05 (d, 6H, J = 7.0Hz); 13C-NMR
(75 MHz): δ 200.5, 154.9, 135.0, 130.1, 130.0, 115.7, 111.5, 50.7,
28.0, 27.8, 20.3 (2C); ms: m/z 193 (M+ À C3H7). Anal. Calcd for
C12H16N2O3: C, 61.02; H, 6.78; N, 11.86. Found: C, 61.11; H,
6.81; N, 11.78.
[7] (a) Campbell, D.; Duron, S. G.; Vollrath, B.; Wade, W. World
Pat WO 2011156775, 2011; Chem Abstr 2011, 156, 65610; (b) Galley,
G.; Groebke Zbinden, K. G.; Norcross, R.; Stalder, H. World Pat WO
2007085558, 2007; Chem Abstr 2007, 147, 841292; (c) Kakihana, M.;
Kato, K.; Mori, M.; Yamashita, T. World Pat 2001076629, 2001; Chem
Abstr 2001, 135, 313624.
Band 3 gave 76 mg (69%) of 2,3-dihydro-1-isobutyl-2,2-di-
methyl-6-nitro-4(1H)-quinolinone (21c) as a light yellow solid,
[8] Gerlach, U.; Brendel, J.; Lang, H. J.; Weidmann, K. Eur Pat
EP 857,724, 1998; Chem Abstr 1998, 129, 175447.
mp 126–127°C. IR: 1690, 1506, 1322 cmÀ1
;
1H-NMR
[9] (a) Roach, S. L.; Hudson, A. R.; Valdez, L. J.; Higuchi, R. I.;
Zhi, L.; Vassar, A. C.; Landry-Bayle, A.; Adams, M. E.; Rowley, C. V.;
Lamer, R. B.; Grant, V. H. S. World Pat WO 2009103007, 2009; Chem
Abstr 2009, 151, 288987; (b) Jones, T. K.; Goldman, M. E.; Pooley, C.
L. F.; Winn, D. T.; Edwards, J. E.; West, S. J.; Tegley, C. M.; Zhi, L.;
Lawrence, G.; Farmer, L. J.; Davis, R. J. World Pat WO 9619458,
1996; Chem Abstr 1996, 125, 142697.
[10] (a) DeNinno, M. P.; Mularski, C. J.; Ruggeri, R. B.; Wester,
R. T. World Pat WO 2000017166, 2000; Chem Abstr 2000, 132, 251081;
(b) DeNinno, M. P.; Magnus-Aryitey, G. T.; Ruggeri, R. B.; Wester,
R. T. World Pat WO 2000017165, 2000; Chem Abstr 2000, 132, 236999;
(c) DeNinno, M. P.; Magnus-Aryitey, G. T.; Ruggeri, R. B.; Wester,
R. T. World Pat WO 2000017164, 2000; Chem Abstr 2000, 132, 251080.
[11] Liu, J.; Wang, Y.; Ying, S.; Marshall, D.; Miao, S.; Tonn, G.;
Anders, P.; Tocker, J.; Tang, L.; Medina, J. Bioorg Med Chem Lett 2009,
19, 6840.
[12] For a similar approach to 2,3-dihydro-1,8-naphthyridine-4
(1H)-ones, see Bunce, R. A.; Squires, S. T.; Nammalwar, B. J Org Chem
2013, 78, 2144.
[13] Gale, D. J.; Wilshire, J. F. K. Aust J Chem 1970, 23, 1063.
[14] For a procedure to prepare chromic acid, see Eisenbraun,
E. J. In Organic Syntheses; Baumgarten, H. G., Ed.; J Wiley and Sons:
New York, 1973; Coll. Vol 5, pp. 310–314.
(300 MHz): δ 8.70 (s, 1H, J = 2.7 Hz), 8.17 (dd, 1H, J = 9.3,
2.7 Hz), 6.79 (d, 1H, J = 9.3 Hz), 3.24 (d, 2H, J = 7.7 Hz), 2.71
(s, 2H), 2.12 (septet, 1H, J = 6.6 Hz), 1.37 (s, 6H), 1.05 (d, 6H,
J = 6.6 Hz); 13C-NMR (75 MHz): δ 191.8, 154.3, 137.5, 129.7,
124.4, 118.5, 114.5, 59.3, 52.2, 51.3, 28.0, 25.3 (br, 2C), 20.3
(2C); ms: m/z 233 (M+ À C3H7). Anal. Calcd for C15H20N2O3:
C, 65.22; H, 7.25; N, 10.14. Found: C, 65.34; H, 7.25; N, 10.05.
Acknowledgments. T. N. and S. A. wish to thank the Oklahoma
State University Department of Chemistry for teaching
assistantships. T. N. would also like to thank OSU for
scholarships to support his undergraduate research (2007–2010).
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] Use of Jones conditions for unhindered substrates was reported
earlier by Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J.
J Org Chem 1993, 58, 611.
[16] A similar 1,3-transposition has been also been reported from
tertiary allylic alcohols using PCC, see Dauben, W. G.; Michno, D.
J Org Chem 1977, 42, 682.
[17] (a) Attenburrow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans,
R. M.; Hems, B. A.; Jansen, A. B. A.; Walker, T. J Chem Soc 1952, 1094;
This same reaction also proceeded using 15 wt% of nano-MnO2, see (b)
Nammalwar, B.; Fortenberry, C.; Bunce, R. A.; Lageshetty, S. K.; Ausman,
K. D. Tetrahedron Lett 2013, 54, 2010.
[18] Bergmann, E. D.; Ginsberg, D.; Pappo, R. Org React 1959,
10, 179.
[19] Bunce, R. A.; Nago, T.; Sonobe, N.; Slaughter, L. M.
J Heterocycl Chem 2008, 45, 551.
[20] Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley-Interscience: New York, 1994; pp. 682–684.
[21] A control experiment with 2-fluoroacetophenone was not
reactive toward intermolecular SNAr-type addition by alkylamines at
50°C, even after 5 days, while 2-fluoro-5-nitroacetophenone gave facile
addition at 50°C after 1 h, Bunce, R. A.; Nago, T., unpublished results.
[22] This reversal of reaction steps has been observed in other hindered
substrates, see Bunce, R. A.; Lee, E. J. J Heterocycl Chem 2010, 47, 1176.
[23] Stabilization of a hydrogen-bonded adduct following an initial
SNAr addition has been observed in a previous report, see Bunce, R. A.;
Grant, M. T. Org Prep Proced Int 2011, 43, 265.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet