Copper-catalyzed oxidative direct cyclization of N-methylanilines with electron-deficient alkenes using molecular oxygen

Article abstract of DOI:10.1021/jo2011329

The oxidative direct cyclizaion of N-methylanilines with electron-deficient alkenes involving maleimides and benzylidene malononitriles through sp ³ and sp² C-H bond cleavage proceeds effectively under a CuCl₂/O₂

Full text of DOI:10.1021/jo2011329

NOTE
pubs.acs.org/joc
Copper-Catalyzed Oxidative Direct Cyclization of N-Methylanilines
with Electron-Deficient Alkenes Using Molecular Oxygen
Mayuko Nishino, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S Supporting Information
b
ABSTRACT:
The oxidative direct cyclizaion of N-methylanilines with electron-deficient alkenes involving maleimides and benzylidene malononitriles
through sp3 and sp2 CꢀH bond cleavage proceeds effectively under a CuCl2/O2 catalysis to provide the corresponding tetrahydroqui-
nolines in good yields.
Scheme 1. Reaction Modes of sp3 CꢀH Bond Adjacent to
etal-mediated dehydrogenative CꢀC bond formation
through CꢀH bond cleavage has received significant
Heteroatom in Dehydrogenative Couplingsa
M
attention in modern organic chemistry since it can skip the
preactivation steps, such as halogenation and stoichiometric
metalation, of the starting materials. In particular, the direct
couplings at an sp3 carbon center adjacent to heteroatoms
involving nitrogen and oxygen have been widely explored.1 This
type of reaction is believed to proceed through the stepwise one-
electron oxidation by the combination of transition metals and
oxidants (Scheme 1). The electrophilic nature of the resultant
iminium cations C allows some nucleophilic, electron-rich olefins
including enols,2 enamines,3 and (hetero)arenes4 to trap the
species.5 In this context, we may envisage that the appropriate
control of the oxidation capacity of catalysts enables the prefer-
able generation of radical intermediate B. If it were feasible, the
reaction with electron-deficient olefins would be possible via
SOMO/LUMO interaction, which provides the complementary
reaction mode of the substrate A. During our study to develop
such type coupling, a copper(II)/molecular oxygen catalyst
system has been found to effectively work in the oxidative direct
cyclization of N-methylanilines with maleimides and benzylidene
malononitrile.6 The reaction occurs under mild conditions to
form the corresponding tetrahydroquinoline derivatives in good
yields, showing the superiority of copper for the transformation.
We initially selected 4,N,N-trimethylaniline (1a) and N-
phenylmaleimide (2a) as model substrates and investigated
various combinations of transition metals and oxidants for
capture of the radical intermediate corresponding to B in
Scheme 1. Representative data are summarized in Table 1.
Treatment of 1a with 2a in the presence of 20 mol % of CuCl2
catalyst and a frequently used peroxide, t-BuOOt-Bu, in MeCN
at room temperature afforded the tetrahydroquinoline skeleton
3aa in 5% GC yield (entry 1). Apparently, the desired reaction
mode was possible, albeit the yield was very low. Then, we
a EWG = electron-withdrawing group, EDG = electron-donating group.
surveyed some oxidants. While t-BuOOH somewhat improved
the reaction efficiency (entry 2), the ideal oxidant, molecular
oxygen, proved to be optimal (entry 3). Moreover, the reaction
under ambient conditions provided a better result, and 3aa was
isolated in 74% yield (entry 4). The coupling with a stoichio-
metric amount of CuCl2 in the absence of O2 was sluggish,
indicating the pivotal role of O2 in the catalytic cycle (entry 5).
Other first transition elements such as nickel, iron, and manga-
nese dropped the yield of 3aa (entries 6ꢀ8).6a Addition of
ligands such as 1,10-phenanthroline and N,N,N0,N0-tetramethy-
lethylenediamine and any changes of solvent system into toluene,
DMF, or DMSO were detrimental (not shown).
With the conditions employed for entry 4 in Table 1, the
cyclization of a variety of N-methylanilines 1 with 2a was
performed (Scheme 2). The methoxy and tert-butyl substituents
at the 4-position were accommodated (3ba and 3ca), while the
nonsubstituted aniline decreased the yield (3da).7 3,4,N,N-
Tetramethylaniline showed high reactivity to furnish a mixture
of regioisomers 3ea and 3ea0 with 93% combined yield in favor of
Received: June 3, 2011
Published: June 30, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2011329 J. Org. Chem. 2011, 76, 6447–6451
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimization Studies for Oxidative Direct Coupling
of 4,N,N-Trimethylaniline (1a) with N-Phenylmaleimide
(2a)a
Scheme 2. Copper-Catalyzed Oxidative Direct Coupling of
Various N-Methylanilines 1 with N-Phenylmaleimide (2a)
entry
M (mol %)
oxidant
3aa, yieldb (%)
1
2
3
4
5
6
7
8
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (100)
NiCl2 (20)
FeCl3 (20)
MnCl2 (20)
t-BuOO-t-Bu (1.0 equiv)
(5)
(40)
58
t-BuOOH (1.0 equiv)
O2 (1 atm, balloon)c
air
74
none
air
(8)
(9)
trace
(43)
air
air
a A mixture of 1a (1.0 mmol), 2a (0.50 mmol), M, and oxidant was stirred
in MeCN (1.0 mL) for 2ꢀ24 h at room temperature under N2. b Yield
determined by GC method in parentheses. c Under O2 (1 atm, balloon).
the formation of more congested 3ea. In addition, a 2,4-disub-
stituted pattern was available for use (3fa). As the substitution on
nitrogen, butyl and benzyl groups were compatible (3ga and
3ha) as well as methyl group. In these cases, the selective reaction
at the Me position occurred, which would inform us about the
reaction mechanism (vide infra). On the other hand, attempts to
apply N,3,4-trimethylaniline (R1 = 3,4-diMe, R2 = H) and N,N-
diethylaniline remained unsuccessful (data not shown).
Next, we investigated the scope of maleimides (Table 2). N-
Arylmaleimides bearing electronically diverse functions such as
methoxy, chloro, and trifluoromethyl underwent the direct
coupling to give the corresponding tetracyclic frameworks
3abꢀad in good yields (entries 1ꢀ3). Aliphatic systems 2e
and 2f also were applicable to the reaction (entries 4 and 5).
We are tempted to assume the reaction mechanism as follows
(Scheme 3). Initial single electron transfer from N-methylaniline
1 to the copper complex is followed by deprotonation to give the
R-amino radical 4. Subsequent electrophilic radical addition to
maleimide 2 and cyclization onto the aromatic ring proceeds to
generate the corresponding cyclohexadienyl radical 5, which is
then readily rearomatized by the second electron transfer/proton
elimination leading to the product 3.6a,8 The trapping of 4 with 2
could take place much faster than the second one electron
oxidation under the present CuCl2/air system to suppress the
overoxidation into the iminium cation 6, en route to decomposi-
tion. The proposed mechanism also can account for the regios-
electivity observed in the reaction with 1e (Scheme 2, 3ea +
3ea0): the radical addition to methyl-substituted arenes prefer-
ably occurs at the ortho-position because of the stabilization
through hyperconjugation.9 We attribute the selective oxidation
of 1 beyond the radical intermediate 4 to an association between
4 and the copper complex. The assumption is also consistent
with the exclusive production of 3ga and 3ha (Scheme 2), in
which the CꢀC bond formation predominantly occurs at the less
congested Me position probably due to the steric factors in the
copper association despite the fact that the corresponding
Table 2. Copper-Catalyzed Oxidative Direct Coupling of 4,
N,N-Trimethylaniline (1a) with Various Maleimides 2a
entry
R 2
3, yield (%)
1b
2
4-MeOC6H4 (2b)
4-ClC6H4 (2c)
4-CF3C6H4 (2d)
Me (2e)
3ab, 56
3ac, 75
3ad, 63
3ae, 68
3af, 52
3
4
5
Bn (2f)
a A mixture of 1a (1.0 mmol), 2 (0.50 mmol), and CuCl2 (0.10 mmol)
was stirred in MeCN (2.0 mL) for 24 h at room temperature under air.
b Under O2 (1 atm, balloon).
secondary and benzyl radicals are generally more stable than
the methylene one. However, further efforts are essential for
elucidation of the detailed mechanism.10
To demonstrate the synthetic utility of the process, we carried
out the transformation of the product 3aa (Scheme 4). The
reduction upon treatment with Red-Al in heating toluene
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dx.doi.org/10.1021/jo2011329 |J. Org. Chem. 2011, 76, 6447–6451

The Journal of Organic Chemistry
NOTE
Scheme 3. Plausible Mechanism
In conclusion, we have developed a simple copper/O2 catalyst
system for the oxidative cyclization of N-methylanilines with electron-
deficient olefins. By an appropriate control of the catalyst oxidation
capacity, the complementary reaction mode of N-methylanilines
becomes effectively available. The catalysis provides a direct, dehydro-
genative access to tetrahydroquionoline frameworks of importance
in medicinal and pharmaceutical chemistry.
’ EXPERIMENTAL SECTION
Typical Procedure for Copper-Catalyzed Oxidative Cycli-
zation of N-Methylanilines with 1. Synthesis of 3aa (Table 1,
entry 4) is representative. CuCl2 (13 mg, 0.10 mmol), 4,N,N-trimethy-
laniline (1a, 135 mg, 1.0 mmol), N-phenylmaleimide (2a, 87 mg, 0.50
mmol), MeCN (2.0 mL), and dibenzyl (ca. 40 mg, internal standard)
were placed in a 20 mL two-necked reaction flask equipped with a drying
tube lined with calcium chloride. The solution was stirred at room
temperature for 24 h under air. The formation of 3aa was confirmed by
GC analysis, and the resulting mixture was then quenched with water.
The mixture was extracted with ethyl acetate, and the combined organic
layer was dried over sodium sulfate. The mixture was then concentrated
in vacuo and purified by silica gel column chromatography with n-
hexane/ethyl acetate (5:1, v/v) to afford an analytically pure (3aR*,
9bS*)-5,8-dimethyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]quino-
line-1,3(2H)-dione (3aa, 113 mg, 0.37 mmol) in 74% yield.
Scheme 4
(3aR*,9bS*)-2,5,8-Trimethyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3aa): mp 195ꢀ196 °C; 1H
NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.80 (s, 3H), 3.05 (dd, J = 11.4,
4.4 Hz, 1H), 3.50 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.58 (dd, J = 11.4, 2.6 Hz,
1H), 4.11 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.2
Hz, 1H), 7.25ꢀ7.28 (m, 2H), 7.34ꢀ7.37 (m, 2H), 7.40ꢀ7.44 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 20.6, 39.7, 42.3, 43.7, 51.1, 112.7, 118.7,
126.5, 128.6, 129.1, 129.4, 131.0, 132.2, 146.5, 176.0, 177.9 (one signal was
overlapped by other one.); HRMS (EI) m/z (M+) calcd for C19H18N2O2
306.1368, found 306.1367.
(3aR*,9bS*)-8-Methoxy-5-methyl-2-phenyl-3a,4,5,9b-tet-
rahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ba): oil;
1H NMR (400 MHz, CDCl3) δ 2.78 (s, 3H), 3.01 (dd, J = 11.3, 4.4 Hz,
1H), 3.49 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.55 (dd, J = 11.3, 2.6 Hz, 1H),
3.78 (s, 3H), 4.10 (d, J = 9.5 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.80 (dd, J =
8.8, 2.9 Hz, 1H), 7.12 (d, J = 2.9 Hz, 1H), 7.25ꢀ7.28 (m, 2H), 7.34ꢀ7.36
(m, 1H), 7.40ꢀ7.44 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 39.9, 42.6,
43.6, 51.4, 55.81, 113.6, 114.5, 115.8, 119.9, 126.5, 128.6, 129.1, 132.1,
142.9, 153.3, 175.7, 177.8; HRMS m/z (M+) calcd for C19H18N2O3
322.1317, found 322.1320.
Scheme 5
(3aR*,9bS*)-8-tert-Butyl-5-methyl-2-phenyl-3a,4,5,9b-tet-
rahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ca): mp
1
182ꢀ184 °C; H NMR (400 MHz, CDCl3) δ 1.32 (s, 9H), 2.81 (s,
3H), 3.09 (dd, J = 11.4 4.6 Hz, 1H), 3.49 (ddd, J= 9.6, 4.6, 3.2 Hz, 1H), 3.56
(dd, J = 11.4, 3.2 Hz, 1H), 4.14 (d, J = 9.6 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H),
7.23ꢀ7.28 (m, 3H), 7.32ꢀ7.35 (m, 1H), 7.39ꢀ7.43 (m, 2H), 7.56 (d, J =
2.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 31.5, 34.1, 39.6, 42.3, 43.5,
50.8, 112.2, 118.1, 125.5, 126.5, 127.6, 128.6, 129.1, 132.1, 142.4, 146.2, 176.0,
177.9; HRMS m/z (M+) calcd for C22H24N2O2 348.1838, found 348.1836.
(3aR*,9bS*)-5-Methyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3da): mp 184ꢀ186 °C; 1H
NMR (400 MHz, CDCl3) δ 2.83 (s, 3H), 3.11 (dd, J = 11.5, 4.6 Hz, 1H),
3.52 (ddd, J = 9.6, 4.6, 2.8 Hz, 1H), 3.60 (dd, J = 11.5, 2.8 Hz, 1H), 4.15
(d, J = 9.6 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.90 (dd, J = 7.8, 7.3 Hz,
1H), 7.21ꢀ7.27 (m, 3H), 7.33ꢀ7.36 (m, 1H), 7.40ꢀ7.44 (m, 2H),
7.52 (d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 39.6, 42.2,
43.7, 50.76, 112.7, 118.7, 119.8, 126.5, 128.6, 128.8, 129.1, 130.4,
132.1, 148.6, 175.9, 177.8; HRMS m/z (M+) calcd for C18H16N2O2
292.1212, found 292.1208.
afforded the corresponding pyrroloquinoline 7 in 60% yield with
maintenance of the cis-configuration (eq 1).11 Moreover, the
reaction with hydrazine monohydrate resulted in the highly
functionalized tetrahydropyridazinedione 8, which could be a
useful synthetic handle for further manipulation (eq 2).12
Finally, we evaluated some other electron-deficient alkenes,
and to our delight, benzylidene malononitrile was found to be a
suitable substrate class for the oxidative coupling with N-methy-
lanilines 1 (Scheme 5).13 The reaction proceeded regioselec-
tively under somewhat modified conditions (EtCN, 60 °C, O2)
to produce the multiply substituted tetrahydroquinolines 9.
While preliminary, it shows the potential of the catalyst system
for the radical-mediated process of N-methylaniline derivatives.
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NOTE
Mixture of (3aR*,9bS*)-5,8,9-trimethyl-2-phenyl-3a,4,5,9b-
tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ea) and
(3aR*,9bS*)-5,7,8-trimethyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione(3ea0) (66:34): oil; 1HNMR
(400 MHz, CDCl3) for mixture δ 2.20 (s, 0.34 ꢁ 3H, for 3ea0), 2.22 (s, 0.34
ꢁ 3H, for 3ea0), 2.25 (s, 0.66 ꢁ 3H, for 3ea), 2.44 (s, 0.66 ꢁ 3H, for
3ea),2.73 (s, 0.66 ꢁ 3H, for 3ea), 2.77 (s, 0.34 ꢁ 3H, for 3ea0), 2.86 (dd, J =
11.2, 4.7 Hz, 0.66 ꢁ 1H, for 3ea), 2.99 (dd, J = 11.6, 4.4 Hz, 0.34 ꢁ 1H, for
3ea0), 3.41ꢀ3.47 (m, 1H), 3.51ꢀ3.55 (m, 1H), 4.03 (d, J = 9.8 Hz, 0.34 ꢁ
1H, for 3ea0), 4.57 (d, J = 9.8 Hz, 0.66 ꢁ 1H, for 3ea0), 6.52ꢀ6.54 (m, 1H),
7.01 (d, J = 8.4 Hz, 0.66 ꢁ 1H, for 3ea), 7.21ꢀ7.42 (m, 5.34H); 13C NMR
(100 MHz, CDCl3) for mixture δ 16.5, 18.8, 20.0, 20.4, 39.6, 39.7, 39.9, 41.8,
43.5, 44.7, 51.0, 52.6, 110.1, 114.1, 116.0, 120.0, 126.4, 126.5, 127.7, 128.5,
128.5, 128.9, 129.0, 129.0, 129.6, 131.3, 132.1, 132.2, 136.95, 136.97, 146.6,
148.3, 175.6, 176.1, 177.9, 178.7; HRMS for mixture m/z (M+) calcd for
C20H20N2O2 320.1525, found 320.1524 and 320.1526.
134.3, 146.5, 175.7, 177.7; HRMS m/z (M+) calcd for C19H17ClN2O2
340.0979, found 340.0981.
(3aR*,9bS*)-5,8-Dimethyl-2-[4-(trifluoromethyl)phenyl]-
3a,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-
dione (3ad): oil; 1H NMR (400 MHz, CDCl3)δ 2.30 (s, 3H), 2.79 (s,
3H), 3.04 (dd, J = 11.4, 4.6 Hz, 1H), 3.52 (ddd, J =9.6, 4.6, 2.8 Hz, 1H), 3.58
(dd, J = 11.4, 2.8 Hz, 1H), 4.12 (d, J = 9.6 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H),
7.04 (dd, J = 8.2, 1.8 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 8.7 Hz,
2H), 7.68 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 20.5, 39.7,
42.3, 43.8, 51.0, 112.8, 118.3, 123.8 (q, J = 272.2 Hz), 126.2 (q, J = 3.9 Hz),
123.7, 129.3, 129.5, 130.4 (q, J = 32.6 Hz), 130.9, 135.2, 145.5, 175.6, 177.5;
HRMS m/z (M+) calcd for C20H17F3N2O2 374.1242, found 374.1243.
(3aR*,9bS*)-2,5,8-Trimethyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ae): mp 173ꢀ176 °C; 1H
NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.78 (s, 3H), 2.96 (dd, J = 11.7,
4.4 Hz, 1H), 2.98 (s, 3H), 3.34 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.51 (dd, J =
11.7, 2.6 Hz, 1H), 3.95 (d, J = 9.5 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 7.01
(dd, J = 8.4, 1.8 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.4, 25.4, 39.6, 42.2, 43.7, 50.9, 112.6, 118.8, 129.1, 129.3, 130.8,
146.4, 177.0, 179.0; HRMS m/z (M+) calcd for C14H16N2O2 244.1212,
found 244.1206.
(3aR*,9bS*)-6-Methoxy-5,8-dimethyl-2-phenyl-3a,4,5,9b-
tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3fa):
1
oil; H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 2.85 (s, 3H), 3.38
(dd, J = 12.8, 6.2 Hz, 1H), 3.47ꢀ3.55 (m, 2H), 3.88 (s, 3H), 4.12 (d, J =
9.2 Hz, 1H), 6.65 (s, 1H), 7.12 (s, 1H), 7.26ꢀ7.28 (m, 2H), 7.36ꢀ7.39
(m, 1H), 7.43ꢀ7.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5,
38.8, 41.5, 42.0, 51.5, 55.7, 111.3, 122.8, 123.1, 126.4, 128.7, 129.3, 132.1,
133.8, 134.5, 152.7, 175.7, 177.6; HRMS m/z (M+) calcd for
C20H20N2O3 336.1474, found 336.1478.
(3aR*,9bS*)-2-Benzyl-5,8-dimethyl-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3af): mp 119ꢀ
1
121 °C; H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.75 (s, 3H),
2.96 (dd, J = 11.7, 4.4 Hz, 1H), 3.31 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.45
(dd, J = 11.7, 2.6 Hz, 1H), 3.92 (d, J = 9.5 Hz, 1H), 4.60 (d, J = 14.3 Hz,
1H), 4.67 (d, J = 14.3 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 8.4,
1.8 Hz, 1H), 7.22ꢀ7.31 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 20.6,
39.5, 42.2, 42.9, 43.8, 51.2, 112.6, 118.9, 127.9, 128.5, 128.7, 129.1,
129.3, 130.8, 135.7, 146.4, 176.6, 178.6; HRMS m/z (M+) calcd for
C20H20N2O2 320.1525, found 320.1522.
(3aR*,9bS*)-5-Butyl-8-methyl-2-phenyl-3a,4,5,9b-tetra-
hydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ga): oil; H
1
NMR (400 MHz, CDCl3)δ 0.92 (t, J = 7.4 Hz, 3H), 1.29ꢀ1.39 (m, 2H),
1.47ꢀ1.62 (m, 2H), 2.28 (s, 3H), 2.99ꢀ3.07 (m, 1H), 3.09 (dd, J = 11.6,
4.4 Hz, 1H), 3.20ꢀ3.27 (m, 1H), 3.47 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.61
(dd, J = 11.6, 2.6 Hz, 1H), 4.06 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H),
7.00 (dd, J = 8.3, 1.8 Hz, 1H), 7.23ꢀ7.33 (m, 2H), 7.33ꢀ7.36 (m, 2H),
7.39ꢀ7.43 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 20.4, 20.5, 28.3,
42.5, 44.2, 48.6, 50.6, 112.6, 118.8, 126.4, 128.37, 128.5, 129.1, 129.2, 131.2,
132.2, 146.5, 176.0, 178.0; HRMS m/z (M+) calcd for C22H24N2O2
348.1838, found 348.1839.
Typical Procedure for Copper-Catalyzed Oxidative Cycli-
zation of N-Methylanilines with Benzylidene Malononitrile
(Scheme 5). Synthesis of 9c is representative. CuCl2 (6.7 mg, 0.050
mmol) was placed in a 20-mL two-necked reaction flask, which was then
filled with O2 using the standard Schlenk technique. A solution of 4-tert-
butyl-N,N-dimethylaniline (1c, 222 mg, 1.3 mmol), benzylidene mal-
ononitrile (39 mg, 0.25 mmol), and 1-methylnaphthalene (ca. 20 mg,
internal standard) in EtCN (2.0 mL) was added, and the mixture was
then heated at 60 °C. After being stirred for 4 h, the resulting solution
was poured into water and extracted with ethyl acetate. The combined
organic layer was dried over sodium sulfate followed by evaporation and
silica gel column purification (n-hexane/ethyl acetate =10:1, v/v) to
furnish 6-tert-butyl-1-methyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-
dicarbonitrile (9c, 41 mg, 0.13 mmol) in 50% yield.
(3aR*,9bS*)-5-Benzyl-8-methyl-2-phenyl-3a,4,5,9b-tetra-
hydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ha): mp
168ꢀ170 °C; 1H NMR (400 MHz, CDCl3) δ 2.28 (s, 3H), 3.20 (dd, J
= 11.7, 4.4 Hz, 1H), 3.52 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.66 (dd, J = 11.7,
2.6 Hz, 1H), 4.14 (d, J = 9.5 Hz, 1H), 4.22 (d, J = 15.4 Hz, 1H), 4.44 (d, J =
15.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.4, 1.8 Hz, 1H),
7.22ꢀ7.31 (m, 7H), 7.35ꢀ7.40 (m, 2H), 7.43ꢀ7.48 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 20.6, 42.6, 44.3, 49.5, 55.6, 113.6, 119.1, 126.5, 127.4,
127.6, 128.7, 129.18, 129.21, 129.24, 129.3, 131.1, 132.2, 138.0, 145.5, 176.0,
177.8; HRMS m/z (M+) calcd for C25H22N2O2 382.1681, found 382.1682.
(3aR*,9bS*)-2-(4-Methoxyphenyl)-5,8-dimethyl-3a,4,5,9b-
tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ab):
6-Methoxy-1-methyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-
dicarbonitrile (9b): mp 147ꢀ149 °C; 1H NMR (400 MHz, CDCl3) δ
2.97 (s, 3H), 3.46 (dd, J = 12.0 Hz, 3.5 Hz, 1H), 3.63 (dd, J = 11.5 Hz, 3.5 Hz,
1H), 3.02 (s, 3H), 3.85 (dd, J = 12.0 Hz, 11.5 Hz, 1H), 6.73 (d, J = 9.1 Hz,
1H), 6.96 (dd, J = 9.1 Hz, 2.9 Hz, 1H), 7.07 (d, J = 2.9 Hz, 1H), 7.44ꢀ7.47
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 39.4, 42.8, 46.1, 51.8, 56.1, 113.5,
113.5, 114.2, 114.5, 115.4, 118.9, 128.6, 129.3, 129.5, 135.0, 139.0, 152.0;
HRMS m/z (M+) calcd for C19H17N3O 303.1372, found 303.1369.
6-tert-Butyl-1-methyl-3-phenyl-2,3-dihydroquinoline-
1
mp 172ꢀ174 °C; H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 2.80
(s, 3H), 3.04 (dd, J = 11.4, 4.6Hz, 1H), 3.48 (ddd, J = 9.6, 4.6, 2.7Hz, 1H),
3.57 (dd, J = 11.4, 2.7 Hz, 1H), 3.80 (s, 3H), 4.08 (d, J = 9.6 Hz, 1H), 6.64
(d, J = 8.2 Hz, 1H), 6.91ꢀ6.95 (m, 2H), 7.04 (dd, J = 8.2, 1.8 Hz, 1H),
7.16 ꢀ7.20 (m, 2H), 7.35 (d, J = 1.8, 1H); 13C NMR (100 MHz, CDCl3)
δ 20.5, 39.6, 42.2, 43.6, 51.0, 55.5, 112.6, 114.4, 118.7, 124.8, 127.7, 129.0,
129.3, 130.9, 146.5, 159.4, 176.2, 178.1; HRMS m/z (M+) calcd for
C20H20N2O3 336.1474, found 336.1471.
1
4,4(1H)-dicarbonitrile (9c): mp 128ꢀ130 °C; H NMR (400 MHz,
CDCl3) δ1.32 (s, 9H), 3.00 (s, 3H), 3.46 (dd, J = 12.4 Hz, 3.7 Hz, 1H), 3.60
(dd, J= 11.4 Hz, 3.7 Hz, 1H), 3.92 (dd, J= 12.4 Hz, 11.4 Hz, 1H), 6.70 (d, J=
8.7 Hz, 1H), 7.37 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.44ꢀ7.46 (m, 5H), 7.50 (d,
J = 2.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 31.5, 34.2, 39.0, 42.8, 46.0,
51.6, 112.4, 112.7, 114.4, 115.5, 125.6, 128.6, 129.0, 129.3, 129.5, 135.1, 141.0,
142.1; HRMS m/z (M+) calcd for C22H23N3 329.1892, found 329.1889.
Reduction of 3aa (Scheme 4, eq 1). The tetrahydroquinoline
3aa (61 mg, 0.20 mmol) was placed in a 20-mL reaction flask, and the
flask was flushed with nitrogen. Toluene (1.0 mL) and Red-Al (3.3 M
(3aR*,9bS*)-2-(4-Chlorophenyl)-5,8-dimethyl-3a,4,5,9b-
tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3ac): mp
172ꢀ175 °C; 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.78 (s, 3H),
3.02 (dd, J = 11.4, 4.4 Hz, 1H), 3.48 (ddd, J = 9.5, 4.4, 2.6 Hz, 1H), 3.57
(dd, J = 11.4, 2.6 Hz, 1H), 4.09 (d, J = 9.5 Hz, 1H), 6.64 (d, J = 8.4 Hz,
1H), 7.03 (dd, J = 8.4, 2.2 Hz, 1H), 7.21 ꢀ7.25 (m, 2H), 7.31 (d, J = 2.2,
1H), 7.36ꢀ7.39 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.6, 39.7,
42.3, 42.7, 51.0, 112.7, 118.5, 127.7, 129.2, 129.3, 129.5, 130.6, 130.9,
6450
dx.doi.org/10.1021/jo2011329 |J. Org. Chem. 2011, 76, 6447–6451

The Journal of Organic Chemistry
NOTE
toluene solution, 0.27 mL, 0.88 mmol) were sequentially added drop-
wise. The mixture was heated at 100 °C for 1 h. After being allowed to
cool to room temperature, the resulting solution was carefully quenched
with a minimum amount of water. The suspension was then filtered
through a short pad of neutral alumina and evaporated under reduced
pressure. The obtained crude material was purified by column chroma-
tography on silica gel with n-hexane/ethyl acetate (10:1, v/v) as eluent
to provide (3aR*, 9bS*)-5,8-dimethyl-2-phenyl-2,3,3a,4,5,9b-hexahy-
dro-1H-pyrrolo[3,4-c]quinoline (7, 33 mg, 0.12 mmol) in 60% yield.
(3aR*,9bS*)-5,8-Dimethyl-2-phenyl-2,3,3a,4,5,9b-hexahy-
dro-1H-pyrrolo[3,4-c]quinoline (7): oil; 1H NMR (400 MHz,
CDCl3) δ 2.26 (s, 3H), 2.74ꢀ2.82 (m, 1H), 2.87 (s, 3H), 2.92 (dd, J =
11.4, 11.4 Hz, 1H), 3.07 (dd, J = 11.4, 4.8 Hz, 1H), 3.17 (dd, J = 9.5, 2.2 Hz,
1H), 3.20 (dd, J = 9.1, 9.1 Hz, 1H), 3.48ꢀ3.54 (m, 1H), 3.70 (dd, J = 9.5,
6.6 Hz, 1H), 3.81 (dd, J= 9.1, 9.1 Hz, 1H), 6.55 (d, J= 8.0 Hz, 2H), 6.63 (d,
J = 8.0 Hz, 2H), 6.67 (t, J = 7.3 Hz, 2H), 6.94ꢀ6.97 (m, 2H), 7.20ꢀ7.24
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.4, 35.4, 39.6, 39.8, 52.1, 52.3,
55.1, 111.8, 112.2, 115.9, 123.8, 126.48, 128.3, 129.3, 130.3, 144.4, 147.8;
HRMS m/z (M+) calcd for C19H22N2 278.1783, found 278.1782.
Reaction of 3aa with Hydrazine (Scheme 4, eq 2). The
tetrahydroquinoline 3aa (306 mg, 1.0 mmol), hydrazine monohydrate
(75 mg, 1.5 mmol), and MeOH (10 mL) were placed in a 20-mL
reaction flask and then heated at 80 °C for 21 h under N2. After the
solvent and volatile materials were removed under reduced pressure, the
residue was dissolved in dichloromethane and washed with 10% aq citric
acid. Extraction with dichloroethane, evaporation, and silica gel column
purification with n-hexane/ethyl acetate (1:4, v/v) produced (4aR*,
10bS*)-6,9-dimethyl-2,3,5,6-tetrahydropyridazino[4,5-c]quinoline-1,4-
(4aH,10bH)-dione (8, 188 mg, 0.77 mmol) in 77% yield.
Nomura, M. Heterocycles 1992, 34, 1177. (d) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 3672. (e) Huang, L.; Zhang, X.; Zhang, Y. Org.
Lett. 2009, 11, 3730. Metal-free process:(f) Zhang, Y.; Li, C.-J. J. Am.
Chem. Soc. 2006, 128, 4242. Electrochemical conditions:(g) Baslꢀe, O.;
Borduas, N.; Dubois, P.; Chapuzet, J. M.; Chan, T.-H.; Lessard, J.; Li, C.-
J. Chem.ꢀEur. J. 2010, 16, 8162. Photochemical conditions:(h) Rueping,
M.; Vila, C.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C. Chem.
Commun. 2011, 47, 2360. An elegent mechanistic study:(i) Boess, E.;
Sureshkumar, D.; Sud, A.; Wirtz, C.; Farꢁes, C.; Klussmann, M. J. Am.
Chem. Soc. 2011, 133, 8106.
(3) (a) Sud, A.; Sureshkumar, D.; Klussmann, M. Chem. Commun.
2009, 3169. (b) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett. 2010, 22, 5214.
(4) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (b) Ohta,
M.; Quick, M. P.; Yamaguchi, J.; W€unsch, B.; Itami, K. Chem.ꢀAsian J.
2009, 4, 1416. (c) Wang, M.-Z.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M.
Chem.ꢀEur. J. 2010, 16, 5723. (d) Shirakawa, E.; Uchiyama, N.;
Hayashi, T. J. Org. Chem. 2011, 76, 25. (e) Huang, L.; Niu, T.; Wu, J.;
Zhang, Y. J. Org. Chem. 2011, 76, 1759 and ref 2e.
(5) Trapping with organometallic reagents or intermediates. Acet-
ylides: (a) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. J. Chem.
Res., Synop. 1993, 434. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004,
126, 11810. (c) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (d) Zhao, L.; Li,
C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075. (e) Rao, C. M.; Vogel, P. Org.
Lett. 2009, 11, 1701. Arylboronic acids:(f) Baslꢀe, O.; Li, C.-J. Org. Lett.
2008, 10, 3661. Trifluoromethylsilane:(g) Chu, L.; Qing, F.-L. Chem.
Commun. 2010, 46, 6285.
(6) We previously found the preliminary activity of Mn(NO3)2 in a
similar transformation. However, the process required relatively forcing
conditions, and its efficiency and selectivity were rather low. (a) Murata,
S.; Teramoto, K.; Miura, M.; Nomura, M. Heterocycles 1993, 36, 2147.
Although an oxidative cyclization of N-alkyltetrahydroisoquinolines
with maleimides was reported, the reaction proceeded through the
corresponding 1,3-dipolar azomethine ylide. (b) Yu, C.; Zhang, Y.;
Zhang, S.; Li, H.; Wang, W. Chem. Commun. 2011, 47, 1036. A relevant
radical-mediated reaction: (c) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett.
2009, 11, 2908.
(4aR*,10bS*)-6,9-Dimethyl-2,3,5,6-tetrahydropyridazino-
[4,5-c]quinoline-1,4(4aH,10bH)-dione (8): mp 220ꢀ222 °C; 1H
NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.75 (s, 3H), 2.96 (dd, J = 11.4
Hz, 4.4 Hz, 1H), 3.33 (ddd, J = 9.5 Hz, 4.4 Hz, 2.6 Hz, 1H), 3.52 (dd, J =
11.4 Hz, 2.6 Hz, 1H), 3.95 (d, J = 9.5 Hz, 1H), 4.26 (s, 2H), 6.60 (d, J =
8.4 Hz, 1H), 7.01 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 20.6, 39.6, 40.7, 42.3, 50.8, 112.7, 118.3,
129.3, 129.5, 130.8, 146.5, 174.2, 175.9; HRMS m/z (M+) calcd for
C13H15N3O2 245.1164, found 245.1163.
(7) An oxidative dimerization competitively occurred. See ref 2b.
(8) A related radical pathway initiated by benzoyl peroxide: (a) Roy,
R. B.; Swan, G. A. Chem. Commun. 1968, 1446. (b) Roy, R. B.; Swan,
G. A. J. Chem. Soc. C 1969, 1886.
(9) (a) Anslyn, E. V.; Doughtery, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006. (b) Nꢀu~nez,
A.; Sꢀanchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004,
60, 6217. (c) Vallꢀee, F.; Mousseau, J. J.; Charette, A. B. J. Am. Chem.
Soc. 2010, 132, 1514.
(10) Although the pathway involving [4 + 2] cycloaddition of the
cationic species 6 with maleimides could not be completely excluded, it
does not meet electronic demands: both coupling partners are electron-
deficient π components.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
(11) Pyrroloquinolines in pharmaceutical chemistry: (a) Fevig,
J. M.; Mitchell, I. S.; Lee, T.; Chen, W.; Cacciola, J. PCT Int. Appl.
Corresponding Author
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.
osaka-u.ac.jp.
ꢁ
2002, WO 2002059124, A2 20020801 (CAN 137:125150). (b) Fevig,
J. M.; Feng, J.; Ahmad, S. U.S. Pat. Appl. 2006, US 20060014778, A1
20060119 (CAN 144:128957). The relative stereochemistry was deter-
mined by NOE analysis. See the Supporting Information.
(12) (a) Aly, A. A. Org. Biomol. Chem. 2003, 1, 756. (b) Wolff, O.;
Waldvogel, S. R. Synthesis 2007, 761.
’ ACKNOWLEDGMENT
This work was supported by Grants-in-Aid for Scientific
Research from MEXT and JSPS, Japan. K.H. acknowledges
Kansai Research Foundation for the Promotion of Science.
(13) Attempts to apply acrylonitrile and acrylate esters remained
unsuccessful.
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dx.doi.org/10.1021/jo2011329 |J. Org. Chem. 2011, 76, 6447–6451