Synthesis of acridines and persubstituted phenols from cyclobutenones and active methylene ketones

Article abstract of DOI:10.1021/jo300615t

A new benzannulation strategy that proceeds via a regiospecific [4 + 2] cycloaddition of readily available cyclobutenones and active methylene ketones has been developed. On the basis of this strategy, persubstituted phenols/anilines with up to six different functional groups on the benzene ring were synthesized in a single step. In addition, a series of acridine derivatives were prepared in excellent yield from persubstituted phenols/anilines.

Full text of DOI:10.1021/jo300615t

Note
pubs.acs.org/joc
Synthesis of Acridines and Persubstituted Phenols from
Cyclobutenones and Active Methylene Ketones
Xiao-Dan Han, Yu-Long Zhao,* Jia Meng, Chuan-Qing Ren, and Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R. China
S
* Supporting Information
ABSTRACT: A new benzannulation strategy that proceeds via a
regiospecific [4 + 2] cycloaddition of readily available cyclobute-
nones and active methylene ketones has been developed. On the
basis of this strategy, persubstituted phenols/anilines with up to six
different functional groups on the benzene ring were synthesized in a
single step. In addition, a series of acridine derivatives were prepared
in excellent yield from persubstituted phenols/anilines.
Table 1. Optimization of Reaction Conditions
ubstituted phenols are important structural motifs found in
a variety of natural products, biologically active compounds,
S
and agrochemicals.1 In the past few decades, the efficient synthesis
of substituted phenols from acyclic precursors with high atom and
step economy has become a powerful tool in the arsenal of syn-
thetic organic chemist.2−4 In this context, the significance of
cyclobutenones in the synthesis of six-membered carbocycles5 and,
in particular, substituted phenols via Moore rearrangement6 or by
reaction with alkynes has been described.7 The predication of the
regiochemistry is still a stimulating challenge, especially for highly
functionalized benzene derivatives.1−4,6,7,9,10 As a continuing
interest in the development of new benzannulation3 and hetero-
cyclization8 reactions, we report here a new strategy for the
regiospecific synthesis of persubstituted phenols via a formal
[4 + 2] cycloaddition between cyclobutenones (as 1,4-dipoles)
and active methylene ketones (carbon−carbon dipolarophiles) in a
single step. In addition, the efficient synthesis of acridine deriv-
atives from persubstituted phenols is also described.
In the present work, the reaction of the readily available 3-
aminocyclobutenone 1a11 with methyl acetoacetate 2a was first
examined under various conditions (Table 1). It was found that
persubstituted phenol 3a could be obtained in 85% yield under
optimized reaction conditions, where 1a (0.5 mmol) was treated
with 2a (0.6 mmol) in the presence of LDA (1.0 mmol, LDA =
lithium diisopropylamide) in THF (2.0 mL) in a sealed tube at
80 °C for 8 h (Table 1, entry 1). In this case, enaminone 4a was
also obtained as the byproduct in 3% yield (entry 1). Decreasing
the amount of LDA led to lower yields of 3a (entries 2 and 3).
Under otherwise identical conditions, however, highly substituted
α-pyrone 5a instead of 3a was produced in excellent yields when
NaOH, t-BuOK or LiOH was used as the base (entries 4−6).
Among the solvents tested, THF was the best choice (entry 1).
Other solvents, such as DMF and dioxane, gave lower yields of 3a
a
a
a
time
(h)
3a
4a
5a
entry
1
base (equiv)
solvent
(%)
(%)
(%)
LDA (2.0)
LDA (0.5)
LDA (1.5)
NaOH (2.0)
t-BuOK (2.0)
LiOH (2.0)
LDA
THF
THF
8
12
8
85
18
60
0
3
20
10
0
0
0
b
2
c
3
THF
0
4
5
6
7
8
9
THF
8
90
91
86
80
71
88
30
THF
8
0
0
THF
8
0
0
DMF
dioxane
toluene
DCE
15
15
15
15
13
23
0
0
LDA
0
LDA
0
d
10
LDA
0
0
a
b
c
Isolated yield. 1a was recovered in 50% yield. 1a was recovered in
d
14% yield. 1a was recovered in 61% yield.
(entries 7 and 8). In comparison, no 3a could be detected with
DCE (1,2-dichloroethane) or toluene as the solvent (entries 9
and 10).
Received: March 29, 2012
Published: May 7, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
a
Table 2. Synthesis of Persubstituted Phenols 3
b
entry
1
R
Ar
R1
R2
CO2Me (2a)
temp (°C)
time (h)
yield (%)
1
2
1a
1b
1c
1d
1e
1f
Et
4-NO2C6H4
4-ClC6H4
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
80
80
8
8
3a (85)
3b (65)
3c (85)
3d (81)
3e (80)
3f (78)
3g (80)
3h (70)
3i (80)
3j (78)
3k (77)
3l (68)
3m (76)
3n (71)
3o (75)
3p (68)
3q (64)
Et
CO2Me
3
Et
CO2Me
80
8
4
Et
4-MeC6H4
2-MeC6H4
2,4-Me2C6H3
4-MeOC6H4
1-naphthyl
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
CO2Me
80
8
5
Et
CO2Me
80
8
6
Et
CO2Me
80
10
8
7
1g
1h
1i
Et
CO2Me
80
8
Et
CO2Me
80
8
9
Me
MeO
Et
CO2Me
80
8
10
11
12
13
14
15
16
1j
CO2Me
80
8
1d
1d
1d
1d
1d
1d
1d
CO2Et (2b)
CO2Me (2c)
CO2Et (2d)
CONHPh (2e)
CONH(4-MeC6H4) (2f)
CONH2 (2g)
COMe (2h)
80
9
Et
80
12
8
Et
Ph
130
130
130
130
140
Et
Me
Me
Me
Ph
8
Et
8
Et
8
c
17
Et
12
a
b
c
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), LDA (1.0 mmol), THF (2.0 mL), 8−12 h. Isolated yield. 8.0 equiv of 2h was used.
The above results indicate that the reaction of 3-amino-
3-oxo-N-p-tolylbutanamide 2f (Table 2, entry 15), 3-
oxobutanamide 2g (Table 2, entry 16), and benzoyl acetone
2h (Table 2, entry 17) as carbon−carbon dipolarophiles were
examined. As a result, the corresponding phenols 3l−q were
prepared in good to high yields (Table 2, entries 11−17).
To gain insight into the reaction mechanism, the reaction of
methyl acetoacetate 2a with cyclobutenone 1k having a dialkyl-
amino group (piperidin-1-yl) was performed under similar
conditions as in Table 2. As a result, the desired persubstituted
phenol 3r was obtained in 60% and 61% yields under the con-
ditions with 2.0 equiv of LDA at 120 °C for 10 h and with 1.0
equiv of LDA at 120 °C for 12 h, respectively (Scheme 1). The
cyclobutenone 1a with methyl acetoacetate 2a can afford
persubstituted phenol 3a successfully or 3-aminocyclobutenone
1a itself is converted to highly substituted α-pyrone 5a, depend-
ing on the reaction conditions. In the formation of 3a, the
methyl, N-aryl, and propionyl groups on the cyclobutenone
ring of 1a and the methoxycarbonyl group of 2a remained
intact, and no other benzannulation products were detected. To
our knowledge, the successful synthesis of 3a represents a new
synthetic strategy for highly functionalized phenols from
cyclobutenones6,7 in a regiospecific manner.3a In this regio-
specific benzannulation reaction, cyclobutenones act as four-
carbon 1,4-dipoles,3b while a methylene ketone plays the role of
carbon−carbon dipolarophiles. Thus, the formal [4 + 2]
cycloaddition reaction (see Scheme 3) for the preparation of 3a
(also a persubstituted aniline) substantially expands the synthetic
potential of cyclobutenones 1.7b,11,12 Prompted by this observation,
the scope of the [4 + 2] cycloaddition reaction was investigated
under the optimal conditions (Table 1, entry 1), and the results are
summarized in Table 2.
Scheme 1. Synthesis of Persubstituted Phenol 3r
On the basis of the experimental results, the [4 + 2] cyclo-
addition reaction shows broad tolerance for various N-aryl-
substituted cyclobutenones 1, including phenyl (Table 2, entry 3),
electron-deficient (Table 2, entries 1 and 2), electron-rich
(Table 2, entries 4−7) N-aryl groups and N-(1-naphthyl)
(Table 2, entry 8). All of the reactions of 1a−h with methyl
acetoacetate 2a gave the corresponding persubstituted phenols
3a−h in good to high yields (Table 2, entries 1−8). Similarly,
the desired phenols 3i and 3j were synthesized in 80% and 78%
yields from reactions 1i (R = Me) and 1j (R = MeO) with 2a,
respectively (Table 2, entries 9 and 10).13
To extend the scope of the [4 + 2] cycloaddition reaction,
the reactions of 1d with active methylene ketones, including
ethyl acetoacetate 2b (Table 2, entry 11), methyl propionyla-
cetate 2c (Table 2, entry 12), ethyl benzoylacetate 2d (Table 2,
entry 13), 3-oxo-N-phenylbutanamide 2e (Table 2, entry 14),
above results indicate that the [4 + 2] benzannulation reaction can
tolerate various amino groups on the cyclobutenone ring (see also
Table 2) and exhibit good flexibility.
It was noted that in the absence of active methylene ketones
an enaminone product, (E)-3-(4-chlorophenylamino)-N,N-
diisopropyl-2-propionylpent-2-enamide 4b, was obtained in
75% yield by treatment of cyclobutenone 1b with LDA (2.0
equiv) in THF at 80 °C for 10 h (Scheme 2).13 Similarly, under
essentially identical conditions, highly substituted α-pyrone 5b
was produced in 90% yield when NaOH (2.0 equiv) or t-BuOK
(2.0 equiv) was used as the base (Scheme 2; see also Table 1,
entries 4 and 5). Furthermore, the reaction of 5b with 2a was
attempted. As a result, 5b was recovered in nearly quantitative
yield after treatment of the mixture of 5b (0.5 mmol) and 2a
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The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of Enaminone 4b and α-Pyrone 5b
temperature for 10−12 h (Scheme 4). Since acridine derivatives
display a broad spectrum of biological activities,16 the synthesis
Scheme 4. Synthesis of Acridine Derivatives 6 and 8
(0.6 mmol) with LDA (1.0 mmol) in THF (2.0 mL) at 80 °C
for 10 h (Scheme 2).
The α-pyrone ring system has been found in various
important natural products and has found versatile applications
in organic synthesis.14,15 The transformation of cyclobutenone 1
to 5 (Table 1, entries 4−10, and Scheme 2) provides a convenient
pathway for the synthesis of α-pyrones and deserves further
research, whereas according to the experimental results (Scheme 2,
reaction 5b with 2a), α-pyrone 5 would not be involved in the
formation of persubstituted phenols 3. Therefore, a mechanism for
the [4 + 2] benzannulation between cyclobutenones 1 and met-
hylene ketones 2 is proposed in Scheme 3. In the presence of
of substituted 9,10-dihydroacridins 8b−d were further exam-
ined. To our delight, dihydroacridins 8b−d could be prepared
in excellent total yields by a one-pot procedure, including
reduction of 3b−d with NaBH4 (1.0 equiv) in methanol at room
temperature for 2 h followed by treatment of the reaction mix-
ture with BF3·OEt2 (1.0 equiv) at 50 °C for 15 min (Scheme 4).
Thus, the above transformation provides an efficient approach
for the synthesis of acridine derivatives with flexible substitu-
ents.16,17
Scheme 3. Proposed Mechanism for Formation of Phenols 3
In summary, a new benzannulation strategy has been developed.
Using this strategy, persubstituted phenols (anilines) were
prepared from the reaction of cyclobutenones (as four-carbon
1,4-dipoles) with active methylene ketones (as carbon−carbon
dipolarophiles) via a formal [4 + 2] cycloaddition. This base-pro-
moted benzannulation reaction is totally regiocontrolled with
respect to the relative orientation of coupling partners and various
functional groups are introduced into the benzene ring in a single
step. In addition, highly substituted acridine derivatives were
synthesized in excellent yields from the persubstituted benzenes.
Further investigations are focused on expanding the scope of this
benzannulation reaction with respect to the dipolarophiles, and
will be reported in due course.
LDA, the reaction starts from the deprotonation of 2 and sub-
sequent intermolecular aldol reaction with 1 to give cyclo-
butenolate intermediate I. Then a ring-opening process (I→II, see
also the transformation of 1b→4b in Scheme 2) followed by
intramolecular aldol cyclization to afford six-membered inter-
mediate III. Finally, the benzannulation product 3 is formed via a
sequential protonation (III→IV), dehydration (IV→V), and
aromatization (V→3) process.
Obviously, the above benzannulation reaction provides a
simple and efficient procedure for the synthesis of persub-
stituted phenols 3 from easily available starting materials. In this
cyclization reaction, the carbonyl oxygen on the cyclobutenone
ring is converted into the hydroxyl group of phenols 3. Other
functional groups on the cyclobutenone ring and the R3 and R4
groups on the methylene ketones 2 are introduced onto the
benzene ring in a regiospecific manner (Scheme 3). Next, to
explore the synthetic potential of these highly functionalized
phenols (anilines), the cyclization reaction of 3 was examined.
It was found that the highly substituted acridines 6b−d could
be easily obtained in excellent yield by treatment of selected
3b−d (having a phenyl (3c), electron-deficient (3b), and
electron-rich N-aryl groups (3d), respectively) in the presence
of In(OTf)3 (8.0 mol %) in 1,2-dichloroethane (DCE) at reflux
EXPERIMENTAL SECTION
■
Commercially available reagents were used without further purifica-
tion. All solvents were purified and dried according to standard
methods prior to use. Chromatography was carried on flash silica gel
(300−400 mesh). All reactions were monitored using TLC on silica
gel plates. Unless noted, the 1H NMR spectra were recorded at 500 or
600 MHz in CDCl3 and the 13C NMR spectra were recorded at 125 or
150 MHz in CDCl3 with TMS as internal standard. All coupling
constants (J values) are reported in hertz (Hz). High-resolution mass
spectra (ESI/HRMS) were recorded on a mass spectrometer.
General Procedure for Synthesis of 3 (3a, for Example). An
oven-dried Schlenck tube charged with 3-aminocyclobutenone 1a (0.5
mmol, 137 mg) and a magnetic bar was evacuated and refilled with N2
three times. Then methyl acetoacetate 2a (0.6 mmol, 0.065 mL), LDA
(1.0 mmol, 0.12 mL), and 2 mL of dried THF were injected under N2
via syringe, and the reaction mixture was stirred at 80 °C for 8 h. After
completion of the reaction (monitored by TLC), the reaction mixture was
poured into water (30 mL) and extracted with CH2Cl2 (10 mL × 3). The
combined organic extracts were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to yield the corresponding
crude product, which was purified by silica gel chromatography
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Note
(petroleum ether/acetone = 6/1, v/v) to give 3a (158 mg, 85%) as a
yellow solid.
(s, 3H), 2.46 (s, 3H), 2.97 (q, J = 7.0 Hz, 2H), 4.00 (s, 3H), 6.47 (d,
J = 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H),
7.51−7.58 (m, 2H), 7.85 (t, J = 7.5 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H),
8.72 (s, 1H), 11.97 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 9.1, 16.2,
19.8, 37.6, 52.3, 109.4, 113.0, 118.5, 121.6, 121.8, 122.8, 125.7, 125.9,
126.2, 126.3, 128.4, 134.5, 139.9, 143.9, 146.3, 160.4, 172.0, 207.9;
Methyl 2-hydroxy-5,6-dimethyl-4-(4-nitrophenylamino)-3-
propionylbenzoate (3a): yellow solid (158 mg, 85%); mp 184−
186 °C; 1H NMR (CDCl3, 500 MHz) δ 1.01 (t, J = 7.5 Hz, 3H), 1.97
(s, 3H), 2.47 (s, 3H), 2.88 (q, J = 7.0 Hz, 2H), 4.00 (s, 3H), 6.56 (d,
J = 9.0 Hz, 2H), 7.83 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 11.64 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ 8.7, 15.6, 19.6, 37.5, 52.8, 114.2 (3C),
+
HRMS (ESI-TOF) calcd for C23H24NO4 ([M + H]+) 378.1700,
found 378.1715.
120.8, 125.5, 126.1 (2C), 140.1, 140.3, 143.8, 150.3, 158.6, 171.2,
Methyl 3-acetyl-2-hydroxy-5,6-dimethyl-4-(p-tolylamino)-
1
+
207.5; HRMS (ESI-TOF) calcd for C19H21N2O6 ([M + H]+):
benzoate (3i): yellow solid (131 mg, 80%); mp 162−164 °C; H
NMR (CDCl3, 500 MHz) δ 1.93 (s, 3H), 2.28 (s, 3H), 2.43 (s, 3H),
2.60 (s, 3H), 3.99 (s, 3H), 6.62 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0
Hz, 2H), 8.34 (s, 1H), 12.18 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ
16.3, 19.7, 20.6, 32.7, 52.3, 110.4, 117.3, 117.8 (2C), 122.3, 129.7
(2C), 130.6, 141.7, 144.2, 145.7, 160.7, 171.5, 204.1; HRMS (ESI-
373.1394, found 373.1381.
Methyl 4-(4-chlorophenylamino)-2-hydroxy-5,6-dimethyl-3-
propionylbenzoate (3b): yellow solid (117 mg, 65%); mp 210−
212 °C; 1H NMR (CDCl3, 500 MHz) δ 1.05 (t, J = 7.5 Hz, 3H), 1.92
(s, 3H), 2.45 (s, 3H), 2.94 (q, J = 7.0 Hz, 2H), 3.99 (s, 3H), 6.57 (d, J =
8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.89 (s, 1H), 11.82 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 8.9, 16.1, 19.7, 37.5, 52.4, 110.7, 118.2
(2C), 119.2, 123.4, 125.4, 129.1 (2C), 142.8, 143.8, 143.9, 159.7,
171.6, 207.8; HRMS (ESI-TOF) calcd for C19H21ClNO4+ ([M + H]+)
362.1154, found 362.1153.
+
TOF) calcd for C19H22NO4 ([M + H]+) 328.1543, found 328.1541.
Dimethyl 2-hydroxy-4,5-dimethyl-6-(p-tolylamino)-
isophthalate (3j): yellow solid (134 mg, 78%); mp 170−172 °C;
1H NMR (CDCl3, 500 MHz) δ 1.91 (s, 3H), 2.26 (s, 3H), 2.27
(s, 3H), 3.91 (s, 3H), 3.96 (s, 3H), 6.57 (d, J = 8.5 Hz, 2H), 7.02 (d,
J = 8.5 Hz, 2H), 7.48 (s, 1H), 11.19 (s, 1H); 13C NMR (CDCl3, 125
MHz) δ 15.7, 18.5, 20.6, 52.4, 52.9, 105.3, 117.3 (2C), 117.8, 122.9,
129.7 (2C), 130.3, 142.1, 142.8, 144.3, 157.6, 169.1, 170.0; HRMS
Methyl 2-hydroxy-5,6-dimethyl-4-(phenylamino)-3-propio-
nylbenzoate (3c): yellow solid (139 mg, 85%); mp 166−168 °C;
1H NMR (CDCl3, 500 MHz) δ 1.04 (t, J = 7.5 Hz, 3H), 1.94 (s, 3H),
+
2.45 (s, 3H), 2.95 (q, J = 7.5 Hz, 2H), 3.99 (s, 3H), 6.67 (d, J = 8.0
Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 2H), 7.85
(s, 1H), 11.86 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 8.9, 16.1, 19.7,
37.4, 52.4, 110.7, 117.2 (2C), 119.0, 120.8, 123.4, 129.1 (2C), 143.6,
144.2 (2C), 159.6, 171.6, 208.0; HRMS (ESI-TOF) calcd for
(ESI-TOF) calcd for C19H22NO5 ([M + H]+) 344.1492, found
344.1508.
Ethyl 2-hydroxy-5,6-dimethyl-3-propionyl-4-(p-tolylamino)-
1
benzoate (3k): yellow solid (137 mg, 77%); mp 131−133 °C; H
NMR (CDCl3, 600 MHz) δ 1.04 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2
Hz, 3H), 1.91 (s, 3H), 2.26 (s, 3H), 2.45 (s, 3H), 2.94 (q, J = 7.2 Hz,
2H), 4.45 (q, J = 7.2 Hz, 2H), 6.58 (d, J = 7.8 Hz, 2H), 7.00 (d, J = 8.4 Hz,
2H), 7.87 (s, 1H), 11.89 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 8.9,
14.2, 16.2, 19.7, 20.6, 37.5, 61.7, 110.2, 117.6 (2C), 118.6, 122.9, 129.6
(2C), 130.3, 141.9, 143.5, 144.9, 159.8, 171.3, 207.9; HRMS (ESI-TOF)
calcd for C21H26NO4+ ([M + H]+) 356.1856, found 356.1850.
+
C19H22NO4 ([M + H]+) 328.1543, found 328.1531.
Methyl 2-hydroxy-5,6-dimethyl-3-propionyl-4-(p-
tolylamino)benzoate (3d): yellow solid (138 mg, 81%); mp 162−
164 °C; 1H NMR (CDCl3, 500 MHz) δ 1.05 (t, J = 7.5 Hz, 3H), 1.92
(s, 3H), 2.27 (s, 3H), 2.43 (s, 3H), 2.95 (q, J = 7.5 Hz, 2H), 3.98
(s, 3H), 6.58 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 7.89
(s, 1H), 11.87 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 8.9, 16.2, 19.7,
20.6, 37.4, 52.3, 110.0, 117.6 (2C), 118.5, 122.8, 129.6 (2C), 130.4,
141.7, 143.6, 145.0, 159.8, 171.7, 207.9; HRMS (ESI-TOF) calcd for
Methyl 2-ethyl-6-hydroxy-3-methyl-5-propionyl-4-(p-
tolylamino)benzoate (3l): yellow solid (121 mg, 68%); mp 155−
157 °C; 1H NMR (CDCl3, 500 MHz) δ 1.03 (t, J = 7.5 Hz, 3H), 1.17
(t, J = 7.0 Hz, 3H), 1.98 (s, 3H), 2.26 (s, 3H), 2.86 (q, J = 7.5 Hz,
2H), 2.93 (q, J = 7.0 Hz, 2H), 3.98 (s, 3H), 6.57 (d, J = 8.0 Hz, 2H),
7.00 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 11.87 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 8.9, 14.1, 14.8, 20.6, 25.5, 37.2, 52.3, 110.7,
117.3 (2C), 118.7, 122.4, 129.8 (2C), 130.3, 141.9, 145.0, 148.9, 159.5,
+
C20H24NO4 ([M + H]+) 342.1700, found 342.1687.
Methyl 2-hydroxy-5,6-dimethyl-3-propionyl-4-(o-
tolylamino)benzoate (3e): yellow solid (136 mg, 80%); mp 146−
148 °C; 1H NMR (CDCl3, 600 MHz) δ 1.05 (t, J = 7.2 Hz, 3H), 1.85
(s, 3H), 2.34 (s, 3H), 2.45 (s, 3H), 2.95 (q, J = 7.2 Hz, 2H), 3.98 (s,
3H), 6.38 (d, J = 6.6 Hz, 1H), 6.84 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.2
Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 11.91 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 9.0, 16.2, 17.9, 19.7, 37.5, 52.3, 109.5,
116.5, 118.5, 121.1, 122.9, 126.4, 126.6, 130.5, 142.5, 143.6,
+
171.3, 208.0; HRMS (ESI-TOF) calcd for C21H26NO4 ([M + H]+)
356.1856, found 356.1864.
Ethyl 3-hydroxy-6-methyl-4-propionyl-5-(p-tolylamino)-
biphenyl-2-carboxylate (3m): yellow solid (159 mg, 76%); mp
1
1
+
118−120 °C; H NMR (CDCl3, 500 MHz) δ H NMR (CDCl3, 600
MHz) δ 0.70 (t, J = 7.5 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H), 1.57 (s, 3H),
2.27 (s, 3H), 3.03 (q, J = 7.0 Hz, 2H), 3.90 (q, J = 7.0 Hz, 2H), 6.69
(d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.5 Hz, 2H),
7.34 (t, J = 7.0 Hz, 3H), 8.34 (s, 1H), 12.02 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 8.8, 12.9, 17.7, 20.6, 37.7, 60.9, 107.7, 118.6
(2C), 122.1, 126.7, 127.8 (2C), 128.2 (2C), 128.5, 129.6 (2C), 131.0,
141.2, 141.9, 146.3, 147.5, 160.3, 171.1, 207.7; HRMS (ESI-TOF)
145.7, 160.2, 171.9, 207.7; HRMS (ESI-TOF) calcd for C20H24NO4
([M + H]+) 342.1700, found 342.1702.
Methyl 4-(2,4-dimethylphenylamino)-2-hydroxy-5,6-di-
methyl-3-propionylbenzoate (3f): yellow solid (139 mg, 78%);
1
mp 179−181 °C; H NMR (CDCl3, 500 MHz) δ 1.05 (t, J = 7.0 Hz,
3H), 1.82 (s, 3H), 2.25 (s, 3H), 2.31 (s, 3H), 2.44 (s, 3H), 2.95 (q, J =
7.0 Hz, 2H), 3.98 (s, 3H), 6.30 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.5 Hz,
1H), 6.98 (d, J = 5.0 Hz, 1H), 7.95 (s, 1H), 11.96 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 9.0, 16.3, 18.0, 19.8, 20.6, 37.5, 52.2, 108.9,
117.2, 118.0, 122.4, 126.8, 127.1, 130.8, 131.3, 140.1, 143.6,
+
calcd for C26H28NO4 ([M + H]+) 418.2013, found 418.2030.
2-Hydroxy-5,6-dimethyl-N-phenyl-3-propionyl-4-(p-
tolylamino)benzamide (3n): yellow solid (143 mg, 71%); mp 193−
195 °C; 1H NMR (CDCl3, 500 MHz) δ 0.99 (t, J = 7.0 Hz, 3H), 2.04
(s, 3H), 2.26 (s, 3H), 2.41 (s, 3H), 2.93 (q, J = 7.0 Hz, 2H), 6.13
(s, 1H), 6.56 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 7.17(t, J =
7.5 Hz, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.66
(s, 1H), 11.81 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 9.0, 14.3, 18.6,
20.5, 36.1, 115.4 (2C), 117.2, 120.1 (2C), 121.6, 123.9, 124.7, 129.1
(2C), 129.7, 130.1 (2C), 137.7, 141.6, 142.6, 142.7, 156.4, 166.3,
+
146.4, 160.4, 172.0, 207.7; HRMS (ESI-TOF) calcd for C21H26NO4
([M + H]+) 356.1856, found 356.1866.
Methyl 2-hydroxy-4-(4-methoxyphenylamino)-5,6-dimeth-
yl-3-propionylbenzoate (3g): yellow solid (143 mg, 80%); mp
200−202 °C; 1H NMR (CDCl3, 500 MHz) δ 1.06 (t, J = 7.5 Hz, 3H),
1.88 (s, 3H), 2.43 (s, 3H), 2.97 (q, J = 7.5 Hz, 2H), 3.76 (s, 3H), 3.97
(s, 3H), 6.66 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 8.13
(s, 1H), 11.94 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 9.0, 16.3, 19.7,
37.6, 52.2, 55.5, 109.0, 114.4 (2C), 117.7, 119.8 (2C), 122.0, 137.8,
143.8, 146.2, 154.6, 160.4, 171.9, 207.8; HRMS (ESI-TOF) calcd for
+
208.7; HRMS (ESI-TOF) calcd for C25H27N2O3 ([M + H]+)
403.2016, found 403.2028.
+
C20H24NO5 ([M + H]+) 358.1649, found 358.1670.
2-Hydroxy-5,6-dimethyl-3-propionyl-N-p-tolyl-4-(p-
tolylamino)benzamide (3o): yellow solid (156 mg, 75%); mp 190−
192 °C; 1H NMR (CDCl3, 500 MHz) δ 0.99 (t, J = 7.0 Hz, 3H), 2.03
(s, 3H), 2.26 (s, 3H), 2.35 (s, 3H), 2.41 (s, 3H), 2.93 (q, J = 7.0 Hz,
Methyl 2-hydroxy-5,6-dimethyl-4-(naphthalen-1-ylamino)-
3-propionylbenzoate (3h): yellow solid (132 mg, 70%); mp 114−
116 °C; 1H NMR (CDCl3, 500 MHz) δ 1.03 (t, J = 7.5 Hz, 3H), 1.85
5176
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The Journal of Organic Chemistry
Note
2H), 6.19 (s, 1H), 6.56 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.5 Hz, 2H), 7.18
(d, J = 7.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 11.76 (s, 1H);
13C NMR (CDCl3, 150 MHz) δ 9.0, 14.4, 18.7, 20.5, 20.9, 36.2, 115.4
(2C), 117.4, 120.2 (2C), 121.5, 124.1, 129.6 (2C), 129.8, 130.1 (2C),
134.4, 135.2, 141.6, 142.4, 142.7, 156.4, 166.4, 208.7; HRMS (ESI-TOF)
calcd for C26H29N2O3+ ([M + H]+) 417.2173, found 417.2190.
syringe, and the reaction mixture was stirred at 80 °C for 10 h. After 1b was
consumed (monitored by TLC), the reaction mixture was poured into
water (25 mL) and extracted with CH2Cl2 (10 mL × 3). The combined
organic extracts were dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure to yield the corresponding crude product,
which was purified by silica gel chromatography (petroleum ether/acetone =
3/1, v/v) to give 5b (118 mg, 90%) as a white solid.
4-(4-Chlorophenylamino)-6-ethyl-3-methyl-2H-pyran-2-one
(5b): white solid (158 mg, 90%); mp 195−197 °C; 1H NMR (CDCl3,
500 MHz) δ 1.15 (t, J = 7.5 Hz, 3H), 2.01 (s, 3H), 2.41 (q, J = 7.5 Hz,
2H), 5.85 (s, 1H), 6.18 (s, 1H), 7.09 (d, J = 8.5 Hz, 2H), 7.37 (t, J = 8.5
Hz, 2H),; 13C NMR (CDCl3, 125 MHz) δ 9.3, 11.2, 27.1, 94.4, 94.6, 125.5
(2C), 129.7 (2C), 131.1, 137.0, 151.9, 164.5, 165.3; HRMS (ESI-TOF)
calcd for C14H15ClNO2+ ([M + H]+) 264.0786, found 264.0785.
General Procedure for the Preparation of 6 (6d as Example).
To a solution of phenol 3d (0.5 mmol, 171 mg) in 1,2-dichloroethane
(3.0 mL) was added In(OTf)3 (22.5 mg, 0.04 mmol) in one portion.
Then the reaction mixture was heated at reflux for 10 h until compound 3d
was consumed (monitored by TLC). The reaction mixture was poured into
water (25 mL) and extracted with CH2Cl2 (10 mL × 3). The combined
organic extracts were dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure to yield the corresponding crude product,
which was purified by silica gel chromatography (petroleum ether/acetone
= 30/1, v/v) to give 6d (152 mg, 94%) as a yellow solid.
2-Hydroxy-5,6-dimethyl-3-propionyl-4-(p-tolylamino)-
1
benzamide (3p): yellow solid (111 mg, 68%); mp 131−133 °C; H
NMR (DMSO-d6, 500 MHz) δ 0.84 (t, J = 7.25 Hz, 3H), 1.89 (s, 3H),
2.14 (s, 3H), 2.19 (s, 3H), 2.70 (q, J = 7.5 Hz, 2H), 6.38 (d, J = 8.5
Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 7.55 (s, 2H), 7.71 (s, 1H), 10.47 (s,
1H); 13C NMR (DMSO-d6, 150 MHz) δ 8.4, 14.2, 17.7, 20.1, 36.0,
113.6 (2C), 122.1, 124.3, 125.1, 126.3, 129.6 (2C), 138.5, 138.7,
+
144.1, 152.0, 169.4, 207.0; HRMS (ESI-TOF) calcd for C19H23N2O3
([M + H]+) 327.1703, found 327.1709.
1-(3-Benzoyl-2-hydroxy-4,5-dimethyl-6-(p-tolylamino)-
phenyl)propan-1-one (3q): yellow solid (124 mg, 64%); mp 135−
137 °C; 1H NMR (CDCl3, 500 MHz) δ 1.12 (t, J = 7.5 Hz, 3H), 1.57
(s, 3H), 1.69 (s, 3H), 2.29 (s, 3H), 3.06 (q, J = 7.5 Hz, 2H), 6.78 (d,
J = 7.0 Hz, 2H), 7.06 (d, J = 7.5 Hz, 2H), 7.20 (d, J = 6.5 Hz, 2H),
7.42 (t, J = 7.0 Hz, 3H), 9.12 (s, 1H), 13.77 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 8.9, 18.4, 20.7, 31.4, 37.9, 116.3, 117.2, 119.5
(2C), 120.5, 128.3 (2C), 128.7 (2C), 129.6, 129.7 (2C), 131.7, 140.7,
141.0, 147.8, 148.4, 162.5, 205.7, 207.6; HRMS (ESI-TOF) calcd for
+
C25H26NO3 ([M + H]+) 388.1907, found 388.1914.
Methyl 7-chloro-9-ethyl-1-hydroxy-3,4-dimethylacridine-2-
carboxylate (6b): yellow solid (160 mg, 93%); mp 168−170 °C;
1H NMR (CDCl3, 500 MHz) δ 1.50 (t, J = 7.0 Hz, 3H), 2.60 (s, 3H),
Methyl 2-hydroxy-5,6-dimethyl-4-(piperidin-1-yl)-3-propio-
1
nylbenzoate (3r): yellow solid (96 mg, 60%); mp 152−154 °C; H
NMR (CDCl3, 500 MHz) δ 1.23 (t, J = 7.5 Hz, 3H), 1.59 (s, broad,
6H), 2.18 (s, 3H), 2.43 (s, 3H), 2.88 (q, J = 7.5 Hz, 2H), 2.93
(s, broad, 4H), 3.95 (s, 3H), 10.91 (s, 1H); 13C NMR (CDCl3, 125
MHz) δ 8.1, 15.2, 19.5, 24.2, 26.6 (2C), 38.2, 52.2 (3C), 109.9, 125.7,
126.8, 140.9, 153.6, 156.7, 171.7, 207.6; HRMS (ESI-TOF) calcd for
2.77 (s, 3H), 3.88 (q, J = 6.5 Hz, 2H), 4.03 (s, 3H), 7.66 (d, J = 9.0
Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 8.26 (s, 1H), 13.20 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 14.0, 16.0, 20.2, 24.1, 52.4, 106.8, 116.7,
123.2, 125.5, 126.5, 131.1, 131.5, 132.3, 134.5, 147.4, 150.2, 152.6,
162.8, 173.6; HRMS (ESI-TOF) calcd for C19H19ClNO3+ ([M + H]+)
344.1048, found 344.1050.
+
C18H26NO4 ([M + H]+) 320.1856, found 320.1868.
Procedure for Preparation of 4 (4b, for Example). An oven-
dried Schlenck tube charged with 3-aminocyclobutenone 1b
(0.5 mmol, 132 mg) and a magnetic bar was evacuated and refilled
with N2 three times. Then LDA (1.0 mmol, 0.12 mL) and 2 mL of
dried THF were injected under N2 via syringe, and the reaction
mixture was stirred at 80 °C for 10 h. After completion of the reaction
(monitored by TLC), the reaction mixture was poured into water
(30 mL) and extracted with CH2Cl2 (10 mL × 3). The combined organic
extracts were dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to yield the corresponding crude product, which
was purified by silica gel chromatography (petroleum ether/acetone =
8/1, v/v) to give 4b (137 mg, 75%) as a white solid.
Methyl 9-ethyl-1-hydroxy-3,4-dimethylacridine-2-carboxy-
1
late (6c): yellow solid (148 mg, 96%); mp 139−141 °C; H NMR
(CDCl3, 500 MHz) δ 1.52 (t, J = 7.5 Hz, 3H), 2.61 (s, 3H), 2.80
(s, 3H), 3.95 (q, J = 7.5 Hz, 2H), 4.02 (s, 3H), 7.52 (t, J = 7.0 Hz,
1H), 7.75 (t, J = 7.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 9.0
Hz, 1H), 13.24 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.1, 16.1,
20.2, 24.1, 52.3, 106.2, 116.3, 124.5, 125.1, 125.3, 126.4, 130.5, 130.6,
134.0, 149.2, 150.2, 153.6, 163.2, 173.7; HRMS (ESI-TOF) calcd for
+
C19H20NO3 ([M + H]+) 310.1438, found 310.1448.
Methyl 9-ethyl-1-hydroxy-3,4,7-trimethylacridine-2-carbox-
1
ylate (6d): yellow solid (152 mg, 94%); mp 155−157 °C; H NMR
(CDCl3, 500 MHz) δ 1.51 (t, J = 7.0 Hz, 3H), 2.60 (s, 6H), 2.79
(s, 3H), 3.93 (q, J = 6.5 Hz, 2H), 4.02 (s, 3H), 7.59 (d, J = 9.0 Hz,
1H), 8.05 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 13.19 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 14.0, 16.0, 20.1, 22.2, 23.9, 52.1, 106.3, 116.4,
122.8, 125.1, 126.5, 130.4, 133.1, 133.4, 134.9, 148.1, 149.8, 152.3,
(E)-3-(4-Chlorophenylamino)-N,N-diisopropyl-2-propionyl-
pent-2-enamide (4b): white solid (137 mg, 75%); mp 136−138 °C;
1H NMR (CDCl3, 500 MHz) δ 0.97 (t, J = 7.5 Hz, 3H), 1.11 (t, J =
7.5 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H), 1.49 (d, J =
6.5 Hz, 3H), 1.52 (d, J = 6.5 Hz, 3H), 2.27−2.40 (m, 3H), 2.61 (q, J =
7.5 Hz, 1H), 3.47 (q, J = 7.0 Hz, 1H), 4.23 (q, J = 6.5 Hz, 1H), 7.08 (d, J =
8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 12.94 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 8.8, 12.3, 19.9, 20.2, 20.8, 21.0, 22.9, 32.3, 45.7, 51.0, 109.2,
126.8 (2C), 129.4 (2C), 131.7, 137.2, 162.7, 169.1, 197.8; HRMS (ESI-
TOF) calcd for C20H30ClN2O2+ ([M + H]+) 365.1990, found 365.1996.
(E)-N,N-Diisopropyl-2-propionyl-3-(p-tolylamino)pent-2-en-
+
163.1, 173.7; HRMS (ESI-TOF) calcd for C20H22NO3 ([M + H]+)
324.1594, found 324.1609.
General Procedure for Preparation of 8 (8d, for Example).
To a solution of phenol 3d (0.5 mmol, 171 mg) in CH3OH (5.0 mL)
was added NaBH4 (0.5 mmol, 19 mg) in one portion. The reaction
mixture was stirred for 2 h at room temperature until 3d was consumed
(monitored by TLC). Then BF3·OEt2 (0.5 mmol, 0.062 mL) was added,
and the mixture was stirred at 50 °C for 15 min. After completion of the
reaction (monitored by TLC), the reaction mixture was poured into water
(25 mL) and extracted with CH2Cl2 (10 mL × 3). The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to yield the corresponding crude product, which
was purified by silica gel chromatography (petroleum ether/acetone =
1/1, v/v) to give 8d (154 mg, 95%) as a white solid.
Methyl 7-chloro-9-ethyl-1-hydroxy-3,4-dimethyl-9,10-dihy-
droacridine-2-carboxylate (8b): white solid (164 mg, 95%); mp
190−192 °C; 1H NMR (CDCl3, 500 MHz) δ 0.77 (t, J = 7.0 Hz, 3H),
1.60−1.74 (m, 2H), 2.16 (s, 3H), 2.48 (s, 3H), 3.94 (s, 3H), 4.34 (t,
J = 6.0 Hz, 1H), 6.28 (s, 1H), 6.72 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 8.5
Hz, 1H), 7.15 (s, 1H), 11.60 (s, 1H); 13C NMR (CDCl3, 125 MHz)
δ 9.9, 12.4, 19.1, 30.5, 36.4, 51.7, 105.6, 107.5, 111.3, 115.1, 126.1, 126.3,
1
amide (4d): white solid (138 mg, 80%); mp 100−102 °C; H NMR
(CDCl3, 500 MHz) δ 0.96 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 6.5 Hz, 6H),
1.16 (d, J = 6.5 Hz, 3H), 1.48 (d, J = 6.5 Hz, 3H), 1.52 (d, J = 6.5 Hz,
3H), 2.21−2.32 (m, 2H), 2.34 (s, 3H), 2.35−2.42 (m, 1H), 2.60 (q,
J = 7.0 Hz, 1H), 3.45 (q, J = 7.0 Hz, 1H), 4.26 (q, J = 6.5 Hz, 1H),
7.03 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 12.93 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 8.9, 12.4, 19.9, 20.2, 20.9, 21.0 (2C), 23.0,
32.2, 45.6, 50.9, 108.3, 125.7 (2C), 129.8 (2C), 135.7, 136.1, 163.7,
+
169.5, 197.0; HRMS (ESI-TOF) calcd for C21H33N2O2 ([M + H]+)
345.2537, found 345.2552.
Procedure for Preparation of 5b. An oven-dried Schlenck tube
charged with 3-aminocyclobutenone 1b (0.5 mmol, 132 mg), NaOH
(1.0 mmol, 40 mg), and a magnetic bar was evacuated and refilled with
N2 three times. Then 2 mL of dried THF was injected under N2 via
5177
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The Journal of Organic Chemistry
Note
126.6, 128.7, 137.1, 137.2, 142.6, 158.6, 172.6; HRMS (ESI-TOF) calcd for
C19H21ClNO3+ ([M + H]+) 346.1204, found 346.1219.
Methyl 9-ethyl-1-hydroxy-3,4-dimethyl-9,10-dihydroacri-
dine-2-carboxylate (8c): white solid (151 mg, 97%); mp 201−203 °C;
1H NMR (CDCl3, 500 MHz) δ 0.76 (t, J = 7.5 Hz, 3H), 1.63−1.72
Cha, D. D.; Danheiser, R. L. Org. Lett. 2000, 2, 3407−3410.
(d) Auvinet, A.-L.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2011, 50,
2769−2772. (e) Kondo, T.; Niimi, M.; Nomura, M.; Wada, K.;
Mitsudo, T. Tetrahedron Lett. 2007, 48, 2837−2839.
(8) For selected recent reports, see: (a) Li, Y.; Xu, X.; Tan, J.; Xia, C.;
Zhang, D.; Liu, Q. J. Am. Chem. Soc. 2011, 133, 1775−1777. (b) Tan,
J.; Xu, X.; Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009, 48,
2868−2872. (c) Wang, H.; Zhao, Y.-L.; Ren, C.-Q.; Diallo, A.; Liu, Q.
Chem. Commun. 2011, 47, 12316−12308.
(9) For recent reviews on benzannulation reactions, see: (a) Galan,
B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830−2834.
(b) Domínguez, G.; Perez-Castells, J. Chem. Soc. Rev. 2011, 40, 3430−
́
3444 ([2 + 2 + 2] cycloadditions). (c) Feist, H.; Langer, P. Synthesis
2007, 327−347 ([3 + 3] cyclizations). (d) van Otterlo, W. A. L.;
de Koning, C. B. Chem. Rev. 2009, 109, 3743−3782 (metathesis).
(e) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901−2915.
(f) Kotha, S.; Misra, S.; Halder, S. Tetrahedron 2008, 64, 10775−10790.
(10) For selected reports on [4 + 2] benzannulation reactions, see:
(a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.; Tando, K.;
Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 3970−3971. (b) Rubina,
M.; Conley, M.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 5818−
5827. (c) Kraus, G. A.; Riley, S.; Cordes, T. Green Chem. 2011, 13,
2734−2736. (d) Gevorgyan, V.; Takeda, A.; Yamamoto, Y. J. Am. Chem.
Soc. 1997, 119, 11313−11314. (e) Danheiser, R. L.; Gould, A. E.; de la
Pradilla, R. F.; Helgason, A. L. J. Org. Chem. 1994, 59, 5514−5515.
(11) For preparation of 3-aminocyclobutenones, see: Zhao, Y.-L.;
Yang, S.-C.; Di, C.-H.; Han, X.-D.; Liu, Q. Chem. Commun. 2010, 46,
7614−7616.
(m, 2H), 2.17 (s, 3H), 2.48 (s, 3H), 3.94 (s, 3H), 4.36 (t, J = 6.5 Hz,
1H), 6.30 (s, 1H), 6.79 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 7.0 Hz, 1H),
7.15 (d, J = 6.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 11.61 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ 10.2, 12.5, 19.2, 30.6, 36.5, 51.7,
105.4, 108.2, 111.3, 114.0, 121.6, 124.6, 126.7, 129.1, 136.9, 138.5,
+
143.1, 158.7, 172.7; HRMS (ESI-TOF) calcd for C19H22NO3 ([M +
H]+) 312.1594, found 312.1590.
Methyl 9-ethyl-1-hydroxy-3,4,7-trimethyl-9,10-dihydroacri-
dine-2-carboxylate (8d): white solid (154 mg, 95%); mp 195−197 °C;
1H NMR (CDCl3, 500 MHz) δ 0.75 (t, J = 7.5 Hz, 3H), 1.59−1.73 (m,
2H), 2.16 (s, 3H), 2.31 (s, 3H), 2.47 (s, 3H), 3.93 (s, 3H), 4.33 (t, J =
6.5 Hz, 1H), 6.23 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz,
1H), 6.99 (s, 1H), 11.62 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 10.1,
12.5, 19.2, 20.8, 30.7, 36.4, 51.7, 105.1, 108.0, 111.2, 113.9, 124.6, 127.2,
129.5, 130.9, 136.2, 136.8, 143.4, 158.8, 172.7; HRMS (ESI-TOF) calcd for
C20H24NO3+ ([M + H]+) 326.1751, found 326.1750.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 3−6 and 8. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(12) For selected recent reports on the synthesis of substituted
anilines, see: (a) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem.
Soc. 2006, 128, 4586−4587. (b) Zhang, K.; Louie, J. J. Org. Chem.
2011, 76, 4686−4691. (c) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem.
Soc. 2005, 127, 5776−5777. (d) Stoll, A. H.; Knochel, P. Org. Lett.
2008, 10, 113−116 (fully substituted anilines).
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supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
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AUTHOR INFORMATION
Corresponding Author
*E-mail: zhaoyl351@nenu.edu.cn, liuqun@nenu.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Sciences
Foundation of China (21172032 and 20972026) is gratefully
acknowledged.
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