Synthesis of Dihydroanthracenes via Palladium-Catalyzed Tandem Mizoroki-Heck/Reductive Heck Reactions Using Cyclic Diaryliodoniums and Alkenes

Article abstract of DOI:10.1055/a-1343-5455

An efficient Pd-catalyzed domino Mizoroki-Heck and reductive Heck reaction of terminal alkenes with six-membered cyclic diaryliodoniums is reported for the facile access to a diverse set of novel dihydroanthracenes. The scope of alkenes is general, leading to concise generation of 30 dihydroanthracenes which are not easily accessed by conventional methods. Furthermore, one of the newly synthesized dihydroanthracene displayed excellent antiproliferative activity against PANC-1 cancer cells (IC ₅₀= 11.74 μM).

Full text of DOI:10.1055/a-1343-5455

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 636–640
letter
636
en
X. Peng et al.
Letter
Synlett
Synthesis of Dihydroanthracenes via Palladium-Catalyzed Tandem
Mizoroki–Heck/Reductive Heck Reactions Using Cyclic Diaryliodo-
niums and Alkenes
Xiaopeng Peng*
30 examples
Pd(0)
R1
R2
Jianfeng Yang
Xinhua Qiu
R1
R2
+
R
High functional-group tolerance
I
Two cycles of Heck reaction
Anticancer activity
OTf
R = alkyl, aryl
Yuansheng Duan
Zeqing Bao
R
Jingfeng Chen
School of Pharmaceutical Sciences, Zhaoqing Medical College,
Zhaoqing 526000, P. R. of China
pengxp12345@163.com
H
N
CN
COOEt
PANC-1 IC50 = 16.37 mM
O
PANC-1 IC50 = 11.74 mM
HCT116 IC50 = 19.68 mM
XSecMiahaooipColeolpnroergfnePgPshpxeaopnr1ngmd23ianc4ge5uA@tu1ict6ah3lo.Scrcoimences, Zhaoqing Medical College, Zhaoqing 526000, P. R. of China
Received: 31.10.2020
Accepted after revision: 28.12.2020
Published online: 28.12.2020
OH
O
O
HN
HN
N
H
OH
OH
OH
O
O
OH
DOI: 10.1055/a-1343-5455; Art ID: St-2020-u0578-l
COOH
H
N
OH
Abstract An efficient Pd-catalyzed domino Mizoroki–Heck and re-
ductive Heck reaction of terminal alkenes with six-membered cyclic dia-
ryliodoniums is reported for the facile access to a diverse set of novel
dihydroanthracenes. The scope of alkenes is general, leading to concise
generation of 30 dihydroanthracenes which are not easily accessed by
conventional methods. Furthermore, one of the newly synthesized di-
hydroanthracene displayed excellent antiproliferative activity against
PANC-1 cancer cells (IC50 = 11.74 M).
1b
mitoxantrone
1a
rhein
O
OH
O
HO
O
O
OH
OH
OH
O
H
HO
OH
O
O
OH
O
O
Key words cyclic diaryliodoniums, terminal alkenes, dihydroanthra-
1c
cenes, Heck reaction
1d
doxorubicin
NH2
topopyrone C
Figure 1 Representative compounds containing anthracene
Anthracene-based derivatives are essential structural
motifs in a great number of anticancer drugs,1 organic func-
tional materials,2 and natural products.3 For instance, rhein
(1a) possesses an anthracene scaffold and exhibits an excel-
lent anti-inflammatory activity4 (Figure 1). Just like other
anthracene-based compounds, there are several anthra-
cene-based drugs such as mitoxantrone (1b), topopyrone C
(1c), and doxorubicin (1d) with anticancer activities proba-
bly due to their noncovalent binding to DNA duplexes and
these drugs are used for treatment of various cancers5 (Fig-
ure 1). In recent years, some studies have found that an-
thracene-based derivatives can also be used as an effective
antidepressant with similar pharmacological properties to
tricyclic antidepressants (TCAs).6
Thus, the synthesis of various anthracenes had attracted
extensive attention by organic chemists and medicinal
chemists. A variety of synthetic methods have been devel-
oped to construct dihydroanthracene scaffolds over the
past few years, including benzylation of arenes,7 modifica-
tion of the existing dihydroanthracenes core,8 and Friedel–
Crafts alkylation9 (Scheme 1a and 1b). However, these pres-
ent methods still have some challenges that need to be ad-
dressed, including harsh conditions, limited substrate
scopes, poor accessibility of starting materials, and low
yields. In the past decades, cyclic diaryliodonium salts have
found numerous applications as electrophilic arylating re-
agents in both transition-metal-catalyzed and metal-free
reactions to construct diverse arenes or heterocycles due to
their high reactivity and environmentally benign nature.10
In our previous study, we demonstrated that dual aryla-
tion of dicarbonyl and C–N Buchwald coupling of nitriles
with cyclic diaryliodonium salts could lead to the construc-
tion of fluorenes and acridines conveniently.11 To continue
our interest in constructing libraries of complex molecules
with cyclic diaryliodonium salts, we envisioned that the
careful modulation of two tandem Mizoroki–Heck reac-
tions including one conventional Mizoroki–Heck reaction
and one reductive Heck reaction between terminal alkenes
and six-membered cyclic diaryliodonium salts could pro-
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 636–640
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

637
X. Peng et al.
Letter
Synlett
Previous work
Et3SiH
DCE
R2
R1
a
b
+
R2
R1
CF3
H2
organolithium reagent
R2
R2
R1
R1
Current work
Pd(PPh3)4
R1
R2
R2
R1
R3
R3 = alkyl, aryl
c
+
Et3N/HCOONa
DCE, 100 °C
I
OTf
R3
Scheme 1 The strategies to build dihydroanthracenes
vide an alternative route to dihydroanthracenes. Herein, we
report an efficient access to modularly generate 9,10-dihy-
droanthracenes from six-membered cyclic diaryliodonium
salts with terminal alkenes, catalyzed by Pd(PPh3)4 (Scheme
1c).
Table 1 Optimization of Reaction Conditionsa
O
[Pd]
+
OMe
OMe
base, solvent
I
To test our hypothesis, we initiated the investigation by
reacting the readily available methyl acrylate 3a with six-
membered cyclic diaryliodonium salts 2a using Pd(OAc)2 as
a catalyst and Na2CO3 as the base in DMF under an argon at-
mosphere at 120 °C (Table 1). The reaction provided the de-
sired dihydroanthracene 4a albeit in 6% yield (entry 1). We
then undertook some optimization mainly by changing dif-
ferent palladium species (entries 2–4). When Pd(PPh3)4 was
employed, to our delight the desired compound 4a was ob-
tained with a relatively high yield (16%). Next a base screen-
ing was carried out to optimize the yield (entries 5–8), and
it was found that the yield could be improved to 39% with
trimethylamine as the base source. From these observa-
tions, the base has an apparently influence on the reaction.
Due to the reductive property of HCOONa to accelerate re-
ductive Heck reaction, not surprisingly, its addition in-
creased the yield significantly (entries 9 and 10). Thus, the
Et3N/HCOONa system was selected for further optimization
of reaction conditions (entry 10). The influence of the sol-
vents was then studied (entries 11–14). We found the yield
was improved to 69% by using 1,2-dichloroethane (DCE) as
the solvent, and we were surprised to observe that no de-
sired product was generated in the presence of MeOH as
solvent (entry 13 vs. 14). A further jump in yield could be
attained by reducing the temperature to 100 °C (78%, entry
15).
OTf
2a
O
4a
3a
Entry Catalyst
Base
Solvent
Temp (°C) Yield (%)b
1
2
Pd(OAc)2
PdCl2(dppf)2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
6
8
3
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
11
4
16
5
19
6
NaHCO3
Cs2CO3
Et3N
6
7
trace
39
8
9
Et3N/MeCOONa DMF
35
10
11
12
13
14
15
16
17
18
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
Et3N/HCOONac
DMF
48
DMSO
toluene
MeOH
DCE
39
25
trace
69
DCE
78
DCE
51
DCE
60
32
DCE
rt
trace
a Unless otherwise stated, 2a (1.0 equiv), 3a (2.0 equiv), catalyst (0.1
equiv), base (3.0 equiv), 15 h, Ar (using sealed tube).
b HPLC yield.
However, the yield was dropped to 51% and 32% by de-
creasing the temperature to 80 °C and 60 °C, respectively
(entries 16, 17). And no reaction occurred at room tempera-
ture (entry 18). Thus, the optimal catalytic system for this
c Et3N (3.0 equiv), HCOONa (2.0 equiv); note: DCE, 1,2-dichloroethane.
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 636–640

638
X. Peng et al.
Letter
Synlett
transformation was 0.1 equiv Pd(PPh3)4 and 3 equiv of Et3N
with 2.0 equiv of HCOONa in DCE at 100 °C for 15 h (using
sealed tube).
tigated (Scheme 3). To our delight, generally the styrene de-
rivatives with either simple alkyl (4m) or halogen (4o,p)
substituents all gave excellent yield. Importantly, the sub-
stitution of halogens (F, Cl) in dihydroanthracenes would
provide opportunities to further functionalize the incorpo-
rated arene if needed. In addition, due to the special proper-
ties of fluorine in drug metabolism, the incorporation of
fluorine in arene (4o) might show higher metabolic stabili-
ties and better pharmacokinetic properties. Synthetically,
both fluorinated and chlorinated species (4o,p) could un-
dergo further modifications to broaden the structural com-
plexity. Gratifyingly, even pyridine-substituted alkene also
reacted as well under the optimum conditions (4q). The
motifs of this heterocycle compound are frequently found
in polycyclic heteroarenes and natural products. More
strikingly, we were also pleased to find that alkyl alkenes
such as 4-penten-1-ol, methallyl alcohol, and vinyl carba-
mate were equally effective as the alkenes with electron-
withdrawing substituents (4r–t). The tethered hydroxyl
functional group was compatible and provided opportuni-
ties for further transformation.
With the optimal reaction conditions in hand, we next
examined the scope of this novel tandem process using a
range of commercially available terminal alkenes 3 with
different electron-withdrawing groups (Scheme 2). Yields
were generally good for terminal alkenes while alkyls in ac-
rylate esters were varied, in a range of 65–78% (4a–e). In
our method, other important materials acrolein and acryl-
amides were tolerated to give the corresponding products
in good yields (4f–i). Furthermore, acrylonitrile successfully
provided dihydroanthracenes 4j which could undergo fur-
ther transformations to build complex molecular scaffolds.
Importantly, we were also pleased to find that the sulfone
functional group was suitable in the formation of dihydro-
anthracenes 4k, albeit with lower yields. 2-Methylacrylal-
dehyde also worked smoothly and delivered the corre-
sponding product 4l. Our results demonstrated a broad sub-
strate generality of alkenes, and a variety of unique
dihydroanthracenes could be quickly afforded.
To fully establish the scopes of this one-pot C–C cou-
pling procedure, other types of alkenes were further inves-
Aryl(Alky)
OTf
I+
Pd(PPh3)4
Aryl(Alkyl)
+
Et3N/HCOONa
DCE, 100 °C
EWG
OTf
I+
2a
3
4
Pd(PPh3)4
EWG
Et3N/HCOONa
DCE, 100 °C
F
Cl
2a
3
4
O
O
O
t-Bu
OMe
OEt
O
4m 52%
4n 40%
4o 56%
4p 65%
4a
78%
O
4b
4c 71%
72%
O
O
NH2
N
OH
O
OH
O
O
Bu
H
O
4q 60%
4r 67%
4s 62%
4t 56%
4f 56%
68%
O
4d
65%
O
4e
Scheme 3 The scope of terminal arylalkenes and alkylalkenes. Re-
agents and conditions: 2a (1.0 equiv), 3 (2.0 equiv), Pd(PPh3)4 (0.1
equiv), Et3N (3.0 equiv), HCOONa (2.0 equiv), DCE (3.0 mL), 100 °C, 15
h, Ar (using sealed tube).
N
NH2
N
H
O
4h 59%
4i 61%
The scope of six-membered cyclic diaryliodonium salts
was finally investigated for this transformation (Scheme 4).
Acrylonitrile was used as alkenes source since the attached
nitriles could be further transformed. Under the standard
reaction conditions, the iodoniums with either electron-do-
nating or electron-withdrawing groups attached were all
transformed to the desired dihydroanthracenes at modest
to good yields. Initially we tested the reactions of symmet-
rical cyclic diaryliodonium salts with acrylonitrile, which
afforded the corresponding dihydroanthracenes in moder-
ate to good yields (5a–c). Next, a series of unsymmetrical
4g 57%
O
O
S
O
CN
4j 69%
62%
4k
4l
52%
Scheme 2 The scope of ,-unsaturated alkenes. Reagents and condi-
tions: 2a (1.0 equiv), alkene 3 (2.0 equiv), Pd(PPh3)4 (0.1 equiv), Et3N
(3.0 equiv), HCOONa (2.0 equiv), DCE (3.0 mL), 100 °C, 15 h, Ar (using
sealed tube).
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 636–640

639
X. Peng et al.
Letter
Synlett
cyclic diaryliodonium salts were examined (5d–l). It was
found that both electron-donating groups and electron-
withdrawing substituents on cyclic diaryliodonium salts
reacted smoothly, although the yield was decreased when
the electronically poor substituted unsymmetrical cyclic di-
aryliodonium salts were employed (5d–h).
Table 2 In Vitro Antiproliferative Activity of the Dihydroanthracenes
Com-
IC50 (M ± SEM)
pound
PANC-1
Capan-2
HCT116
HL-60
4a
4b
4h
4j
19.48 ± 2.10
16.37 ± 2.36
>100
25.29 ± 3.62
34.57 ± 3.58
21.30 ± 4.69
26.18 ± 4.58
>100
49.31 ± 1.90
36.77 ± 4.25
19.68 ± 2.51
>100
>100
>100
NC
OTf
I+
33.28 ± 4.83
77.58 ± 6.55
51.22 ± 7.61
26.21 ± 7.32
51.29 ± 6.56
22.25 ± 1.31
Pd(PPh3)4
11.74 ± 3.29
23.24 ± 5.30
18.35 ± 5.27
16.33 ± 3.21
9.08 ± 2.76
R1
CN
NC
R2
R2
R1
+
Et3N/HCOONa
DCE, 100 °C
4q
4s
36.50 ± 5.69
>100
2
3
5
46.55 ± 6.74
31.40 ± 4.28
32.40 ± 3.70
5h
5-Fu
>100
NC
NC
10.59 ± 9.53
F
F
Cl
Cl
involved one conventional Mizoroki–Heck reaction and one
reductive Heck reaction between cyclic iodoniums and ter-
minal alkenes. Except traditional acrylates and alkenes with
-electron-withdrawing functional groups, both aryl
alkenes and alkyl alkenes are suitable. The present method
is straightforward for the diversified synthesis of dihydro-
anthracenes, providing a complementary strategy to the re-
ported synthetic routes. More importantly, the screening of
our new synthetic dihydroanthracenes successfully leads to
the discovery of several novel compounds with potent anti-
proliferative activities.
5a 67%
NC
5c 61%
5b 59%
NC
NC
F
5e 66%
5d 60%
5f 67%
NC
NC
NC
OCF3
MeO
OMe
5g 72%
NC
5h 65%
5i 71%
NC
NC
CF3
COOMe
Funding Information
This work was supported by the Guangdong Provincial Department of
Education Youth Innovation Talents Project (2017GkQNCX099) and
the Guangdong Medical Research Foundation (A2018497), P. R. of Chi-
5k 56%
5j 70%
5l 51%
Scheme 4 The scope of cyclic iodoniums. Reagents and conditions: 2
(1.0 equiv), alkene 3 (2.0 equiv), Pd(PPh3)4 (0.1 equiv), Et3N (3.0 equiv),
HCOONa (2.0 equiv), DCE (3.0 mL), 100 °C, 15 h, Ar (using sealed tube).
na.
G
ua
n
g
d
o
n
g
Me
d
i
cal
R
esearchFo
u
n
dation(A
2
0
1
8
4
9
7)
Supporting Information
Supporting information for this article is available online at
Based on our observation and previous literature, a pos-
sible reaction mechanism was proposed in Scheme S1 (see
the Supporting Information). As mentioned above, many
dihydroanthracene-containing motifs possess anticancer
properties due to their noncovalent binding to DNA duplex-
es. Therefore, the biological applications of the products
were also investigated using a well-established MTT assay
(Table 2). To our delight, several new synthesized com-
pounds displayed potent antiproliferative activities against
the human cancer cell lines. Among them, 4j displayed the
highest cytotoxicity against PANC-1 cell (IC50 = 11.74 M).
Further structural optimization and structure–activity rela-
tionship study of these new scaffolds are currently in prog-
ress.
https://doi.org/10.1055/a-1343-5455. Su
p
p
orti
n
gInformatio
n
Su
p
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ortingInformatio
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References and Notes
(1) (a) Pommier, Y.; Leo, E.; Zhang, H.; Marchand, C. Chem. Biol.
2010, 17, 421. (b) Tikhomirov, A. S.; Shtil, A. A.; Shchekotikhin,
A. E. Recent Pat. Anticancer Drug Discov. 2018, 13, 159. (c) Malik,
E. M.; Müller, C. E. Med. Res. Rev. 2016, 36, 705. (d) Badria, F. A.;
Ibrahim, A. S. Drug Discov. Ther. 2013, 7, 84.
(2) (a) Matsuo, Y.; Okada, H.; Kondo, Y.; Jeon, I.; Wang, H.; Yu, Y.;
Matsushita, T.; Yanai, M.; Ikuta, T. ACS Appl. Mater. Interfaces
2018, 10, 11810. (b) Haldar, S.; Chakraborty, D.; Roy, B.;
Banappanavar, G.; Rinku, K.; Mullangi, D.; Hazra, P.; Kabra, D.;
Vaidhyanathan, R. J. Am. Chem. Soc. 2018, 140, 13367. (c) Fonari,
A.; Corbin, N. S.; Vermeulen, D.; Goetz, K. P.; Jurchescu, O. D.;
McNeil, L. E.; Bredas, J. L.; Coropceanu, V. J. Chem. Phys. 2015,
143, 224503.
In summary, we have successfully achieved a general
and efficient one-pot procedure with six-membered cyclic
iodoniums and various commercially available terminal
alkenes for the construction of structurally diverse dihydro-
anthracenes derivatives.12 Two C–C bonds were formed and
(3) (a) Singh, A. J.; Gorka, A. P.; Bokesch, H. R.; Wamiru, A.; O’Keefe,
B. R.; Schnermann, M. J.; Gustafson, K. R. J. Nat. Prod. 2018, 81,
2750. (b) Liang, Y. K.; Yue, Z. Z.; Li, J. X.; Tan, C.; Miao, Z. H.; Tan,
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 636–640

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X. Peng et al.
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Synlett
W. F.; Yang, C. H. Eur. J. Med. Chem. 2014, 84, 505. (c) Mariani, A.;
Mai, T. T.; Zacharioudakis, E.; Hienzsch, A.; Bartoli, A.; Caneque,
T.; Rodriguez, R. Chem. Commun. 2016, 52, 1358.
(12) Procedure to Synthesize Dihydroanthracene 4a
To a seal tube was added cyclic diaryliodonium salt 2a (0.1 g,
0.226 mmol, 1.0 equiv), methyl acrylate 3a (0.039 g, 0.45 mmol,
2.0 equiv), Pd(PPh3)4 (0.026 g, 0.022 mmol, 0.1 equiv), Et3N
(0.069 g, 0.67 mmol, 3.0 equiv), HCOONa (0.031 g, 0.45 mmol,
2.0 equiv), and DCE (3.0 mL). Then the tube was sealed,
degassed, and recharged with argon. The reaction proceeded at
100 °C for 15 h under argon atmosphere. The remained mixture
was extracted with DCM (20 mL), the combined organic layers
were washed with H2O (3 × 2 mL) and brine, dried over anhy-
drous Na2SO4, and evaporated in vacuo. The residue was puri-
fied by column chromatography on a silica gel (PE/EtOAc = 50:1
(4) Cannon, C. P.; Bhatt, D. L.; Oldgren, J.; Lip, G. Y. H.; Ellis, S. G.;
Kimura, T.; Maeng, M.; Merkely, B.; Zeymer, U.; Gropper, S.;
Nordaby, M.; Kleine, E.; Harper, R.; Manassie, J.; Januzzi, J. L.;
Ten Berg, J. M.; Steg, P. G.; Hohnloser, S. H. N. Engl. J. Med. 2017,
377, 1513.
(5) (a) Ye, M. Y.; Yao, G. Y.; Wei, J. C.; Pan, Y. M.; Liao, Z. X.; Wang, H.
S. Int. J. Mol. Sci. 2013, 14, 9424. (b) Yang, X.; Sun, G.; Yang, C.;
Wang, B. ChemMedChem 2011, 6, 2294. (c) Tan, J. H.; Zhang, Q.
X.; Huang, Z. S.; Chen, Y.; Wang, X. D.; Gu, L. Q.; Wu, J. Y. Eur. J.
Med. Chem. 2006, 41, 1041. (d) Shchekotikhin, A. E.; Shtil, A. A.;
Luzikov, Y. N.; Bobrysheva, T. V.; Buyanov, V. N.;
Preobrazhenskaya, M. N. Bioorg. Med. Chem. 2005, 13, 2285.
(e) Huang, Q.; Lu, G.; Shen, H. M.; Chung, M. C.; Ong, C. N. Med.
Res. Rev. 2007, 27, 609. (f) Donnelly, S.; Scott, D. L.; Emery, P.
Baillieres Clin. Rheumatol. 1992, 6, 251.
1
to 20:1) to provide compound 4a (0.036 g, 78%). H NMR (400
MHz, CDCl3):  = 7.78 (d, J = 7.6 Hz, 2 H), 7.51 (d, J = 7.6 Hz, 2 H),
7.41 (t, J = 7.2 Hz, 2 H), 7.33–7.29 (m, 2 H), 4.46 (t, J = 7.2 Hz, 1
H), 4.07 (s, 2 H), 3.81 (s, 3 H), 2.80 (d, J = 7.2 Hz, 2 H). 13C NMR
(101 MHz, CDCl3):  = 173.14, 146.39, 140.91, 127.63, 127.33,
124.47, 120.10, 51.99, 43.72, 41.79, 38.63. HRMS (ESI): m/z
calcd for C17H17O2 [M + H]+: 253.1150; found: 253.1146.
(6) Karama, U.; Sultan, M. A.; Almansour, A. I.; El-Taher, K. E. Mole-
cules 2016, 21, 61.
Procedure to Synthesize Dihydroanthracene 5a
(7) Wang, F.; Ueda, W. Chem. Eur J. 2009, 15, 742.
To a seal tube was added cyclic diaryliodonium salt 2 (0.1 g,
0.213 mmol, 1.0 equiv), acrylonitrile 3 (0.022 g, 0.426 mmol, 2.0
equiv), Pd(PPh3)4 (0.024 g, 0.021 mmol, 0.1 equiv), Et3N (0.065
g, 0.639 mmol, 3.0 equiv), HCOONa (0.029 g, 0.426 mmol, 2.0
equiv), and DCE (3.0 mL). Then the tube was sealed, degassed,
and recharged with argon. The reaction proceeded at 100 °C for
15 h under argon atmosphere. The remained mixture was
extracted with DCM (20 mL), the combined organic layers were
washed with H2O (3 × 2 mL) and brine, dried over anhydrous
Na2SO4, and evaporated in vacuo. The residue was purified by
column chromatography on a silica gel (PE/EtOAc = 50:1 to
20:1) to provide compound 5a (0.033 g, 67%). 1H NMR (400
MHz, CDCl3):  = 7.62 (d, J = 7.6 Hz, 2 H), 7.45 (d, J = 0.4 Hz, 2 H),
7.23 (d, J = 8.0 Hz, 2 H), 4.10 (t, J = 7.2 Hz, 1 H), 4.01 (s, 2 H), 2.79
(d, J = 7.2 Hz, 2 H), 2.44 (s, 6 H). 13C NMR (101 MHz, CDCl3):  =
144.22, 138.37, 137.19, 129.22, 125.09, 119.82, 118.73, 42.79,
41.75, 22.24, 21.78. HRMS (ESI): m/z calcd for C18H18N [M + H]+:
248.1361; found: 248.1375.
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