Catalyst-Free Synthesis of Aminals from Indole-Derived α,α-Dicyanoolefins

Article abstract of DOI:10.1055/s-0037-1611940

We have developed an efficient synthesis of indole fused aminals with nucleophilic imines and indole-derived α,α-dicyanoolefins via N -sulfonyl group transfer. The combination of two privileged frameworks, tetrahydroisoquinoline or tetrahydro-β-carboline

Full text of DOI:10.1055/s-0037-1611940

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
H.-L. Cui et al.
Letter
Synlett
Catalyst-Free Synthesis of Aminals from Indole-Derived α,α-Di-
cyanoolefins
Hai-Lei Cui*a
Yin Shia
Hui-Qing Denga
Jin-Ju Leia
Xing-Jie Xua,b
Xu Tianb
Jie Qiaoa
0
0
0
0-
0
0
0
2-8
2
4
8-6
6
2
7
CN
CN
CN
CN
4 Å MS, DMF, 50 °C
R1
R1
Ar
+
N
N
N
O
O
Ar
R2
S
S
O
N
R2
O
12 examples, 25–77% yield
R1 = MeO, Me, Cl, H
R2 = Ph, 4-MePh, 4-ClPh, 2-Np, n-Pr, Me
Lin Zhoua
a Laboratory of Asymmetric Synthesis, Chongqing University of
Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing,
402160, P. R. of China
cuihailei616@163.com
b Key Laboratory of Molecular Target & Clinical Pharmacology,
School of Pharmaceutical Sciences & the Fifth Affiliated Hospital,
Guangzhou Medical University, Guangzhou, Guangdong
511436, P. R. of China
Received: 14.10.2018
Accepted after revision: 26.11.2018
Published online: 19.12.2018
mation of 1,n-dipoles as key intermediates.4a,4b,4e,7 To search
approaches for the easy construction of privileged scaffold
incorporated molecules, we hypothesized that dihydroiso-
quinoline, as an electron-rich imine, may undergo 1,6-Mi-
chael addition with indole-derived electron-deficient olefin
to deliver tetrahydroisoquinoline fused carboline deriva-
tives (Scheme 1). However, instead of the desired carboline,
an unexpected indole fused aminal was obtained. Pleasing-
ly, it seems that indole-incorporated aminal is a key unit oc-
curring in plenty of natural molecules and synthetic com-
pounds possessing a wide range of activities.8 For example,
both natural (–)-Goniomitine and unnatural (+)-Goniomi-
tine show antiproliferative activity; indole alkaloid Alsto-
DOI: 10.1055/s-0037-1611940; Art ID: st-2018-v0665-l
Abstract We have developed an efficient synthesis of indole fused am-
inals with nucleophilic imines and indole-derived α,α-dicyanoolefins via
N-sulfonyl group transfer. The combination of two privileged frame-
works, tetrahydroisoquinoline or tetrahydro-β-carboline and indole, can
be realized by this approach to the construction of aminals. The syn-
thetic application of this method was further demonstrated by the
straightforward transformations into highly functionalized aminals pos-
sessing carbonyl groups through oxidative cleavage of the nitrile moiety.
Key words aminal, tetrahydroisoquinoline, tetrahydro-β-carboline,
indole, α,α-dicyanoolefin
Indole and tetrahydroisoquinoline are both privileged
frameworks that are widely present in numerous natural
products and bioactive compounds.1,2 As the combination
of privileged scaffolds acts as a useful method for creating
potential biological-related molecules for biomedical re-
search and drug discovery,3 the efficient construction of
novel molecules combining privileged frameworks is a
longstanding focus for us.4 In our previous work, we have
successfully incorporated tetrahydroisoquinoline into
spirooxindole, delivering various functionalized tetrahy-
droisoquinoline fused spirooxindoles. Along this line, we
envisioned that the synthesis of indole fused tetrahydroiso-
quinoline derivatives could be achieved by following an
electrocyclization pathway.
Our design for the combination of isoquinoline and indole moieties:
OMe
OMe
CN
CN
CN
N
CN
MeO
MeO
Catalyst-free
+
N
1,6-annulation
N
N
Ts
Ts
CN
CN
OMe
OMe
via
N
N
Ts
Unexpected aminal obtained in our study:
CN
CN
CN
MeO
MeO
CN
Catalyst-free
OMe
OMe
N
+
N
Recently, 1,n-dipole based annulation has become a
powerful strategy for the easy assembly of complex azacy-
cles.5,6 Inspired by pioneering reports,5,6 we have developed
several methods for the synthesis of nitrogen-containing
molecules from readily available material through the for-
N
Ts
N
1a
Ts
2a
3a
Scheme 1 Our design for the combination of isoquinoline and indole
moieties
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
H.-L. Cui et al.
Letter
Synlett
scholarisine A, isolated from the leaves of Alstonia scholaris,
exhibits significant ability to promote adult neural stem
cells proliferation and differentiation at low concentrations
(Figure 1). Thus, the synthesis of indole-incorporated ami-
nals has attracted much attention from the field of synthet-
ic chemistry and medicinal chemistry. A great number of
elegant methods have been developed in this regard.9,10,11
However, there is still a challenging task in the field of or-
ganic chemistry and medicinal chemistry to create more
structurally diversified aminals and to develop novel meth-
ods for the combination of privileged frameworks from
simple starting materials. Here, we report our development
of the synthesis of aminals by combining both indole and
tetrahydroisoquinoline scaffolds.
Table 1 Reaction Developmenta
CN
CN
CN
CN
MeO
OMe
OMe
+
N
N
MeO
N
Ts
N
Ts
1a
2a
3a
Entry
Ratio (1a/2a) Solvent
T (°C)
t (h)
Yield (%)b
1
2
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
3:1
DMF
PhCl
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
75
50
50
50
143
46
<5
161
161
161
161
161
106
22
3
MeOH
DCE
<5
4
<5
Me
5
MeCN
DMSO
NMP
DMF
DMF
DMF
DMF
<5
OH
H
6
<10
25
20
65
70
77
N
N
O
7
H
Me
HN
N
8
Me
(–)-Goniomitine
Alstoscholarisine A
9
24
10c
11c
24
MeOOC
N
N
14
Me
H
H
OH
a Reaction conditions: 1a (0.3 mmol), 2a (0.1 mmol), solvent (0.5 mL).
b Isolated yield.
OH
N
H
H
N
c 4 Å MS (100.0 mg) was added.
H
COOMe
N
Me
N
H
N
Alstoscholarisine H
methyl or methoxy groups at the C-5 position reacted with
imine 1a to smoothly deliver 3b and 3c in 50% and 63%
yields, respectively. In contrast, only a trace amount of 3d
HO
Cytotoxicity
1
Figure 1 Representative examples of compounds possessing an in-
was observed by H NMR analysis of the crude material,
dole-fused aminal moiety
suggesting that the electron-withdrawing substituent (Cl)
had a significant effect on the reaction. Both electron-do-
nating and electron-deficient groups substituted at the 6-
position of the indole moiety were tolerated in this process,
giving the corresponding products in 63% and 48% yield, re-
spectively (3e and 3f). The use of 6-methoxy-3,4-dihy-
droisoquinoline provided compound 3g in 61% yield; no re-
action occurred in the case of 3,4-dihydroisoquinoline as
nucleophilic imine. These results suggest that electron-do-
nating groups in the imines are critical for transfer of the
sulfonyl group. The relative configuration of 3e was con-
firmed by single-crystal X-ray analysis.12
Next, other types of sulfonyl groups were examined.
Benzenesulfonyl, naphthalenesulfonyl, 4-chlorobenzensul-
fonyl, methanesulfonyl, and propane-1-sulfonyl groups
were all tolerated in this process, affording the correspond-
ing aminals in 25–64% yields (compounds 3i–m). It is nota-
ble that tetrahydro-β-carboline could also be successfully
employed in this approach, delivering indole-incorperated
β-carboline 3n in 66% yield.
We started our investigation with the catalyst-free reac-
tion of dihydroisoquinoline 1a and 2-((1-tosyl-1H-indol-3-
yl)methylene)malononitrile (2a) at room temperature. Sur-
prisingly, what we obtained was not the designed α-carbo-
line derivative, but an indole fused aminal 3a (46% yield, Ta-
ble 1, entry 1). To develop a useful method for the straight-
forward construction of indole-incorporated aminals, we
first optimized this reaction by screening the solvent. None
of the other tested solvents (PhCl, MeOH, DCE, MeCN, DM-
SO, NMP) were effective, with only trace amounts of prod-
uct being observed (entries 2–7). Lower temperature gave
better yields; higher temperature led to the decomposition
of starting material 2a in the presence of nucleophilic imine
1a (entry 8), while the reaction at 50 °C afforded better
yield (65%; entry 9). Both using 4 Å MS as additive and in-
creasing the amount of imine improved the yield (entries
10 and 11).
With the optimized reaction conditions in hand, we
next examined the generality of this methodology. As
shown in Scheme 2, indole derived dicyano olefins bearing
To demonstrate the application of indole-fused aminals,
we further transformed the products into highly function-
alized aldehydes by oxidative cleavage of the nitrile moiety
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
H.-L. Cui et al.
Letter
Synlett
CN
CN
CN
CN
CHO
CN
CN
KMnO4, Na2SO4
MeCN
R
4 Å MS, DMF, 50 °C
OMe
OMe
N
OMe
N
N
Ar
+
R
O
N
r.t.
O
Ts
N
N
Ar
S
Ts
N
N
OMe
S
R
R
O
1
O
4a, 20 min, 46%
2
3
3a
CN
CN
CN
CN
CN
CN
CN
CHO
N
CN
Me
MeO
KMnO4, Na2SO4
MeCN
OMe
OMe
N
OMe
OMe
OMe
OMe
N
N
N
r.t.
Ts
N
OMe
Ts
N
OMe
Ts
Ts
Ts
N
N
N
OMe
OMe
4b, 20 min, 41%
3e
3a, 14 h, 77%
3c, 13 h, 63%
3b, 12 h, 50%
Scheme 3 Transformations of aminals 3a and 3e
CN
CN
CN
CN
Cl
all failed to provide the desired indole fused aminals 6a–c.
The results suggest that dicyano groups act as activating
groups and are essential for the improvement of electro-
philic reactivity of the tosyl group.
OMe
OMe
N
OMe
N
Me
Ts
N
Ts
N
OMe
3e, 13 h, 63%
3d, 14 h, <5%
CN
CN
CN
CN
MeO
4 Å MS, DMF, 50 °C
OMe
N
+
CN
CN
N
N
MeO
Ts
N
OMe
Ts
OMe
N
N
Cl
1a
N
5a
Ts
Ts
6a, 36 h, 0%
N
Ts
OMe
N
N
OMe
CHO
3f, 13 h, 48%
3h, 72 h, 0%
3g, 12 h, 61%
CHO
MeO
MeO
4 Å MS, DMF, 50 °C
CN
CN
CN
OMe
+
N
N
N
N
CN
CN
CN
Ts
OMe
Ts
1a
5b
OMe
OMe
OMe
N
N
N
O
O
O
6b, 24 h, 0%
O
O
O
S
S
S
N
N
OMe
N
OMe
CN
OMe
CN
MeO
MeO
4 Å MS, DMF, 50 °C
OMe
+
N
N
Cl
N
N
3j, 22 h, 59%
3k, 22 h, 64%
3i, 14 h, 53%
Ts
OMe
Ts
1a
CN
5c
CN
CN
CN
6c, 24 h, 0%
CN
CN
Scheme 4 Further attempts to expand the substrate scope
Bn
N
OMe
OMe
N
N
N
O
O
N
O
O
S
S
Ts
N
OMe
N
OMe
Based on the obtained results, a possible mechanism
was proposed for this reaction (Scheme 5). Indole derivative
2a acts as sulfonylation reagent in this reaction, which can
be attacked by the nucleophilic imine 1a. Iminium ion
would be formed and the final aza-Mannich reaction gives
product 3a.
3n, 16 h, 66%
3m, 22 h, 42%
3l, 9 h, 25%
Scheme 2 Examination of substrate scope. Reaction conditions: 1a (3
equiv, 0.3 mmol), 2a (1 equiv, 0.1 mmol), 4 Å MS (100 mg), DMF (0.5
mL).
In summary, we have developed a convenient synthesis
of indole fused aminals with nucleophilic imines and indole
derived dicyano olefins via N-sulfonyl group transfer.14 The
combination of two privileged frameworks, tetrahydroiso-
quinoline and indole, into aminals, can be realized by using
this approach. The synthetic application of this methodolo-
gy was further demonstrated by the straightforward trans-
formations into highly functionalized indole-fused aminals.
with KMnO4.13 As shown in Scheme 3, the desired aminals
4a and 4b could be afforded in 46% and 41% yields, respec-
tively, by using a known procedure.
As shown in Scheme 4, further extensions of the sub-
strate scope of the strategy for indole-fused aminals as well
as control experiments were performed. Treatment of 1-to-
syl-indole 5a, 1-tosyl-indole-3-carbaldehyde 5b and 1-to-
syl-indole-3-carbonitrile 5c under the standard conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Synlett
CN
CN
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MeO
MeO
MeO
MeO
O
N
O
+
S
N
N
N
S
1a
O
Me
O
NC
CN
2a
Me
CN
CN
CN
CN
MeO
OMe
N
+
N
N
MeO
Ts
Ts
N
OMe
3a
Scheme 5 Proposed reaction pathway
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Funding Information
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We are grateful for the support provided for this study by the National
Natural Science Foundation of China (21502013, 21871035) and
Chongqing University of Arts and Sciences (R2015BX01).
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Acknowledgment
We thank Ms. Han-Zhao Liu (International Academy of Targeted Ther-
apeutics and Innovation, Chongqing University of Arts and Sciences)
for NMR spectrum acquisition.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611940.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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2016, 138, 2560. (i) Takano, S.; Sato, T.; Inomata, K.; Ogasawara,
K. J. Chem. Soc., Chem. Commun. 1991, 462. (j) Morales, C. L.;
Pagenkopf, B. L. Org. Lett. 2008, 10, 157. (k) Mizutani, M.;
Inagaki, F.; Nakanishi, T.; Yanagihara, C.; Tamai, I.; Mukai, C. Org.
Lett. 2011, 13, 1796. (l) Zhou, Y.; Zhou, S. Org. Lett. 2014, 16,
3416. (m) Lewin, G.; Bernadat, G.; Aubert, G.; Cresteil, T. Tetra-
hedron 2013, 69, 1622. (n) Hewlett, N. M.; Tepe, J. J. Org. Lett.
2011, 13, 4550. (o) Pan, Z.-Q.; Qin, X.-J.; Liu, Y.-P.; Wu, T.; Luo,
X.-D.; Xia, C.-F. Org. Lett. 2016, 18, 654.
(11) For recent examples on the combination of indole and tetrahy-
droisoquinoline, see: (a) Yu, L.; Zhong, Y.; Yu, J.; Gan, L.; Cai, Z.;
Wang, R.; Jiang, X. Chem. Commun. 2018, 2353. (b) Liu, Y.; Wang,
C.; Xue, D.; Xiao, M.; Li, C.; Xiao, J. Chem. Eur. J. 2017, 23, 3051.
(12) CCDC 1871844 for compound 3e. See the Supporting Informa-
tion for details.
(13) (a) Alemán, J.; Jacobsen, C. B.; Frisch, K.; Overgaard, J.;
Jørgensen, K. A. Chem. Commun. 2008, 632. (b) Cheng, C.; Lu, X.;
Ge, L.; Chen, J.; Cao, W.; Wu, X.; Zhao, G. Org. Chem. Front. 2017,
4, 101.
m/z [M+H]+ calcd. for C31H29N4O4S+: 553.1904; found: 553.1899.
Compound 3c: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 35.7 mg (63%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.90–7.87 (m, 3 H), 7.38–7.35 (m, 3 H),
7.11–7.04 (m, 4 H), 6.59 (s, 1 H), 6.41 (s, 1 H), 3.97 (dd, J = 14.5,
5.0 Hz, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.69 (s, 3 H), 3.33 (ddd,
J = 14.4, 11.8, 5.0 Hz, 1 H), 2.78–2.33 (m, 2 H), 2.33 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3): δ = 157.1, 150.3, 149.8, 148.8,
144.0, 136.4, 132.9, 131.5, 129.5, 128.4, 127.0, 126.8, 120.9,
115.1, 115.0, 114.8, 113.4, 111.3, 111.0, 109.6, 100.2, 73.1, 65.7,
56.1, 56.0, 55.9, 39.4, 26.4, 21.5; HRMS (ESI): m/z [M+Na]+ calcd.
for C31H28N4NaO5S+: 591.1673; found: 591.1669.
Compound 3e: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 34.6 mg (63%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.88 (d, J = 4.8 Hz, 2 H), 7.82 (s, 1 H), 7.56
(d, J = 8.2 Hz, 1 H), 7.41 (s, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.23 (d,
J = 8.2 Hz, 1 H), 7.02 (d, J = 8.1 Hz, 2 H), 6.60 (s, 1 H), 6.39 (s,
1 H), 4.01 (dd, J = 14.4, 5.7 Hz, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H),
3.39–3.36 (m, 1 H), 2.90–2.65 (m, 2 H), 2.56 (s, 3 H), 2.32 (s,
3 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 150.2, 150.0, 148.7,
148.7, 143.9, 137.1, 136.4, 136.4, 135.4, 132.1, 129.5, 126.7,
125.5, 125.0, 121.1, 117.7, 115.0, 112.2, 111.2, 109.5, 73.6, 65.3,
56.1, 56.0, 39.5, 26.5, 22.7, 21.5; HRMS (ESI): m/z [M+Na]+ calcd.
for C31H28N4NaO4S+: 575.1724; found: 575.1723.
Compound 3f: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 27.5 mg (48%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.01–7.95 (m, 2 H), 7.87 (s, 1 H), 7.59 (d,
J = 8.5 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 2 H), 7.38–7.33 (m, 2 H), 7.06
(d, J = 8.1 Hz, 2 H), 6.60 (s, 1 H), 6.38 (s, 1 H), 4.01 (dd, J = 14.4,
5.3 Hz, 1 H), 3.87 (s, 3 H), 3.69 (s, 3 H), 3.40–3.29 (m, 1 H), 2.85–
2.67 (m, 2 H), 2.32 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ =
150.4, 149.5, 148.8, 144.1, 136.9, 136.3, 133.0, 131.2, 129.6,
127.1, 126.7, 125.7, 124.4, 120.5, 119.0, 114.6, 112.6, 111.3,
110.9, 109.5, 100.0, 75.2, 65.7, 56.2, 56.0, 39.5, 26.4, 21.5; HRMS
(ESI): m/z [M+H2O+H]+ calcd. for C30H28ClN4O5S+: 591.1463;
found: 591.1467.
(14) Synthesis of Compound 3; General Procedure: A mixture of
3,4-dihydro-isoquinoline imine 1 (0.3 mmol), 2-((1-sulfonyl-
1H-indol-3-yl)methylene)malononitrile
2 (0.1 mmol), 4 Å
molecular sieves (100 mg) and DMF (0.5 mL) was stirred at
50 °C. Upon the consumption of 2 (monitored by TLC), the reac-
tion was diluted with CH2Cl2 (3 mL) and washed with water (3
mL) and brine (3 mL). The organic layer was concentrated and
purified by a silica gel flash chromatography (PE/EtOAc) to
afford compound 3.
Compound 3g: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 30.7 mg (61%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.97 (d, J = 8.4 Hz, 1 H), 7.94 (s, 1 H), 7.90
(s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.39 (t, J =
7.6 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.89
(d, J = 8.4 Hz, 1 H), 6.74 (dd, J = 8.8, 2.4 Hz, 1 H), 6.68 (d, J =
2.0 Hz, 1 H), 4.06 (dd, J = 14.1, 4.6 Hz, 1 H), 3.79 (s, 3 H), 3.39
(ddd, J = 14.1, 11.8, 4.7 Hz, 1 H), 2.97–2.78 (m, 2 H), 2.31 (s,
3 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 160.2, 149.7, 143.9,
136.7, 136.3, 135.7, 132.4, 129.5, 128.9, 127.2, 126.6, 125.1,
123.7, 121.8, 118.0, 114.9, 114.4, 113.5, 112.3, 111.2, 73.8, 65.4,
55.4, 39.7, 27.7, 21.4; HRMS (ESI): m/z [M+Na]+ calcd. for
Spectral Data for Selected Compounds
Compound 3a: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 43.3 mg (77%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.03 (d, J = 8.3 Hz, 1 H), 7.97 (s, 1 H), 7.93
(s, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.50–7.44 (m, 2 H), 7.41 (t, J =
7.2 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 6.60
(s, 1 H), 6.40 (s, 1 H), 3.99 (dd, J = 14.3, 5.1 Hz, 1 H), 3.87 (s, 3 H),
3.67 (s, 3 H), 3.36 (ddd, J = 14.4, 11.8, 5.1 Hz, 1 H), 2.84–2.68 (m,
2 H), 2.32 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 150.3,
149.8, 148.8, 144.0, 136.6, 136.3, 132.6, 129.5, 127.3, 127.0,
126.7, 125.2, 123.8, 120.9, 118.1, 114.9, 112.4, 111.3, 111.2,
109.5, 77.4, 65.5, 56.1, 56.0, 39.4, 26.4, 21.5; HRMS (ESI): m/z
[M+H]+ calcd. for C30H27N4O4S+: 539.1748; found: 539.1743.
Compound 3b: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 28.1 mg (50%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.90 (s, 1 H), 7.88 (d, J =
8.4 Hz, 1 H), 7.47 (s, 1 H), 7.41 (s, 1 H), 7.34 (d, J = 8.2 Hz, 2 H),
7.29 (s, 1 H), 7.03 (d, J = 8.1 Hz, 2 H), 6.59 (s, 1 H), 6.40 (s, 1 H),
3.98 (dd, J = 14.2, 5.1 Hz, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.35
(ddd, J = 14.4, 11.8, 5.0 Hz, 1 H), 2.85–2.67 (m, 2 H), 2.53 (s, 3 H),
2.33 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 150.2, 149.9,
148.7, 143.9, 136.3, 135.0, 133.7, 132.5, 129.5, 127.6, 127.0,
126.9, 126.8, 126.7, 121.0, 117.8, 115.0, 112.1, 111.2, 110.9,
109.5, 73.4, 65.5, 56.1, 56.0, 39.4, 26.5, 21.6, 21.5; HRMS (ESI):
C
29H24N4NaO3S+: 531.1461; found: 531.1458.
Compound 3i: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 28.0 mg (53%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.03 (d, J = 8.0 Hz, 1 H), 7.98 (s, 1 H), 7.92
(s, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.47–7.40 (m, 4 H), 7.42–7.40
(m, 2 H), 7.22 (t, J = 7.6 Hz, 2 H), 6.59 (s, 1 H), 6.40 (s, 1 H), 4.08–
3.98 (m, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.43–3.33 (m, 1 H),
2.79–2.78 (m, 2 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 150.3,
149.9, 148.8, 139.3, 136.6, 132.9, 132.5, 128.9, 127.3, 126.9,
126.6, 125.2, 123.8, 120.9, 118.1, 114.9, 114.8, 112.4, 111.3,
111.2, 109.5, 74.2, 65.5, 56.1, 56.0, 39.5, 26.5; HRMS (ESI): m/z
[M+Na]+ calcd. for C29H24N4NaO4S+: 547.1410; found: 547.1411.
Compound 3j: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 32.9 mg (59%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.02 (d, J = 8.4 Hz, 1 H), 7.85 (s, 1 H), 7.81
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
H.-L. Cui et al.
Letter
Synlett
(d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.66–7.61 (m, 2 H),
7.57–7.43 (m, 7 H), 7.40 (t, J = 7.2 Hz, 1 H), 6.58 (s, 1 H), 6.36 (s,
1 H), 4.25 (dd, J = 13.7, 4.8 Hz, 1 H), 3.83 (s, 3 H), 3.62 (s, 3 H),
3.46 (td, J = 13.6, 4.2 Hz, 1 H), 2.98–2.77 (m, 2 H); 13C{1H} NMR
(100 MHz, CDCl3): δ = 150.2, 149.1, 148.8, 136.8, 135.9, 134.6,
131.7, 131.7, 129.3, 129.2, 129.1, 127.9, 127.7, 127.4, 127.0,
126.9, 125.3, 123.7, 121.4, 121.4, 118.1, 114.8, 114.7, 112.0,
111.2, 109.3, 73.8, 65.3, 56.1, 56.0, 40.4, 27.5; HRMS (ESI): m/z
[M+Na]+ calcd. for C33H26N4NaO4S+: 597.1567; found: 597.1561.
Compound 3k: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 35.4 mg (64%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.99–7.97 (m, 2 H), 7.93 (s, 1 H), 7.69 (d, J
= 8.0 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.43–7.40 (m, 2 H), 7.34
(d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.62 (s, 1 H), 6.39 (s,
1 H), 4.05 (dd, J = 13.2, 5.2 Hz, 1 H), 3.89 (s, 3 H), 3.66 (s, 3 H),
3.44–3.36 (m, 1 H), 2.85–2.80 (m, 2 H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 150.4, 149.7, 148.9, 139.6, 137.7, 136.6, 132.1, 129.1,
128.0, 127.2, 126.7, 125.3, 123.9, 120.8, 118.2, 114.9, 114.7,
112.1, 111.3, 111.2, 109.5, 65.4, 56.1, 56.0, 39.8, 29.7, 26.7;
HRMS (ESI): m/z [M+Na]+ calcd. for C29H23ClN4NaO4S+:
581.1021; found: 581.1023.
Compound 3l: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 14.6 mg (25%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.12 (s, 1 H), 8.01–7.99 (m, 2 H), 7.75 (d, J
= 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H),
7.36 (s, 1 H), 6.77 (s, 1 H), 6.42 (s, 1 H), 3.99 (dd, J = 14.0, 6.0 Hz,
1 H), 3.93 (s, 3 H), 3.69 (s, 3 H), 3.40 (td, J = 12.4, 4.4 Hz, 1 H),
3.25–3.16 (m, 1 H), 2.93 (dd, J = 12.8, 3.6 Hz, 1 H), 2.62 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3): δ = 150.5, 150.0, 148.9, 136.4,
132.8, 127.5, 127.0, 125.3, 124.0, 120.6, 118.4, 114.9, 114.7,
112.3, 111.5, 111.2, 109.8, 74.9, 65.3, 56.1, 56.1, 40.2, 38.9, 27.1;
HRMS (ESI): m/z [M+Na]+ calcd. for C24H22N4NaO4S+: 485.1254;
found: 485.1249.
Compound 3m: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 20.0 mg (42%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.17 (s, 1 H), 8.02 (s, 1 H), 7.96 (d, J =
8.4 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.41
(t, J = 7.6 Hz, 1 H), 7.37 (s, 1 H), 6.76 (s, 1 H), 6.39 (s, 1 H), 3.98
(dd, J = 14.0, 6.0 Hz, 1 H), 3.93 (s, 3 H), 3.68 (s, 3 H), 3.47–3.40
(m, 1 H), 3.23–3.14 (m, 1 H), 2.92 (dd, J = 16.4, 2.8 Hz, 1 H),
2.72–2.55 (m, 2 H), 1.75–1.56 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3): δ = 150.4, 150.0, 148.9, 136.4,
132.8, 127.4, 127.1, 125.1, 123.9, 120.9, 118.4, 114.9, 114.8,
112.3, 111.4, 111.2, 109.7, 74.8, 65.1, 56.1, 56.0, 55.2, 39.4, 27.5,
16.9, 12.9; HRMS (ESI): m/z [M+Na]+ calcd. for C26H26N4NaO4S+:
513.1567; found: 513.1563.
Compound 3n: Purified by flash column chromatography
(PE/EtOAc, 4:1); Yield: 32.0 mg (66%); yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.85 (s, 1 H), 7.72 (s, 1 H),
7.58 (d, J = 4.8 Hz, 1 H), 7.56 (d, J = 4.4 Hz, 1 H), 7.50–7.42 (m,
2 H), 7.41–7.29 (m, 3 H), 7.24 (s, 1 H), 7.23–7.18 (m, 2 H), 7.13
(t, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 2 H), 6.96 (d, J = 8.4 Hz,
2 H), 6.51 (d, J = 7.6 Hz, 2 H), 5.03 (d, J = 17.0 Hz, 1 H), 4.79 (d, J =
17.0 Hz, 1 H), 4.12 (dd, J = 14.7, 5.8 Hz, 1 H), 3.53–3.39 (m, 1 H),
2.91 (dd, J = 16.2, 4.1 Hz, 1 H), 2.73 (dd, J = 11.9, 5.6 Hz, 1 H),
2.26 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 149.8, 144.0,
138.2, 136.4, 136.0, 135.8, 129.5, 128.6, 127.7, 126.7, 126.0,
125.7, 125.3, 125.2, 124.2, 123.8, 120.4, 119.6, 118.1, 113.1,
112.1, 111.3, 109.7, 74.4, 61.6, 46.9, 39.9, 21.4, 20.2; HRMS
(ESI): m/z [M+Na]+ calcd. for C37H29N5NaO2S+: 630.1934; found:
630.1943.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F