Synthesis of benzocyclohepta[b]indoles by lewis acid catalyzed annulation of two 3-(1h-isochromen-1-yl)-1h-indoles

Article abstract of DOI:10.1021/jo4024667

A novel Lewis acid catalyzed annulation reaction has been established for the synthesis of benzocyclohepta[b]indoles. This method represents a new annulation strategy to a seven-membered carbocyclic ring system from two 3-(1H-isochromen-1-yl)-1H-indole molecules using Cu(OTf)2 catalyst; moreover, the products, benzocyclohepta[b]indoles, can be used as the rapid mercuric ion colorimetric detection reagents.

Full text of DOI:10.1021/jo4024667

Article
pubs.acs.org/joc
Synthesis of Benzocyclohepta[b]indoles by Lewis Acid Catalyzed
Annulation of Two 3‑(1H‑Isochromen-1-yl)‑1H‑indoles
Ye-Xiang Xie,† Ri-Yuan Tang,*,†,‡ Ren-Jie Song,† Jian-Nan Xiang,† and Jin-Heng Li*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
S
* Supporting Information
ABSTRACT: A novel Lewis acid catalyzed annulation
reaction has been established for the synthesis of
benzocyclohepta[b]indoles. This method represents a new
annulation strategy to a seven-membered carbocyclic ring
system from two 3-(1H-isochromen-1-yl)-1H-indole molecules
using Cu(OTf)2 catalyst; moreover, the products,
benzocyclohepta[b]indoles, can be used as the rapid mercuric
ion colorimetric detection reagents.
efficient routes to the formation of various oxallyl cation species
since the group of Fort reported the first example of [4 + 3]
cycloaddition of the oxallyl cation species, in situ generated
from chlorodibenzyl ketone by 2,6-lutidin base, with furan.4a In
1994, the group of Trost found that trimethylenemethane
equivalents could replace the oxallyl cation species to undergo
the [4 + 3] cycloaddition reaction; however, this method
suffered from the competing [3 + 2] reactions.5 Thus, it is
urgent and highly desirable to develop new annulation
strategies involving new allyl cation species for more
convenient and efficient preparation of the seven-membered
carbocyclic rings.
INTRODUCTION
■
The seven-membered carbocyclic ring system is an important
structural motif in many biologically active natural products and
pharmaceutical molecules (Figure 1).1 As a result, the efficient
Herein, we report a new Lewis acid catalyzed annulation of
3-(1H-isochromen-1-yl)-1H-indoles for selective synthesis of
benzocyclohepta[b]indoles, a new seven-membered carbocyclic
ring system (Scheme 1).4w,6 This annulation method is
achieved by the reaction between two 3-(1H-isochromen-1-
yl)-1H-indole molecules wherein one molecule is used as the
four-atom π-system and another is the allyl cation resource.
Notably, the products, benzocyclohepta[b]indoles, display
Figure 1. Examples of important seven-membered carbocyclic rings.
Scheme 1. Copper-Catalyzed Annulation Reaction
construction of seven-membered carbocyclic compounds has
attracted much attention from both academia and industry,
particularly with regard to the cycloaddition reaction.2−5
Despite the impressive progress in this cycloaddition field,
there have been much less abundant studies on the selective
construction of the seven-membered carbocyclic ring system
attributing the difficulty to enthalpic/entropic factors.1−6 In this
context, the [4 + 3] cycloaddition reaction, the annulation of an
allyl cation with a four-atom π-system, has become an
important methodology frequently utilized for the seven-
membered carbocyclic ring synthesis purpose.3−5 However,
the majority of efforts3,4 focused on the development of
Received: November 6, 2013
Published: December 25, 2013
© 2013 American Chemical Society
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Article
important biological activities7 and can be used as the rapid
mercuric ion colorimetric detection reagents.
ment product, (5H-benzo[b]carbazol-6-yl)(phenyl)methanone
(3a), albeit with a low yield (entry 14).8 Interestingly, the
higher reaction temperatures could improve the reaction rate
(entries 15 and 16): results identical to those at room
temperature could be achieved in 12 h when the reaction was
carried out at either 80 or 100 °C. Among the amounts of
Cu(OTf)2 examined, the reaction at 5 mol % of Cu(OTf)2 was
viable (entries 1, 17, and 18). However, the reaction could not
take place without any Lewis acids (entry 19). Finally, two
Brøsted acids, TfOH and HOAc, were also tested (entries 20
and 21). TfOH could catalyze the reaction, albeit with a lower
yield (entry 20). However, no reaction was observed in the
presence of HOAc alone (entry 21).
RESULTS AND DISCUSSION
■
Our initial attempt with 3-(3-phenyl-1H-isochromen-1-yl)-1H-
indole (1a) and 5 mol % of Cu(OTf)2 in MeCN at room
temperature for 48 h successfully underwent the annulation
reaction to furnish the desired benzocyclohepta[b]indole
product (2a) in 73% yield (entry 1 in Table 1), and the
a
Table 1. Screening Optimal Conditions
With the optimized conditions in hand, we then probed the
scope of this annulation method with respect to 3-(1H-
isochromen-1-yl)-1H-indoles (1) (Table 2). Initially, substrate
Table 2. Cu-Catalyzed Annulation of 3-(1H-Isochromen-1-
a
yl)-1H-indoles (1)
entry
[Cu] (mol %)
solvent
T (°C) time (h) yield (%)
1
Cu(OTf)2 (5)
CuCl2 (5)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
toluene
acetone
MeNO2
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
rt
rt
48
48
48
48
48
48
48
48
48
48
48
48
48
48
12
12
12
12
48
12
12
73
2
17
3
Cu(acac)2 (5)
Cu(OAc)2 (5)
CuOTf (5)
rt
9
4
rt
trace
21
5
rt
6
CuI (5)
rt
trace
48
7
In(OTf)3 (5)
Sc(OTf)3 (5)
Yb(OTf)3 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (10)
Cu(OTf)2 (2)

rt
8
rt
27
9
rt
63
10
11
12
13
rt
42
rt
25
rt
34
rt
58
b
14
rt
trace
73
15
16
17
18
19
20
21
80
100
80
80
rt
74
75
38
0
TfOH (10)
80
80
18
HOAc (10)
trace
a
Reaction conditions: 1a (0.3 mmol), [Cu], and solvent (2 mL) under
argon atmosphere. Some byproducts, including (5H-benzo[b]carbazol-
6-yl)(phenyl)methanone (3a) and 2-(2-(di(1H-indol-3-yl)methyl)-
b
phenyl)-1-phenylethanone (4a), were observed. Only (5H-benzo-
[b]carbazol-6-yl)(phenyl)methanone (3a) was isolated in 8% yields.
structure of product 2a was unambiguously confirmed by the
X-ray single-crystal diffraction analysis (see the Supporting
Information). Inspired by the results, a number of other Cu
catalysts, such as CuCl2, Cu(acac)2, Cu(OAc)2, CuOTf, and
CuI, were investigated (entries 2−6); however, the results
demonstrated that they were less effective than Cu(OTf)2.
Three Lewis acids, In(OTf)3, Sc(OTf)3, and Yb(OTf)3, were
also tested: they all could effect the reaction, albeit lowering
yield of product 2a (entries 7−9). These results suggest that
the real catalyst is a Lewis acid. Subsequently, a series of other
solvents, including CH2Cl2, toluene, acetone, MeNO2, and
DMSO, were tested (entries 10−14). Screening revealed that
solvents CH2Cl2, toluene, acetone, and MeNO2 could effect the
reaction, but they were less active than MeCN (entries 10−13).
Surprisingly, DMSO completely suppressed the reaction and
shifted the chemoselectivity toward to another ring rearrange-
a
Reaction conditions: 1 (0.3 mmol), Cu(OTf)2 (5 mol %), and
MeCN (2 mL) at 80 °C under argon atmosphere for 12 h.
1b, having a p-MeC6H4 group on the 3 position of the 1H-
isochromen-1-yl moiety, was also viable for this annulation
reaction, providing the desired product 2b in 56% yield.
Gratifyingly, the substitution effect on the aromatic ring of the
1H-isochromen-1-yl moiety was investigated (products 2c−g).
The results showed that several substituents, including Me,
MeO, F, and Cl, were well-tolerated. For example, Me-
substituted substrate 1c underwent the reaction with Cu(OTf)2
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smoothly to afford the expected product 2c in 62% yield.
Substrates 1e and 1f with a F or a Cl group were found to be
consistent with the optimal conditions leading to the
corresponding products 2e and 2f in moderate yield. Treatment
of heterocycle-containing substrate 1g with Cu(OTf)2 also
afforded product 2g in 64% yield. We were pleased to find that
the annulation method could be applicable to a diverse range of
substrates bearing substituents on the indole moiety. 7-
Ethylindole 1h, for instance, could be transferred into the
desired benzocyclohepta[b]indole 2h in 62% yield. To our
delight, either electron-donating groups or electron-with-
drawing substituents on the 5 position of the indole ring
were suitable for the annulation reaction (products 2i−m).
Importantly, halogen groups, including F, Cl, and Br, were
compatible with the optimal conditions, thereby facilitating
additional modifications at the halogenated positions (products
2e, 2f, 2k, and 2l).
Consequently, a plausible mechanism outlined in Scheme 2
is proposed.2−6 Initially, the insertion of the CuII species into
Figure 2. Fluorescence emission spectra of product 2a in the absence/
presence of metal ions: Ag+, Ba2+, Bi3+, Co+, Cr3+, Cu2+, Fe3+, Hg2+,
Ni2+, and Zn2+ in CH3CN/H2O (100:1): λex = 358.0 nm, [2a] = 5 ×
10−4 M and [Mn+] = 1 × 10−3 M.
Scheme 2. Possible Mechanism
Figure 3. Use of product 2a as a mercuric ion colorimetric detection
reagent in CH3CN/H2O (100:1). Left: [2a] = 5 × 10−4 M and [Hg2+]
= 1 × 10−3 M. Middle: [Hg2+] = 1 × 10−3 M. Right: [2a] = 5 × 10−4
M.
CONCLUSIONS
■
the C(sp3)−O bond of a molecule 1a afforded intermediate A,
followed by Friedel−Crafts alkylation of the 2 position of the
indole moiety of another molecule 1a with intermediate A
yields intermediate B. Isomerization of intermediate B takes
place easily leading to a carbon anion intermediate C.
Subsequently, the carbon anion intermediate C undergoes
intramolecular nucleophilic addition to generate intermediate
D. Finally, isomerization of intermediate D offers the desired
product 2a.
We next turned our attention to apply the obtained products
2. Generally, highly conjugated polyheterocyclic molecules have
good fluorescence properties and can be used as the metal ion
probes and functional materials.9 As shown in Figure 2, 2 equiv
of Mn+ ion, including Ag+, Ba2+, Bi3+, Co2+, Cr3+, Cu2+, Fe3+,
Hg2+, Ni2+, and Zn2+, was added to the solution of product 2a
in CH3CN/H2O to test the changes of fluorescence emission
intensity. Gratifyingly, four metal ions, Bi3+, Cu2+, Fe3+, and
Hg2+, could quench the fluorescence completely, suggesting
that product 2a is a good probe for the four metal ions.
In particular, the color of the Hg2+(OAc)2/product 2a
solution was distinctly deepened at 50 °C for 8 min or at room
temperature for 20 min (Figure 3), indicating that product 2a
can be used as the rapid mercuric ion colorimetric detection
reagent.10
In summary, we have illustrated a new, efficient annulation
protocol for the construction of the seven-membered
carbocyclic ring system using Cu(OTf)2 catalyst. This novel
annulation strategy is atom-economic and employs two 3-(1H-
isochromen-1-yl)-1H-indole molecules as the reaction partners:
one molecule is played as the four-atom π-system and another
is the allyl cation resource. Most importantly, the products,
benzocyclohepta[b]indoles, were found to be potentially used
as both some metal probes and the rapid mercuric ion
colorimetric detection reagents.
EXPERIMENTAL SECTION
■
General Considerations. The H and 13C NMR spectra were
1
recorded in DMSO-d6 or acetone-d6 on an NMR spectrometer using
TMS as internal standard. LRMS was performed on a GC−MS
instrument, and HRMS was measured on an electrospray ionization
(ESI) apparatus using time-of-flight (TOF) mass spectrometry.
Melting points are uncorrected.
Preparation of 3-(1H-Isochromen-1-yl)-1H-indoles (1). 3-
(1H-Isochromen-1-yl)-1H-indoles (1) were prepared according to
the known procedures.8 Substrates 1a−e,h−i,l,m are the known
compounds.8
Typical Experimental Procedure for Cu(OTf)2-Catalyzed
Annulation of 3-(1H-Isochromen-1-yl)-1H-indoles (1). To a
Schlenk tube were added 3-(1H-isochromen-1-yl)-1H-indoles 1 (0.3
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mmol), Cu(OTf)2 (10 mol %), and MeCN (2 mL). The tube was
charged with argon and stirred at 80 °C for the indicated time until
complete consumption of starting material as monitored by TLC
analysis. After the reaction was finished, the reaction mixture was
washed with brine. The aqueous phase was re-extracted with ethyl
acetate. The combined organic extracts were dried over Na2SO4 and
concentrated in vacuum, and the resulting residue was purified by silica
gel column chromatography (hexane/ethyl acetate) to afford the
desired benzocyclohepta[b]indoles 2.
Substrate 1f: yellow solid (78%, 55.7 mg); mp 135.2−136.4 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.70
− 7.63 (m, 3H), 7.42−7.26 (m, 6H), 7.11 (t, J = 7.5 Hz, 1H), 7.01 (d,
J = 2.3 Hz, 2H), 6.78 (s, 1H), 6.75 (s, 1H); 13C NMR (126 MHz,
DMSO-d6) δ 151.8, 136.7, 134.0, 132.3, 130.5, 130.2, 128.9, 128.4,
127.9, 125.9, 125.7, 125.3, 124.8,124.7, 121.5, 119.3, 119.2, 112.9,
111.9, 99.85, 73.0; IR (neat, cm−1) 1266, 741, 704; HRMS (ESI) calcd
for C23H17ClNO (M + H)+ 358.0993, found 358.0981.
Substrate 1g: yellow solid (65%, 47.7 mg); mp 149.4−151.6 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.69
(d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.4 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H),
7.31−7.23 (m, 3H), 7.10 (t, J = 7.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H),
6.93 (s, 1H), 6.87 (s, 1H), 6.64 (d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 6.00
(d, J = 3.3 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 149.6, 146.9,
145.7, 136.7, 134.4, 128.3, 125.9, 125.8, 125.7, 124.4, 123.9,
121.4,119.4, 119.0, 113.7, 111.8, 105.9, 104.4, 100.9, 100.8, 73.3; IR
(neat, cm−1): 2229, 1971, 1714, 1363, 1223; HRMS (ESI) calcd for
C24H18NO3 (M + H)+ 368.1281, found 368.1267.
Substrate 1j: yellow solid (83%, 58.6); mp 98.1−99.3 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H),
7.69 (d, J = 7.4 Hz, 2H), 7.34−7.24 (m, 7H), 7.17 (t, J = 7 2H), 7.04
(d, J = 7.4 Hz, 1H), 6.82 (d, J = 1.9 Hz, 1H), 6.77−6.72 (m, 3H), 3.73
(s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 153.3, 151.1, 134.4, 131.7,
131.4, 130.2, 128.6, 128.3, 128.0, 126.4, 126.1, 124.9, 124.7, 123.7,
113.7, 112.4, 111.5, 101.2, 100.7, 73.4, 55.3; IR (neat, cm−1) 2998,
2152, 1713, 1363, 1223; HRMS (ESI) calcd for C24H20NO2 (M + H)+
354.1489, found 354.1471.
Substrate 1k: yellow solid (55%, 37.8 mg); mp 113.5−114.7 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.67
(d, J = 7.2 Hz, 2H), 7.41−7.27 (m, 7H), 7.18 (t, J = 7.3 Hz, 1H), 7.05
(d, J = 2.3 Hz, 1H), 7.00−6.94 (m, 2H), 6.76 (s, 1H), 6.73 (s, 1H);
13C NMR (126 MHz, DMSO-d6) δ 156.3 (d, J = 230.5 Hz, 1C), 150.7,
133.7, 132.8, 130.8, 129.5, 128.2, 127.8, 127.6, 127.1, 126.0, 125.6 (d, J
= 10.2 Hz, 1C), 124.3, 124.2, 123.2, 113.5 (d, J = 4.69 Hz, 1C), 112.3
(d, J = 9.54 Hz, 1C), 109.1 (d, J = 25.9 Hz, 1C), 103.5 (d, J = 23.4 Hz,
1C), 100.2, 72.7; IR (neat, cm−1) 1676, 1487, 1279, 1051, 743; HRMS
(ESI) calcd for C23H17FNO (M + H)+ 342.1289, found 342.1297.
Product 2a: white solid (73%, 70.7 mg); mp 190.5−191.7 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H),
11.29 (s, 1H), 8.21 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 7.1 Hz, 1H), 7.67
(t, J = 7.1 Hz, 1H), 7.60−7.55 (m, 3H), 7.37−7.22 (m, 4H), 7.17−
7.00 (m, 6H), 6.96−6.85 (m, 3H), 6.77−6.59 (m, 7H), 6.29 (d, J =
10.9 Hz, 1H), 5.82 (s, 1H), 5.03−5.02 (m, 2H), 4.81 (d, J = 11.0 Hz,
1H); 13C NMR (125 MHz, DMSO-d6) δ 198.9, 198.7, 144.2, 142.9,
137.4, 137.0, 136.8, 136.3, 135.7, 134.7, 134.2, 133.2, 132.8, 130.3,
129.6, 128.8, 128.5, 128.1, 127.7, 127.6, 127.2, 127.1, 126.5, 125.8,
125.6, 123.7, 121.4, 120.6, 119.7, 118.8, 118.2, 117.0, 112.0, 111.9,
110.6, 53.3, 44.0, 42.5, 41.1; IR (neat, cm−1) 1679, 1446, 1271, 1220,
1001; HRMS (ESI) calcd for C46H35N2O2 (M + H)+ 647.2693, found
647.2683.
122.50, 121.87, 120.74, 120.23, 113.45, 113.28, 112.05, 53.48, 46.49,
44.26, 32.08, 22.33, 22.11; IR (neat, cm−1) 3057, 2343, 1731, 1265,
1216; HRMS (ESI) calcd for C48H39N2O2 (M + H)+ 675.3006, found
675.3020.
Product 2c: white solid (62%, 62.7 mg); mp 195.5−196.8 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.32 (s, 1H),
11.25 (s, 1H), 8.20 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.59
(dd, J = 16.0 Hz, 8.1 Hz, 3H), 7.54 (d, J = 8.2 Hz, 1H), 7.29−7.25(m,
2H), 7.14 (t, J = 7.7 Hz, 2H), 7.03 (d, J = 7.2 Hz, 2H), 6.93 (t, J = 7.5
Hz, 1H), 6.89−6.82 (m, 4H), 6.81−6.73 (m, 4H), 6.68 (d, J = 8.0 Hz,
1H), 6.60 (t, J = 7.5 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.22 (d, J =
11.1 Hz, 1H), 5.74 (s, 1H), 4.97−4.94 (m, 2H), 4.73 (d, J = 11.1 Hz,
1H), 2.18 (s, 3H), 2.02 (s, 3H); 13C NMR (125 MHz, acetone-d6) δ
204.4, 204.2, 146.8, 145.6, 143.3, 142.8, 142.6, 142.4, 142.1, 140.9,
140.8, 140.5, 140.3, 139.7, 138.1, 137.6, 135.7, 134.9, 134.2, 133.9,
133.8, 133.3, 133.2, 132.8, 132.4, 131.7, 128.9, 127.0, 126.9, 126.1,
125.6, 124.3, 123.8, 123.5, 118.3, 117.4, 117.0,115.6, 115.5, 49.6, 46.4,
41.2, 39.6, 27.6, 25.3; IR (neat, cm−1) 3055, 2334, 1729, 1268, 1212;
HRMS (ESI) calcd for C48H39N2O2 (M + H)+ 675.3006, found
675.3012.
Product 2d: white solid (57%, 60.4 mg); mp 250.4−251.6 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.39 (s, 1H),
11.35 (s, 1H), 8.18 (d, J = 7.5 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.61−
7.50 (m, 3H), 7.36−7.24 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 7.08−6.91
(m, 5H), 6.90−6.76 (m, 6H), 6.70 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 7.3
Hz, 1H), 6.48−6.38 (m, 2H), 6.17 (d, J = 11.1 Hz, 1H), 5.73 (s, 1H),
4.95 (d, J = 16.3 Hz, 1H), 4.80 (d, J = 16.3 Hz, 1H), 4.72 (d, J = 11.1
Hz, 1H), 3.79 (s, 3H), 3.12 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
δ 199.1, 198.9, 158.2, 157.5, 145.4, 144.2, 137.4, 137.1, 136.5, 135.6,
134.7, 133.1, 132.7, 131.1, 128.7, 128.6, 128.4, 128.2, 128.1, 127.7,
127.6, 126.1, 125.8, 123.3, 121.4, 120.6, 119.7, 119.6, 119.0, 118.2,
117.2, 115.8, 112.3, 112.0, 111.9, 111.8, 111.7,110.6, 55.2, 54.9, 52.5,
44.1, 41.7, 41.6; IR (neat, cm−1) 1772, 1724, 1215, 1028, 745; HRMS
(ESI) calcd for C48H39N2O4 (M + H)+ 707.2904, found 707.2885.
Product 2e: white solid (60%, 61.4 mg); mp 263.1−265.4 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H),
11.28 (s, 1H), 8.20 (d, J = 7.6 Hz, 2H), 7.81 (t, J = 7.0 Hz, 1H), 7.68
(t, J = 7.3 Hz, 1H), 7.63−7.50 (m, 3H), 7.32−7.27 (m, 2H), 7.21−
7.12 (m, 2H), 7.09 (s, 1H), 6.96 (d, J = 7.9 Hz, 4H), 6.87−6.79 (m,
4H), 6.68 (d, J = 7.7 Hz, 2H), 6.62 (d, J = 3.3 Hz, 2H), 6.47 (t, J = 7.3
Hz, 1H), 6.23 (d, J = 10.9 Hz, 1H), 5.84 (s, 1H), 5.05−4.94 (m, 2H),
4.82 (d, J = 11.0 Hz, 1H); 13C NMR (125 MHz, acetone-d6) δ 204.4,
203.0, 167.2 (d, J = 243.6 Hz, 1C), 165.6 (d, J = 239.8 Hz, 1C), 145.2,
144.8, 144.7, 144.6, 143.0, 142.8, 142.1, 140.8, 140.5, 138.3, 138.0,
136.5, 135.2, 133.9, 133.8, 133.7, 133.4, 133.1, 131.5, 129.1, 127.1,
126.4, 125.3, 124.5, 124.0, 123.0, 122.2, 119.9, 118.6, 118.5, 118.3,
117.7, 117.2, 115.8, 58.6, 49.1, 47.3, 46.3; IR (neat, cm−1) 3060, 1732,
1269, 742; HRMS (ESI) calcd for C46H33F2N2O2 (M + H)+ 683.2505,
found 683.2538.
Product 2f: white solid (65%, 69.6 mg); mp 171.3−172.5 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H),
11.43 (s, 1H), 8.20 (d, J = 7.5 Hz, 2H), 7.84 (s, 1H), 7.68 (t, J = 7.2
Hz, 1H), 7.58 (m, 3H), 7.37−7.31 (m, 3H), 7.16−7.09 (m, 3H), 6.99
(d, J = 7.0 Hz, 2H), 6.95−6.88 (m, 6H), 6.76 (d, J = 7.5 Hz, 2H),
6.76−6.65 (m, 2H), 6.10 (d, J = 11.1 Hz, 1H), 5.82 (s, 1H), 5.04−4.91
(m, 2H), 4.84 (d, J = 11.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
δ 198.5, 198.0, 146.0, 145.5, 137.3, 137.1, 136.2, 135.3, 134.8, 133.2,
133.0, 132.6, 131.9, 131.0, 129.2, 129.0, 128.8, 128.4, 128.2, 127.8,
127.6, 127.4, 127.3, 125.7, 125.6, 123.4, 121.6, 121.0, 119.3, 118.5,
116.3, 112.1, 111.3, 110.9, 52.6, 43.3, 41.5, 41.0; IR (neat, cm−1) 1722,
1269, 1203, 744; HRMS (ESI) calcd for C46H3335Cl2N2O2 (M + H)+
715.1914, found 715.1885.
Product 2b: white solid (56%, 56.6 mg); mp 191.3−192.1 °C
1
(uncorrected); H NMR (500 MHz, acetone-d6) δ 10.39 (brs, 1H),
10.29 (brs, 1H), 8.07−8.05 (m, 2H), 7.61−7.59 (m, 1H), 7.47−7.45
(m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.19−7.15 (m, 1H), 7.12−6.98 (m,
7H), 6.87−6.81 (m, 2H), 6.76−6.66 (m, 6H), 6.56−6.43 (m, 4H),
6.32−6.24 (m, 2H), 5.73 (s, 1H), 5.07 (d, J = 16.4 Hz, 1H), 4.81 (d, J
= 16.4 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 2.24 (s, 3H), 1.94 (s, 3H);
13C NMR (126 MHz, acetone-d6) δ 200.36, 200.08, 145.21, 144.72,
144.27, 142.71, 139.18, 137.09, 136.91, 134.15, 132.75, 132.70, 131.38,
131.31, 130.87, 130.83, 130.47, 130.37, 130.35, 130.33, 130.26, 130.17,
130.14, 129.80, 129.25, 129.19, 128.69, 128.63, 127.91, 127.07, 123.34,
1
Product 2g: white solid (64%, 70.5 mg); mp 230.2−232.4 °C; H
NMR (500 MHz, DMSO-d6) δ 11.35 (s, 1H), 11.31 (s, 1H), 8.18 (d, J
= 7.3 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.60−7.51 (m, 3H), 7.37 (s,
1H), 7.33−7.26 (m, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.03−6.92 (m, 4H),
6.89−6.61 (m, 8H), 6.57 (s, 1H), 6.33 (s, 1H), 6.09 (d, J = 11.0 Hz,
1H), 5.99 (d, J = 15.8 Hz, 2H), 5.67 (s, 2H), 4.88−4.86 (m, 2H), 4.71
(d, J = 11.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 198.9, 198.5,
146.3, 145.9, 145.5, 144.7, 137.4, 137.1, 137.0, 136.9, 136.3, 135.9,
689
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Article
134.6, 133.1, 132.9, 129.6, 128.7, 128.6, 128.4, 128.1, 128.0, 127.6,
127.0, 125.7, 123.4, 121.5, 120.6, 119.7, 119.6, 118.9, 118.2, 117.3,
111.9, 111.8, 110.6, 110.4, 107.3, 107.1, 101.2, 100.4, 52.6, 43.4, 42.1,
41.1; IR (neat, cm−1) 1736, 1595, 1436, 1033, 742; HRMS (ESI) calcd
for C48H35N2O6 (M + H)+ 735.2490, found 735.2453.
11.55 (s, 1H), 8.22 (d, J = 7.1 Hz, 2H), 7.57 (m, 3H), 7.39−7.24 (m,
6H), 7.21−7.04 (m, 6H), 6.99−6.72 (m, 8H), 6.19 (d, J = 10.0 Hz,
1H), 5.82 (s, 1H), 5.08 (d, J = 16.4 Hz, 1H), 4.96 (d, J = 16.3 Hz, 1H),
4.78 (d, J = 10.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 198.6,
198.3, 143.5, 142.5, 136.9, 136.6, 135.7, 135.3, 133.7, 133.4, 133.2,
132.9, 131.3, 130.5, 129.8, 129.7, 128.8, 128.6, 128.4, 128.2, 128.1,
128.0, 127.8, 127.6, 127.5, 127.2, 126.7, 126.2, 125.9, 125.4,
124.0,123.5, 123.4, 122.0, 121.9, 121.1, 116.7, 114.0, 113.5, 112.5,
111.5, 111.1, 111.0, 53.3, 43.6, 42.3, 41.0; IR (neat, cm−1) 1733, 1270,
1046, 741; HRMS (ESI) calcd for C46H3379Br2N2O2 (M + H)+
803.0903, found 803.0901.
Product 2m: white solid (65%, 67.9 mg); mp 270.1−271.3 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H),
11.94 (s, 1H), 8.20 (d, J = 7.2 Hz, 2H), 7.90 (d, J = 5.9 Hz, 1H), 7.75
(d, J = 8.3 Hz, 1H), 7.68−7.66 (m, 1H), 7.59 (t, J = 7.4 Hz, 2H), 7.52
(d, J = 8.0 Hz, 2H), 7.42 (s, 2H), 7.37−7.27 (m, 4H), 7.21−7.17 (m,
2H), 7.11 (s, 1H), 7.01−6.96 (m, 2H), 6.80−6.77 (m, 3H), 6.68 (d, J
= 5.9 Hz, 2H), 6.15 (d, J = 10.6 Hz, 1H), 5.91 (s, 1H), 5.23 (d, J =
16.9 Hz, 1H), 4.91 (d, J = 17.1 Hz, 1H), 4.80 (d, J = 10.5 Hz, 1H); 13C
NMR (125 MHz, DMSO-d6) δ 198.9, 198.2, 143.6, 143.3, 141.4,
141.3, 138.8, 137.7, 137.2, 136.7, 136.5, 136.3, 134.6, 133.3, 133.0,
131.1, 130.0, 123.0, 128.9, 128.3, 128.1, 127.7, 127.6, 127.2, 126.8,
126.1, 125.6, 125.4, 125.0, 124.1, 123.8, 120.6, 120.5, 117.6, 113.5,
113.4, 112.0, 101.0, 100.5, 53.3, 43.4, 42.4, 41.1; IR (neat, cm−1) 1736,
1652, 1486, 1262, 1034; HRMS (ESI) calcd for C48H33N4O2 (M +
H)+ 697.2525, found 697.2598.
Product 2h: white solid (62%, 65.3 mg); mp 180.6−181.8 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.32 (s, 1H),
11.26 (s, 1H), 8.23 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.3 Hz, 1H), 7.66
(t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H),
7.29−7.22 (m, 2H), 7.14−7.02 (m, 5H), 6.98−6.89 (m, 2H), 6.85−
6.77 (m, 6H), 6.72 (t, J = 7.5 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.50
(d, J = 8.0 Hz, 1H), 6.39 (d, J = 11.1 Hz, 1H), 5.95 (s, 1H), 5.06−5.02
(m, 2H), 4.83 (d, J = 11.1 Hz, 1H), 3.00 (q, J = 7.4 Hz, 2H), 2.88 (q, J
= 7.4 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H), 1.30 (t, J = 7.5 Hz, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 198.9, 198.8, 144.3, 143.1, 137.4,
137.0, 136.4, 135.8, 135.5, 134.3, 133.5, 133.1, 132.8, 130.2, 129.6,
128.7, 128.5, 128.1, 128.0, 127.7, 127.6, 127.3, 127.2, 127.1, 126.5,
126.1, 125.9, 125.6, 123.3, 120.2, 119.4, 119.2, 118.5, 117.7, 117.5,
117.4, 112.4, 53.3, 43.9, 42.5, 41.2, 23.8, 23.6, 14.6, 14.2; IR (neat,
cm−1) 1763, 1730, 1268, 740; HRMS (ESI) calcd for C50H43N2O2 (M
+ H)+ 703.3319, found 703.3309.
Product 2i: white solid (72%, 72.8 mg); mp 189.6−190.8 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H),
11.13 (s, 1H), 8.20 (d, J = 7.4 Hz, 2H), 7.73 (d, J = 7.0 Hz, 1H), 7.67
(t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.3 Hz, 1H),
7.34 (t, J = 7.0 Hz 1H), 7.27−7.21 (m, 2H), 7.15 (d, J = 8.1 Hz, 1H),
7.09 (d, J = 7.5 Hz, 2H), 7.04−6.97 (m, 3H), 6.90 (t, J = 7.25 Hz 1H),
6.81−6.68 (m, 7H), 6.42 (s, 1H), 6.27 (d, J = 11.1 Hz, 1H), 5.73 (s,
1H), 5.10 (d, J = 16.6 Hz, 1H), 4.92 (d, J = 16.8 Hz, 1H), 4.77 (d, J =
11.0 Hz, 1H), 2.14 (s, 3H), 2.02 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 198.8, 198.7, 144.3, 143.1, 137.4, 136.8, 136.3, 135.7,
135.4, 134.2, 133.2, 133.0, 132.8, 130.4, 129.5, 128.8, 128.6, 128.3,
128.1, 127.7, 127.6, 127.1, 127.0, 126.4, 126.1, 125.4, 123.7, 122.9,
122.1, 119.3, 119.2, 116.5, 111.6, 111.3, 110.2, 53.3, 44.1, 42.2, 41.0,
21.5, 21.0; IR (neat, cm−1)1734, 1270, 741, 703; HRMS (ESI) calcd
for C48H39N2O2 (M + H)+ 675.3006, found 675.2993.
Product 2j: white solid (57%, 60.4 mg); mp 251.2−252.4 °C
(uncorrected); 1H NMR (500 MHz, acetone-d6) δ 10.24 (s, 1H),
10.16 (s, 1H), 8.20 (d, J = 7.5 Hz, 2H), 7.65 (s, 1H), 7.52 (t, J = 7.3
Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.22 (s,
1H), 7.12−7.07 (m, 4H), 6.98 (s, 2H), 6.93 (d, J = 7.0 Hz, 1H), 6.80−
6.68 (m, 6H), 6.56 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.7 Hz, 1H), 6.33−
6.28 (m, 2H), 6.17 (s, 1H), 5.68 (s, 1H), 5.12 (d, J = 16.1 Hz, 1H),
4.90 (d, J = 16.7 Hz, 1H), 4.75 (d, J = 10.1 Hz, 1H), 3.39 (s, 3H), 3.21
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 198.9, 198.7, 152.9, 152.6,
144.0, 142.9, 137.2, 136.9,136.5, 136.0, 134.6, 133.2, 132.8, 132.1,
129.9, 129.7, 129.5, 128.8, 128.4, 128.1,127.8, 127.6, 127.0, 126.5,
126.1, 125.5, 124.1, 116.7, 112.5, 111.8, 111.3, 111.0, 110.7,101.7, 54.9,
54.7, 53.2, 44.0, 42.4, 41.2; IR (neat, cm−1) 1724, 1215, 1029, 745;
HRMS (ESI) calcd for C48H39N2O4 (M + H)+ 707.2904, found
707.2903.
Product 2k: white solid (56%, 57.3 mg); mp 199.5−201.7 °C
(uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.50 (s, 1H),
11.40 (s, 1H), 8.18 (d, J = 7.7 Hz, 2H), 7.77 (d, J = 6.9 Hz, 1H), 7.66
(t, J = 7.1 Hz, 1H), 7.59−7.54 (m, 3H), 7.37 (t, J = 7.8 Hz, 1H), 7.30−
7.24 (m, 3H), 7.17 (s, 1H), 7.12 (t, J = 8.5 2H), 7.01−6.92 (m, 3H),
6.81−6.71 (m, 6H), 6.57 (d, J = 9.7 Hz, 1H), 6.35 (d, J = 10.2 Hz,
1H), 6.21 (d, J = 11.1 Hz, 1H), 5.76 (s, 1H), 5.08 (d, J = 16.8 Hz, 1H),
4.92 (d, J = 16.7 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H); 13C NMR (125
MHz, DMSO-d6) δ 197.7, 197.5, 155.4 (d, J = 229.9 Hz, 1C), 155.2
(d, J = 229.2 Hz, 1C), 142.5, 141.1, 136.3, 136.2, 135.6, 135.3, 133.3,
132.7, 132.1, 131.8, 130.3, 129.6, 128.6, 127.7, 127.3, 127.0, 126.8,
126.5, 126.4, 126.2, 126.0, 125.5, 124.7, 116.8, 115.9, 112.0 (d, J = 9.75
Hz, 1C), 111.2, 110.3 (d, J = 8.84 Hz, 1C), 108.5 (d, J = 26.1 Hz, 1C),
107.6 (d, J = 26.0 Hz, 1C), 103.6 (d, J = 23.6 Hz, 1C), 103.0 (d, J =
23.4 Hz, 1C), 52.1, 42.7, 41.3, 40.1; IR (neat, cm−1) 2352, 1733, 1683,
1487, 1269; HRMS (ESI) calcd for C46H33F2N2O2 (M + H)+
683.2505, found 683.2538.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of spectra and X-ray single-crystal diffraction analysis of
product (2a). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: try@wzu.edu.cn.
*E-mail: jhli@hnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (Nos.
21202121 and 21172060), Specialized Research Fund for the
Doctoral Program of Higher Education (No.
20120161110041), and Hunan Provincial Natural Science
Foundation of China (No. 13JJ2018) for financial support.
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