One-Pot Synthesis of Indole-3-acetic Acid Derivatives through the Cascade Tsuji-Trost Reaction and Heck Coupling

Article abstract of DOI:10.1021/acs.joc.8b01056

A practical palladium-mediated cascade Tsuji-Trost reaction/Heck coupling of N-Ts o-bromoanilines with 4-acetoxy-2-butenonic acid derivatives using a Pd(OAc)₂/P(o-tol)₃/DIPEA system is described for a straightforward synthesis of indole-3-acetic acid derivatives. This methodology was successfully applied to synthesize various substituted indole/azaindole-3-acetic acid derivatives and Almotriptan, which is a drug for the acute treatment of migraines. Moreover, a plausible cyclization mechanism has been proposed.

Full text of DOI:10.1021/acs.joc.8b01056

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Note
One-pot Synthesis of Indole-3-Acetic Acid Derivatives
through Cascade Tsuji-Trost Reaction and Heck Coupling
Dongsheng Chen, Yuanyuan Chen, Zhilong Ma, Lei Zou, Jianqi Li, and Yu Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01056 • Publication Date (Web): 15 May 2018
Downloaded from http://pubs.acs.org on May 16, 2018
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One-pot Synthesis of Indole-3-Acetic Acid Derivatives
through Cascade Tsuji-Trost Reaction and Heck Coupling
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Dongsheng Chen a, b, Yuanyuan Chen a, b, Zhilong Ma a, b, Lei Zou a, b, Jianqi Li * a, b and Yu Liu * a, b
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a Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China
State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China;
b Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry,
China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China
Email of the corresponding authors: lijianqb@126.com (Jianqi Li), liuyu_tianjin@126.com (Yu Liu)
Abstract: A practical palladiumꢀmediated cascade TsujiꢀTrost reaction/Heck coupling of NꢀTs
oꢀbromoanilines with 4ꢀacetoxyꢀ2ꢀbutenonic acid derivatives using a Pd(OAc)2/P(oꢀtol)3/DIPEA
system is described for a straightforward synthesis of indoleꢀ3ꢀacetic acid derivatives. This
methodology was successfully applied to synthesize various substituted indole/azaindoleꢀ3ꢀacetic
acid derivatives and Almotriptan, which is a drug for the acute treatment of migraine. Moreover, a
plausible cyclization mechanism has been proposed.
Indoleꢀ3ꢀacetic acid is an endogenous growth hormone in plants. Its scaffold (Figure 1) is
frequently found in a series of biologically active compounds such as Bunodosine 3911 and
therapeutically effective drugs such as Indomethacin2, Sumatriptan3 and Rizatriptan4. Owing to its
great importance in medicinal chemistry, much effort has been focused on the development of
more effective synthetic methods over the past years (Scheme 1. A).
Figure 1. Examples of bioactive molecules containing indoleꢀ3ꢀacetic acid scaffold.
Among these synthetic methods5ꢀ7, Fischer indole synthesis8ꢀ11 is the most widely used method
which relies on the use of phenylhydrazines and ketones or aldehydes and especially works well
for 5ꢀsubstituted electronꢀrich indoles. Other variant approaches, for examples, domino synthesis
of indoles through Zincꢀpromoted hydrohydrazination of terminal alkynes12 and reductive Fischer
indolization of Nꢀaryl conjugated hydrazones with tertꢀbutyl iodide13, provide more choices for
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the preparation of indoleꢀ3ꢀacetic acid compounds. However, Fischer method has suffered from
some problems when it was applied to synthesize 4ꢀ or 6ꢀmonosubstituted indoles due to its
selectivity. During the past few decades, transitionꢀmetalꢀcatalyzed reactions have offered a
powerful tool for construction of CꢀC and Cꢀheteroatom bonds. The application of these reactions
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such as Heck coupling catalyzed by palladium14ꢀ16 and CꢀH functionalization by Rh2(OAc)4 in
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the synthesis of indoleꢀ3ꢀacetic acid derivatives which greatly enriched the diversity of substrate
structures has also been explored. Despite these advances, the development of a straightforward
method to access indoleꢀ3ꢀacetic acid through oneꢀpot process would be of great value. Herein, we
report a novel palladiumꢀmediated cascade TsujiꢀTrost reaction18ꢀ22/Heck coupling23ꢀ27 to
synthesize indoleꢀ3ꢀacetic acid and its derivatives from readily available starting materials
(Scheme 1. B).
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Scheme 1. Synthetic Routes for the Preparation of Indole-3-acetic acid Compounds
The reaction of NꢀTs oꢀiodoaniline (1a) and ethyl (E)ꢀ4ꢀacetoxybutꢀ2ꢀenoate (2a) was used to
screen for suitable reaction conditions. At first, the reaction was performed in DMA at 100°C in
the presence of Pd(OAc)2 (5 mol %), P(oꢀtol)3 (10 mol %), nꢀBu4NBr (1.2 equiv)28ꢀ30 and K2CO3
(3.0 equiv). Disappointedly, the reaction did not give any products after 16h (Table 1, entry 1).
However, after the base K2CO3 was replaced with KOAc and the amounts of catalyst and ligand
were increased at the same time, the reaction afforded the desired product 3aa in 32% yield after
24h (Table 1, entry 2). Encouraged by the result, we investigated other bases and the results
revealed that the type of the base had a significant effect on the outcome of the reaction. Among
the screened bases, organic bases such as TEA and DIPEA gave the better results than inorganic
bases such as K2CO3 and KOAc (Table 1, entries 1–3). Next, we tried to optimize the amounts of
catalyst and ligand, and found that the yield would decrease significantly when the amounts of
Pd(OAc)2 and P(oꢀtol)3 were reduceed to 3 mol % and 6 mol % respectively (Table 1, entries 3ꢀ5).
Interestedly, the absence of nꢀBu4NBr had no effect on the result (Table 1, entries 4 and 6).
Furthermore, the investigation showed that the ligands play a favorable role in the reaction and
P(oꢀtol)3 could improve the reaction rate more apparently than PPh3 (Table 1, entries 6ꢀ8). A
survey of palladium source on the reaction showed that Pd(OAc)2 and Pd2(dba)3 have similar
catalytic activities (Table 1, entries 6 and 9). Toluene, 1,4ꢀdioxane and CH3CN were screened as
solvents and no one was found to afford a comparable result to DMA (Table 1, entries 10ꢀ12). The
amino of aniline without protection or protected with other protective groups such as CH3CO,
CF3CO, MeSO2, Boc and PMB were also investigated under the condition of entry 6, however,
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they gave quite poor results. Finally, the optimal reaction conditions were determined as follows:
1a (1 equiv), 2a (1.2 equiv), Pd(OAc)2 (5 mol %), P(oꢀtol)3 (10 mol %) and TEA (or DIPEA) (3
equiv) in DMA.
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Table 1. Optimization of the Reaction Conditions
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Cat.
(5 mol %)
L
Base
(3.0 eq.)
Additive
(1.2 eq.)
nꢀBu4NBr
Temp.
(oC)
Time
(h)
3aa[b]
(yield, %)
NR
32[d]
84
Entry
Solvent[a]
(10 mol %)
1
2[c]
3[c]
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
P(oꢀtol)3
P(oꢀtol)3
P(oꢀtol)3
P(oꢀtol)3
P(oꢀtol)3
P(o-tol)3
ꢀꢀꢀ
K2CO3
KOAc
TEA[e]
TEA
DMA
DMA
100
100
100
100
100
100
100
100
100
100
100
80
16
24
24
12
16
10
12
24[g]
12
12
12
16
nꢀBu4NBr
nꢀBu4NBr
DMA
nꢀBu4NBr
DMA
83
23[d]
5[f]
TEA
nꢀBu4NBr
DMA
6
TEA
TEA
---
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
DMA
82
7
DMA
34[d]
83
8
PPh3
TEA
DMA
9
P(oꢀtol)3
P(oꢀtol)3
P(oꢀtol)3
P(oꢀtol)3
TEA
DMA
84
10
11
12
TEA
Toluene
1,4ꢀdioxane
CH3CN
14
TEA
7
TEA
72
Conditions: 1a (1.0 mmol), 2a (1.2 mmol), c = 0.2 M. [a] anhydrous solvent, under N2 atmosphere; [b] isolated
yields; [c] Pd(OAc)2 (12 mol %), P(oꢀtol)3 (20 mol %); [d] 1a has remained; [e] DIPEA gave a similar result; [f]
Pd(OAc)2 (3 mol %), P(oꢀtol)3 (6 mol %); [g] 1a has remained after18h, disappeared after 24h.
Based on the optimized reaction conditions, the scope of this oneꢀpot process was then
examined. Diverse substituted indoleꢀ3ꢀethyl acetate compounds were obtained in moderate to
good yields (Schemes 2). As shown in Scheme 2, for the substrate NꢀTs oꢀhaloanilines, a variety
of substituents (ꢀBr, ꢀCl, ꢀF, ꢀOCF3, ꢀOMe and ꢀCO2Me) were applicable, affording products
3ba~3ma in 41~91% yields. The position and electronic nature of aromatic substituents seem to
affect the yields: electronꢀdonating substituents at paraꢀposition of halogen on anilines lead to
poorer yields (3ha), while electronꢀwithdrawing substituents give better yields (3ga and 3ia); for
substituents at metaꢀposition of halogen on anilines, the electronic effects do not seem to play an
important role in reaction yields (3ba, 3ca, 3da and 3ea); for electronꢀwithdrawing substituents at
orthꢀposition of nitrogen on anilines, the reactions can also give good results (3ja, 3ka and 3la).
Besides, the substituents have a big influence on the reaction rate: the substrates 1e and 1g were
not consumed completely after 24h, while the reaction was finished for 1i, 1k and 1l after 12h.
Scheme 2. Scope of Cascade Tsuji-Trost/Heck Reaction to Form Substituted Indole-
3-Acetates (3xa)ab
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aConditions: 1b~1m (1.0 mmol), 2a (1.2 mmol), Pd(OAc)2 (5 mol %), P(oꢀtol)3 (10 mol %), DIPEA (3 mmol),
anhydrous DMA (5 mL), under N2 atmosphere; bIsolated yield after chromatography.
In order to expand the diversity of the substrates, we examined the cyclization reaction of NꢀTs
oꢀhaloanilines with amide 2b (Scheme 3). The investigation showed that the substrate amide 2b
gave equivalent or better results (1ab~1mb except for 1lb) than its corresponding ester 2a, while
the effects of the position and electronic nature of aromatic substituents were similar to those
displayed for the reactions of 1a~1m with 2a. Interestingly, for substituents at orthꢀposition of
halogen on anilines, the reactions gave better results (3nb, 3ob and 3pb) than its corresponding
ester 2a, while there was almost no reaction between 2a and 1n, 1o, 1p.
Scheme 3. Scope of Cascade Tsuji-Trost/Heck Reaction to Form Substituted Indole-
3-Acetamides (3xb)ab
aConditions: 1a~1i (1.0 mmol), 2b (1.2 mmol), Pd(OAc)2 (5 mol %), P(oꢀtol)3 (10 mol %), DIPEA (3 mmol),
anhydrous DMA (5 mL), under N2 atmosphere; bIsolated yield after chromatography.
The scope of this process was further expanded by utilizing NꢀTs bromoꢀaminopyridines as
substrates (Scheme 4). As expected, azaindoles31-32 were obtained smoothly. The substrate 1q
gave ester 3qa or amide 3qb at 100°C for 24h in 72% yield or for 12h in 81% yield respectively,
while 1r afforded 3ra or 3rb at 120°C for 24h in 67% or 62% yield respectively.
Scheme 4. Scope of Cascade Tsuji-Trost/Heck Reaction to Form Azaindoles ab
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aConditions: 1q/1r (1.0 mmol), 2a/2b (1.2 mmol), Pd(OAc)2 (5 mol %), P(oꢀtol)3 (10 mol %), DIPEA (3 mmol),
anhydrous DMA (5 mL), under N2 atmosphere; bIsolated yield after chromatography.
With this newly established methodology, an efficient approach to the synthesis of
Almotriptan33, a specific serotonin 5ꢀHT 1B/1D agonist for the acute treatment of migraine, has
been accomplished on gram scale (Scheme 5). It is easy to conduct the reaction of 1s and 2a to
afford 3sa in 77% yield. Subsequent reduction and deprotection lead to 3sa-2 in high yield.
Finally, Almotriptan was obtained successfully through a oneꢀpot process from 3sa-2 in 78%
yield.
Scheme 5. Application in the synthesis of Almotriptan
The cascade TsujiꢀTrost/Heck reaction mechanism for the cyclization was preliminarily
confirmed by the phenomena observed during the synthesis of 3ha. Besides desired product 3ha,
another product 3ha’ was separated contemporaneously in 51% yield (Scheme 6, eq (a)), which
indicated cyclization probably started from TsujiꢀTrost alkylation. To further establish the
mechanism of the cyclization reaction, three control experiments were performed. When 1h and
2a were mixed under the conditions without palladium catalyst and ligand, the reaction did not
proceed (Scheme 6, eq (b)), which indicated that 3ha’ was generated via TsujiꢀTrost alkylation.
Under the same conditions as eq (a), 1t was not react with 2a (Scheme 6, eq (c)), while 3ha’ could
be converted into 3ha (Scheme 6, eq (d)) through Heck coupling34.
Scheme 6. The Evidence for the Cascade Tsuji-Trost/Heck Reaction Process
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On the basis of the above results and previous reports, a plausible mechanism for this cascade
reaction has been proposed (Scheme 7). It involves, as a first step, oxidative addition of allyl ester
2a to the palladium complex, forming the electrophilic η3–allyl Pd(II) complex, which
subsequently reacts with nucleophilic NꢀTs oꢀhaloaniline in the presence of base to produce
intermediate 6 and regenerate the Pd(0) catalyst. The next step is the intramolecular Heck
coupling, that is, the palladiumꢀmediated cyclization of 6, to afford cyclization product 9. The
Heck reaction proceeds well under the help of ester group which could stabilize the palladium
species by coordination. The last step is the isomerization of 9, providing indoleꢀ3ꢀactic ester 3.
Scheme 7. Proposed Mechanism for Cyclization
In conclusion, we have developed a practical protocol for the synthesis of substituted
indoleꢀ3ꢀactic acid derivatives through palladium catalyzed TsujiꢀTrost alkylation and Heck
coupling. The cascade reaction could be successfully performed from readily available substrates:
substituted NꢀTs oꢀhaloanilines and allyl ester/amide. This methodology provided an alternative
for the synthesis of indoleꢀ3ꢀactic acid scaffold valuable in medicinal chemistry.
Experimental Section
General Information. Unless otherwise noted, all solvents and reagents are commercially
available and used without further purification. Pd(OAc)2 and P(oꢀtol)3 were purchased from J&K
Scientific Ltd.. Substituted oꢀhaloaniline and anhydrous DMA were purchased from Energy
Chemical. Normalꢀphase column chromatography was performed using silica gel (200–300 mesh).
Unless otherwise noted, all reagents were weighed and handled in air at room temperature. The
1
yields of all the reactions refer to isolated yields. H NMR spectra were recorded on a Brucker
Avance 400 and 600MHz NMR spectrometer, 13C NMR spectra were recorded on a Brucker
Avance 100 and 150MHz NMR spectrometer. Chemical shifts were reported in parts per million
(ppm, δ) (CDCl3: δ = 7.26 ppm for 1H NMR and δ = 77.1 ppm for 13C NMR; DMSOꢀd6: δ = 2.50
1
ppm for HꢀNMR and δ = 39.5 ppm for 13CꢀNMR). Proton coupling patterns are described as
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singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). IR spectra were measured on a PE
Spectrum Two. HRMS spectra were measured on a Waters Xevo G2ꢀXS QTof.
General produce for the preparation of Ts protected o-haloanilines. To a stirred solution of
substituted oꢀhaloaniline (10 mmol) in Pyr/THF (18 mL/6 mL) was added TsCl (12 mmol) slowly
at room temperature. The reaction mixture was allowed to stir at 40°C overnight. After the solvent
was removed under reduced pressure, ethyl acetate (100 mL) was added, and the mixture was
washed with brine (50 mL×2), and dried over anhydrous Na2SO4. The solvent was then removed
under reduced pressure and the residue was purified by column chromatography to yield
corresponding compounds 1a35, 1b36, 1c37, 1d38, 1e39, 1f40, 1g38, 1h41, 1q42, 1r43 and 1t44.
Methyl 4-bromo-3-((4-methylphenyl)sulfonamido)benzoate (1i): EtOAc/PE = 1/10, 2.7 g, 70%,
white solid. Mp:124ꢀ125°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 10.11 (s, 1H), 7.77ꢀ7.73 (m,
1H), 7.60 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H), 2.37 (s, 3H)；13C NMR (100
MHz, DMSOꢀd6) δ (ppm): 165.5, 143.9, 137.7, 136.1, 134.3 130.2, 130.1, 128.4, 128.0, 127.2,
125.9, 53.0, 21.5; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C15H15BrNO4S 383.9905/385.9885,
found 383.9902/385.9882.
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N-(2-bromo-6-fluorophenyl)-4-methylbenzenesulfonamide(1j)：EtOAc/PE = 1/10, 2.1g, 61%,
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white solid. Mp:184ꢀ186°C; H NMR (400 MHz, DMSOꢀd6) δ (ppm): 9.93 (s, 1H), 7.61 (d, J =
8.4 Hz, 2H), 7.51ꢀ7.49 (m, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.29ꢀ7.25 (m, 2H), 2.31 (s, 3H); 13C
NMR (150 MHz, DMSOꢀd6) δ (ppm): 160.0 (d, JC,F = 251 Hz), 143.4, 139.2, 130.7 (d, JC,F = 7.4
Hz), 129.9, 129.3, 127.1, 125.8, 124.2, 124.1, 116.3 (d, JC,F = 21.5 Hz), 21.5; ATR-IR: ν 3249,
1594, 1339, 1156 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C13H12BrFNO2S
343.9756/345.9736, found 343.9759/345.9738.
Methyl 3-bromo-2-((4-methylphenyl)sulfonamido)benzoate(1k): EtOAc/PE = 1/10, 1.4g, 36%,
white solid. Mp:152ꢀ153°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 9.98 (s, 1H), 7.80 (dd, J =
8.0, 2.0 Hz, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.34ꢀ7.30 (m, 3H), 3.66
(s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 166.6, 143.9,137.9, 136.1, 135.4,
129.8, 129.4, 128.9, 127.9, 127.7, 124.6, 52.5, 21.6; ATR-IR: ν 3238, 1596, 1397, 1158 cmꢀ1;
HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C15H15BrNO4S 383.9905/385.9885, found
383.9899/385.9880.
N-(2-bromo-4,6-difluorophenyl)-4-methylbenzenesulfonamide (1l): EtOAc/PE = 1/10, 1.5g,
41%, white solid. Mp:179ꢀ181°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 9.95 (s, 1H), 7.61 (d,
J = 8.0 Hz, 2H), 7.55 (dt, J = 8.0, 2.4 Hz, 1H), 7.42 (dd, J = 10.0, 3.2 Hz, 1H), 7.38 (d, J = 8.4 Hz,
2H), 2.39 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 161.1 (dd, JC,F = 249.3, 13.7 Hz),
160.1 (dd, JC,F = 253.1, 14.9 Hz), 143.5, 139.0, 130.0, 127.1, 126.6 (d, JC,F = 13.1 Hz), 121.2 (d,
JC,F = 15.6 Hz), 116.9 (d, JC,F = 24.0 Hz), 105.2 (t, JC,F = 25.8 Hz), 21.5; ATR-IR: ν 3243, 1590,
1340, 1166 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C13H11BrF2NO2S 361.9662/363.9641,
found 361.9650/363.9630.
N-(2-bromo-6-chloro-4-fluorophenyl)-4-methylbenzenesulfonamide (1m): EtOAc/PE = 1/10,
984mg, 26%, white solid. Mp:163ꢀ166°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 10.03 (s, 1H),
7.70 (dd, J = 7.6, 2.4 Hz, 1H), 7.63ꢀ7.58 (m, 3H), 7.38 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H);13C NMR
(100 MHz, DMSOꢀd6) δ (ppm): 160.4 (d, JC,F = 250.8 Hz), 143.4, 139.7, 136.1 (d, JC,F = 112.6
Hz), 130.4 (d, JC,F = 3.9 Hz), 129.9, 127.5 (d, JC,F = 10.9 Hz), 127.1, 120.1 (d, JC,F = 24.2 Hz),
117.5 (d, JC,F = 25.1 Hz), 21.5; ATR-IR: ν 3266, 1590, 1339, 1162 cmꢀ1; HRMS (ESIꢀTOF) m/z
[M]+ calcd for C13H10BrClFNO2S 376.9288, found 376.9294; m/z [M+Na]+ calcd for
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N-(2-bromo-3-fluorophenyl)-4-methylbenzenesulfonamide (1n): EtOAc/PE = 1/10, 2.3g, 67%,
white solid. Mp:105ꢀ107°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 10.05 (s, 1H), 7.63 (d, J =
8.0 Hz, 2H), 7.39ꢀ7.23 (m, 3H), 7.21 (td, J = 8.4, 1.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 2.38 (s,
3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 159.3 (d, JC,F = 242.1 Hz), 143.9, 137.9, 137.6,
130.2, 129.5 (d, JC,F = 9.2 Hz), 127.2, 122.9, 114.4 (d, JC,F = 22.8 Hz), 107.5 (d, JC,F = 20.9 Hz),
21.5; ATR-IR: ν 3277, 1597, 1322, 1154 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
C13H12BrFNO2S 343.9756/345.9736, found 343.9754/345.9733.
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N-(2-bromo-3-chlorophenyl)-4-methylbenzenesulfonamide (1o): EtOAc/PE = 1/10, 2.3g, 64%,
white solid. Mp:110ꢀ111°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 10.05 (s, 1H), 7.63 (d, J =
8.0 Hz, 2H), 7.46 (dd, J = 8.0, 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 8.4 Hz, 1H), 7.13
(dd, J = 8.4, 1.6 Hz, 1H), 2.38 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 143.9, 137.9,
137.8, 134.8, 130.2, 129.3, 128.4, 127.2, 125.9, 121.0, 21.5; ATR-IR: ν 3270, 1595, 1377, 1167
cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C13H12BrClNO2S 359.9461/361.9440, found
359.9460/361.9437.
N-(2-bromo-3,4-difluorophenyl)-4-methylbenzenesulfonamide (1p): EtOAc/PE = 1/10, 1.5g,
42%, white solid. Mp:100ꢀ101°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 10.09 (s, 1H), 7.59 (d,
J = 8.4 Hz, 2H), 7.46 (q, J = 9.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.02ꢀ6.98 (m, 1H), 2.38 (s, 3H);
13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 148.7 (dd, JC,F = 247.4, 13.8 Hz), 147.7 (dd, JC,F
=
243.5, 14.6 Hz), 143.9, 137.7, 133.1, 130.2, 127.2, 124.0 (d, JC,F = 4.8 Hz), 116.9 (d, JC,F = 18.0
Hz), 110.4 (d, JC,F = 18.6 Hz), 21.5; ATR-IR: ν 3254, 1595, 1378, 1167 cmꢀ1; HRMS (ESIꢀTOF)
m/z [M+H]+ calcd for C13H11BrF2NO2S 361.9662/363.9641, found 361.9656/363.9633.
N-(2-iodo-4-((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-4-methylbenzenesulfonamide (1s): To a
stirred solution of 4ꢀ((pyrrolidinꢀ1ꢀylsulfonyl)methyl)aniline (3.6 g, 15 mmol) in dichloromethane
(4 mL) and pyridine (3.6g, 45 mmol) was added iodine (8.4 g, 33 mmol) at 0°C. After stirred for
4h at room temperature, the reaction mixture was added TsCl (3.4 g, 18 mmol) and stirred for
another 3h at room temperature. Then the mixture was added dichloromethane (60 mL), H2O (45
mL) and Na2S2O3 (4.8 g, 30 mmol). After stirred for 10 minutes at 0°C, the mixture solution was
adjusted pH to 4~5 with 12M HCl solution. Then the organic layer was separated, washed with
H2O (45 mL×2) and dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was dissolved in ethyl acetate (20 mL) while stirring at 80°C. After
cooling to room temperature, the mixture was filtered to obtain a pale yellow solid (6.2 g, 79%).
Mp:215ꢀ217°C;1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 9.73 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H),
7.58 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.4 Hz,
1H), 4.39 (s, 2H), 3.12ꢀ3.09 (m, 4H), 2.38 (s, 3H), 1.78ꢀ1.75 (m, 4H); 13C NMR (150 MHz,
DMSOꢀd6) δ (ppm): 143.6, 142.1, 138.5, 138.1, 131.7, 130.6, 130.1, 127.3, 126.9, 98.3, 52.4, 48.1,
25.8, 21.5; ATR-IR: ν 3238, 2972, 1596, 1327, 1165 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd
for C18H22IN2O4S2 521.0066; Found 521.0067.
Ethyl (E)-4-acetoxybut-2-enoate (2a)45. (Method A) To
a
stirred solution of
(E)ꢀ4ꢀacetoxybutꢀ2ꢀenoic acid46 (46 mmol) and K2CO3 (23 mmol) in DMF (100 mL) was added
iodoethane (50.6 mmol) slowly at 0°C. The reaction mixture was allowed to stir for 2h at room
temperature. The solvent was then removed under reduced pressure and ethyl acetate (150 mL)
was added. The organic mixture was washed with brine (50 mL×3), and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column
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chromatography (EtOAc/PE = 1/10) to yield corresponding compound as colorless oil (6.9g, 87%).
(Method B) A mixture of ethyl (E)ꢀ4ꢀbromobutꢀ2ꢀenoate (52 mmol) and KOAc (104 mmol) in
CH3CN (100 mL) was stirred at room temperature for 5h. The solvent was then removed under
reduced pressure and ethyl acetate (150 mL) was added. The organic mixture was washed with
brine (50 mL×2), and dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by column chromatography (EtOAc/PE = 1/10) to yield
corresponding compound as colorless oil (7.2g, 81%). The characterization data were consistent
with those reported previously.
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(E)-4-morpholino-4-oxobut-2-en-1-yl acetate (2b)47. To a stirred solution of (E)ꢀ4ꢀacetoxybutꢀ2ꢀ
enoic acid (50 mmol), EDCI (60 mol) and DMAP (1 mmol) in DCM (150 mL) was added
morpholine (50 mmol) slowly at 0°C. The reaction mixture was allowed to stirred for 3h, then
washed with 1N HCl (50 mL) and brine (50 mL×2) successively, and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column
chromatography (EtOAc/PE = 1/1) to yield corresponding compound as colorless oil (8.7g, 82%).
The characterization data were consistent with those reported previously.
General produce for the cascade Tsuji-Trost reaction and Heck coupling. A threeꢀnecked
round bottom flask charged with a magnetic stir bar, 1 (1 mmol), 2 (1.2 mmol), Pd(OAc)2 (0.05
mmol), P(oꢀtol)3 (0.1 mmol), DIPEA (3 mmol) was equipped with a condenser, and then
evacuated and backfilled with N2. Anhydrous DMA (5 mL) was added through syringe and the
reaction mixture was stirred for 12~24 h at 100 °C (for iodoaniline) or 120 °C (for bromoaniline)
under nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the
solvent was removed under reduced pressure and ethyl acetate (60 mL) was added. The organic
mixture was washed with brine (20 mL×6), and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue was purified by column chromatography to yield
corresponding compound.
Ethyl 2-(1-tosyl-1H-indol-3-yl)acetate (3aa)48: Et3N as base, 12h, EtOAc/PE = 1/15, 293mg,
82%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.00 (d, J = 8.4 Hz, 1H), 7.78 (d, J =
8.0 Hz, 2H), 7.60 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 8.0 Hz,
1H), 7.23 (d, J = 8.0 Hz, 1H), 4.19 (q, J = 6.8 Hz, 2H), 3.70 (s, 2H), 2.34 (s, 3H), 1.26 (t, J = 6.8
Hz, 3H);13C NMR (150 MHz, CDCl3) δ (ppm): 170.5, 144.9, 135.3, 135.0, 130.5, 129.9, 126.8,
124.8, 124.7, 123.2, 119.6, 115.2, 113.6, 61.1, 31.1, 21.5, 14.2; ATR-IR: ν 2981, 1733, 1596，
1367, 1171 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C19H20NO4S 358.1113; Found
358.1107.
1-Morpholino-2-(1-tosyl-1H-indol-3-yl)ethan-1-one (3ab): 12h, EtOAc/PE = 1/1, 343mg,
86%, white solid. Mp:134ꢀ135°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.92 (d, J = 8.4 Hz,
1H), 7.83 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.39ꢀ7.32 (m, 3H), 7.25 (t, J
= 7.2 Hz, 1H), 3.80 (s, 2H), 3.51ꢀ3.42 (m, 8H), 2.31 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ
(ppm):168.4, 145.9, 134.8, 134.7, 131.2, 130.7, 127.1, 125.2, 125.1, 123.6, 120.9, 117.6, 113.5,
66.5, 66.5, 46.3, 42.2, 30.0, 21.5; ATR-IR: ν 2969, 1649, 1598, 1361, 1170 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C21H23N2O4S 399.1379; Found 399.1380.
Ethyl 2-(5-bromo-1-tosyl-1H-indol-3-yl)acetate (3ba): (24h, EtOAc/PE = 1/20, 178mg, 41%),
1
pale yellow solid. Mp:80ꢀ81°C; H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.88 (d, J = 9.2 Hz,
1H), 7.84 (d, J = 8.4 Hz, 2H), 7.793ꢀ7.788 (m, 2H), 7.50 (dd, J = 2.0, 8.4 Hz, 1H), 7.39 (d, J = 8.4
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Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 2.32 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H);13C NMR
(150 MHz, DMSOꢀd6) δ (ppm): 170.7, 146.2, 134.4, 133.5, 132.8, 130.8, 127.9, 127.1, 127.0,
123.5, 116.5, 115.9, 115.5, 60.9, 30.3, 21.5, 14.5; ATR-IR: ν 2974, 1738, 1593, 1366, 1168 cmꢀ1;
HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C19H19BrNO4S 436.0218/438.0198; Found
436.0212/438.0193.
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2-(5-Bromo-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3bb): 16h, EtOAc/PE = 1/1, 272
mg, 58%, white solid. Mp:178ꢀ180°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 7.88 (d, J = 8.4
Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.76 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.40 (d, J =
8.4 Hz, 2H), 3.81 (s, 2H), 3.51ꢀ3.44 (m, 8H), 2.33 (s, 3H). 13C NMR (100 MHz, DMSOꢀd6) δ
(ppm): 168.2, 146.2, 134.4, 133.6, 133.2, 130.8, 127.8, 127.1, 126.5, 123.6, 117.2, 116.4, 115.5,
66.5, 66.4, 46.2, 42.1, 29.7, 21.5; ATR-IR: ν 2965, 1638, 1598, 1370, 1173 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C21H22BrN2O4S 477.0484/479.0463; Found 477.0484/479.0465.
Ethyl 2-(5-fluoro-1-tosyl-1H-indol-3-yl)acetate (3ca): (16h, EtOAc/PE = 1/20, 309mg, 82%),
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.93 (dd, J = 4.4, 9.2 Hz, 1H), 7.76 (d, J =
8.4 Hz, 2H), 7.61 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 2.4, 9.2 Hz, 1H), 7.06 (dd, J = 2.4,
9.2 Hz, 1H), 4.19 (q, J = 6.8 Hz, 2H), 3.65 (d, J = 1.2 Hz, 2H), 2.37 (s, 3H), 1.27 (t, J = 6.8 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 170.3, 159.6 (d, JC,F = 239.7 Hz), 145.1, 135.1, 131.6
(d, JC,F = 9.3 Hz), 131.4, 129.9, 126.8, 126.4, 115.1 (d, JC,F = 3.5 Hz), 114.7 (d, JC,F = 8.0 Hz),
112.9 (d, JC,F = 23.7 Hz), 105.4 (d, JC,F = 25.0 Hz), 61.2, 31.1, 21.6, 14.1; ATR-IR: ν 2982, 1733,
1595, 1369, 1168 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C19H19FNO4S 376.1019; Found
376.1009.
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2-(5-Fluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3cb): 16h, EtOAc/PE = 1/1, 345
mg, 83%, white solid. Mp:152ꢀ153°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 7.92 (dd, J = 4.2,
9.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.40ꢀ7.37 (m, 3H), 7.20 (dt, J = 8.0, 9.0 Hz,
1H), 3.79 (s, 2H), 3.53ꢀ3.43 (m, 8H), 2.33 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm):
168.2, 159.3 (d, JC,F = 236.2 Hz), 146.1, 134.4, 132.5 (d, JC,F = 9.8 Hz), 131.2, 130.7, 127.1, 127.0,
117.7 (d, J = 3.6 Hz), 115.0 (d, J = 8.7 Hz), 113.0 (d, J = 26.2 Hz), 106.7 (d, J = 24.8 Hz), 66.5,
66.5, 46.2, 42,2, 29.8, 21.5; ATR-IR: ν 2971, 1636, 1594, 1366, 1169 cmꢀ1; HRMS (ESIꢀTOF)
m/z [M+H]+ calcd for C21H22FN2O4S 417.1284; Found 417.1282.
Ethyl 2-(1-tosyl-5-(trifluoromethoxy)-1H-indol-3-yl)acetate (3da): 16h, EtOAc/PE = 1/20,
359mg, 81%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.99 (d, J = 9.2 Hz, 1H), 7.79
(d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.38 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.20 (dd, J =
1.2, 8.8 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.68 (d, J = 0.8 Hz, 2H), 2.38 (s, 3H), 1.27 (t, J = 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 170.2, 145.3, 135.0, 133.2, 131.2, 130.0, 127.6,
126.9, 126.5, 120.6 (d, JC,F = 256.5 Hz), 118.4, 115.0, 14.6, 112.3, 61.2, 31.0, 21.6, 14.1; ATR-IR:
ν 2984, 1734, 1596, 1372, 1162 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C20H19F3NO5S
442.0936; Found 442.0931.
1-Morpholino-2-(1-tosyl-5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one
(3db):
14h,
1
EtOAc/PE = 1/1, 389 mg, 80%, white solid. Mp:141ꢀ142°C; H NMR (600 MHz, DMSOꢀd6) δ
(ppm): 8.02 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.60 (s, 1H), 7.41 (d, J =
8.4 Hz, 2H), 7.34 (d, J = 9.6 Hz, 1H), 3.83 (s, 2H), 3.52ꢀ3.42 (m, 8H), 2.33 (s, 3H); 13C NMR
(100 MHz, DMSOꢀd6) δ (ppm): 168.3, 146.3, 144.8, 144.8, 134.4, 133.1, 132.2, 130.8, 127.19,
127.16, 120.6 (d, JC,F = 254.0 Hz), 118.5, 117.6, 114.9, 113.7, 66.5, 66.5, 46.2, 42.2, 29.6, 21.5;
ATR-IR: ν 3122, 1654, 1597, 1365, 1171 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
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C22H22F3N2O5S 483.1202; Found 483.1204.
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Methyl 3-(2-ethoxy-2-oxoethyl)-1-tosyl-1H-indole-5-carboxylate (3ea): 24h, EtOAc/PE = 1/15,
244mg, 59%；recovered start material 1e 94mg, 84% brsm, pale yellow solid. Mp:133ꢀ134°C; 1H
NMR (600 MHz, DMSOꢀd6) δ (ppm): 8.20 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 9.0 Hz,
1H), 7.89ꢀ7.87 (m, 3H), 7.41 (d, J = 8.4 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.88 (s, 2H), 3.86 (s,
3H), 2.32 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, DMSOꢀd6) δ (ppm): 170.7, 166.6,
146.3, 137.2, 134.4, 130.9, 130.7, 127.2, 127.0, 126.1, 125.2, 122.6, 116.8, 113.7, 61.0, 52.6, 30.4,
21.5, 14.5; ATR-IR: ν 2979, 1735, 1721, 1609, 1593, 1370, 1164 cmꢀ1; HRMS (ESIꢀTOF) m/z
[M+H]+ calcd for C21H22NO6S 416.1168; Found 416.1165.
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Methyl 3-(2-morpholino-2-oxoethyl)-1-tosyl-1H-indole-5-carboxylate (3eb): (24h, EtOAc/PE
= 1/1, 330 mg, 72%), white solid, Mp:208ꢀ209°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 8.23
(s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.83 (s, 1H),
7.41 (d, J = 7.8 Hz, 2H), 3.88 (s, 2H), 3.86 (s, 3H), 3.54ꢀ3.44 (m, 8H), 2.33 (s, 3H); 13C NMR
(100 MHz, DMSOꢀd6) δ (ppm): 168.3, 168.7, 146.3, 137.3, 134.4, 131.2, 130.8, 127.2, 126.5,
126.1, 122.9, 118.1, 113.6, 66.5, 52,6, 46.2, 42.2, 29.7, 21.5; ATR-IR: ν 2953, 1729, 1648, 1613,
1597, 1364, 1174 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C23H25N2O6S 457.1433; Found
457.1430.
Ethyl 2-(6-bromo-1-tosyl-1H-indol-3-yl)acetate (3fa): 16h, EtOAc/PE = 1/15, 253 mg, 58%,
1
pale yellow solid. Mp:86ꢀ87°C; H NMR (400 MHz, DMSOꢀd6) δ (ppm): 8.04 (d, J = 1.6 Hz,
1H), 7.87 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 1.6, 8.4 Hz, 1H),
7.42 (d, J = 8.4 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 2.33 (s, 3H), 1.16 (t, J = 7.2 Hz,
3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 170.6, 146.3, 135.4, 134.4, 130.9, 129.9, 127.1,
126.79, 126.3, 122.6, 118.0, 116,3, 116.0, 60.9, 30.3, 21.5, 14.5; ATR-IR: ν 2982, 1740, 1594,
1369, 1170 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C19H19BrNO4S 436.0218/438.0198;
Found 436.0207/438.0190.
2-(6-Bromo-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3fb): 24h, EtOAc/PE = 1/2, 292
mg, 61%, white solid. Mp:99ꢀ100°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 8.04 (s, 1H), 7.86
(d, J = 9.6 Hz, 2H), 7.75 (s, 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.45ꢀ7.42 (m, 3H), 3.81 (s, 2H),
3.51ꢀ3.42 (m, 8H), 2.34 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm): 168.2, 146.3, 135.4,
130.9, 130.3, 127.1, 126.7, 125.8, 122.9, 117.9, 117.6, 115.9, 66.5, 66.4, 46.2, 42.2, 29.8, 21.5;
ATR-IR: ν 3103, 1647, 1595, 1375, 1167 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
C21H22BrN2O4S 477.0484/479.0463; Found 477.0482/479.0463.
Ethyl 2-(6-fluoro-1-tosyl-1H-indol-3-yl)acetate (3ga) 24h, EtOAc/PE = 1/20, 233mg, 62%；
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recovered start material 1g 31mg, 68% brsm, pale yellow oil. H NMR (400 MHz, CDCl3) δ
(ppm): 7.78 (d, J = 8.0 Hz, 2H), 7.72 (dd, J = 2.4, 9.6 Hz, 1H), 7.55 (s, 1H), 7.45 (dd, J = 5.6, 8.8
Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.02 (dt, J = 2.4, 8.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.67 (d,
J = 0.8 Hz, 2H), 2.38 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm):
170.4, 161.0 (d, JC,F = 239.7 Hz), 145.2, 135.2 (d, JC,F = 12.5 Hz), 135.1, 130.0, 126.9, 126.7,
124.9 (d, JC,F = 3.8 Hz), 120.5 (d, JC,F = 9.8 Hz), 115.0, 111.7 (d, JC,F = 24.0 Hz), 101.0 (d, JC,F
=
27.8 Hz), 61.1, 31.1. 21.6, 14.1; ATR-IR: ν 2924, 1733, 1597, 1369, 1170 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C19H19FNO4S 376.1019; Found 376.1010.
2-(6-Fluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3gb): 24h, EtOAc/PE = 1/1, 249
mg, 60%, white solid. Mp:160ꢀ162°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.88 (d, J = 8.8
Hz, 2H), 7.71ꢀ7.68 (m, 2H), 7.59 (dd, J = 5.6, 8.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.15 (dt, J =
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1.6, 8.8 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 2H), 3.50ꢀ3.41 (m, 8H), 2.33 (s, 3H); 13C NMR (150 MHz,
DMSOꢀd6) δ (ppm): 168.3, 160.6 (d, JC,F = 239.7 Hz), 146.2, 134.8 (d, JC,F = 12.3 Hz), 134.4,
130.8, 127.8, 127.2, 125.5 (d, JC,F = 3.2 Hz), 122.4 (d, JC,F = 10.2 Hz), 117.6, 111.9 (d, JC,F = 22.7
Hz), 100.6 (d, JC,F = 27.8 Hz), 66.5, 66.5, 42.2, 46.3, 29.9, 21.5; ATR-IR: ν 2966, 1651, 1598,
1361, 1169 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C21H22FN2O4S 417.1284; Found
417.1284.
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Ethyl 2-(6-methoxy-1-tosyl-1H-indol-3-yl)acetate (3ha): 24h, EtOAc/PE = 1/20, 166 mg, 43%,
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pale yellow oil. H NMR (400 MHz, CDCl3) δ (ppm): 7.76 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 2.0
Hz, 1H), 7.46 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.89 (dd, J = 2.0, 8.4 Hz,
1H), 4.17 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.65 (s, 2H), 2.36 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13
C
NMR (150 MHz, CDCl3) δ (ppm): 170.6, 158.1, 144.9, 136.1, 135.3, 129.8, 126.8, 124.3, 123.4,
120.1, 115.3, 112.3, 98.0, 61.0, 55.8, 31.2, 21.6, 14.2; ATR-IR: ν 2981, 1732, 1596, 1365, 1168
cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C20H22NO5S 388.1219; Found 388.1216.
Ethyl
(E)-4-((N-(2-bromo-5-methoxyphenyl)-4-methylphenyl)sulfonamido)but-2-enoate
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(3ha’): 24h, EtOAc/PE = 1/20, 198 mg, 51%, pale yellow oil. H NMR (400 MHz, CDCl3) δ
(ppm): 7.768 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 6.90 (dt, J =
6.4, 16.0 Hz, 1H), 6.81ꢀ6.77 (m, 2H), 5.88 (dt, J = 1.2, 14.8 Hz, 1H), 4.41ꢀ4.28 (m, 2H), 4.18 (q, J
= 7.2 Hz, 2H), 3.76 (s, 3H), 2.46 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm):165.6, 159.1, 143.9, 141.8, 138.1, 136.5, 134.1, 129.6, 127.9, 124.4, 118.2, 116.3, 115,1,
60.5, 55.6, 51.9, 21.6, 14.2; ATR-IR: ν 2980, 1717, 1592, 1352, 1159 cmꢀ1; HRMS (ESIꢀTOF)
m/z [M+H]+ calcd for C20H23BrNO5S 468.0480/470.0460; Found 468.0479/470.0458.
2-(6-Methoxy-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3hb): 24h, EtOAc/PE = 1/2,
248 mg, 58%, white solid, Mp:181ꢀ182°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 7.83 (d, J =
7.8 Hz, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.40ꢀ7.39 (m, 3H), 6.90 (d, J = 9.0 Hz, 1H),
3.83 (s, 3H), 3.75 (s, 2H), 3.49ꢀ3.42 (m, 8H), 2.32 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ
(ppm): 168.4, 158.1, 145.9, 135.9, 134.5, 130.7, 127.1, 124.8, 123.6, 121.6, 117.6, 112.4, 97.9,
66.5, 66.4, 56.0, 46.3, 42.1, 30.2,21.5; ATR-IR: ν 3109, 1647, 1596, 1372, 1167 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C22H25N2O5S 429.1484; Found 429.1482.
Methyl 3-(2-ethoxy-2-oxoethyl)-1-tosyl-1H-indole-6-carboxylate (3ia): 12h, EtOAc/PE = 1/15,
358 mg, 86%, pale yellow solid, Mp:99ꢀ100°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 8.52 (s,
1H), 7.98 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.42
(d, J = 8.4 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 2H), 2.32 (s, 3H), 1.17 (t, J =
7.2 Hz, 3H), 13C NMR (100 MHz, DMSOꢀd6) δ (ppm): 170.6, 166.7, 146.3, 134.6, 134.5, 134.3,
130.9, 128.9, 127.0, 126.4, 124.3, 121.0, 116.6, 114.6, 61.0, 52.8, 30.3, 21.5, 14.5; ATR-IR: ν
2955, 1719, 1706, 1594, 1371, 1303, 1170 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
C21H22NO6S 416.1168; Found 416.1164.
Methyl 3-(2-morpholino-2-oxoethyl)-1-tosyl-1H-indole-6-carboxylate (3ib): 12h, EtOAc/PE =
1/2, 406 mg, 89%, white solid, Mp:212ꢀ213°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 8.52 (d,
J = 0.8 Hz, 1H), 7.93 (s, 1H), 7.86 (dd, J = 1.4, 8.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.69 (d, J =
8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 2H), 3.51ꢀ3.42 (m, 8H), 2.32 (s, 3H);
13C NMR (100 MHz, DMSOꢀd6) δ (ppm): 168.2, 168.7, 146.3, 135.0, 134.5, 134.3, 130.9, 128.49,
126.9, 126.3, 124.3, 121.3, 117.9, 114.6, 66.5, 66.5, 52.8, 46.2, 42.2, 29.7, 21.5; ATR-IR: ν 2967,
1710, 1645, 1593, 1370, 1169 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C23H25N2O6S
457.1433; Found 457.1435.
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Ethyl 2-(7-fluoro-1-tosyl-1H-indol-3-yl)acetate (3ja): 24h, EtOAc/PE = 1/10~1/5, 316mg, 84%,
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pale yellow oil. H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 7.6 Hz, 2H), 7.79 (s, 1H),
7.32ꢀ7.28 (m, 3H), 7.19ꢀ7.14 (m, 1H), 7.00ꢀ6.95 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.73 (s, 2H),
2.40 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ (ppm): 170.4, 149.7 (d, JC,F
= 249.1 Hz), 145.0, 135.5, 134.7 (d, JC,F = 249.1 Hz), 129.8, 127.7 (d, JC,F = 3.0 Hz), 127.2, 123.9
(d, JC,F = 7.4 Hz), 122.1 (d, JC,F = 10.9 Hz), 115.4 (d, JC,F = 3.6 Hz), 113.8 (d, JC,F = 2.1 Hz), 111.4
(d, JC,F = 19.8 Hz), 61.2, 31.0, 21.6, 14.2; ATR-IR: ν 2982, 1595, 1369, 1171 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C19H19FNO4S 376.1019, found 376.1017.
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2-(7-fluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3jb): 16h, EtOAc/PE = 1/1~1/3,
353mg, 85%, pale yellow solid. Mp:190ꢀ192°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.84 (s,
1H), 7.78 (d, J = 7.6 Hz, 2H), 7.45ꢀ7.41 (m, 3H), 7.25ꢀ7.20 (m, 1H), 7.14ꢀ7.09 (m, 1H), 3.86 (s,
2H), 3.57ꢀ3.45 (m, 8H), 2.35 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 168.2, 149.3 (d,
JC,F = 246.0 Hz), 145.9, 135.6, 135.1, 130.7, 127.7, 127.5, 124.7 (d, JC,F = 6.2 Hz), 121.5 (d, JC,F
=
9.2 Hz), 117.1, 116.6, 111.7 (d, JC,F = 21.0 Hz), 66.6, 46.3, 42.2, 29.7, 21.5; ATR-IR: ν 2980,
1655, 1596, 1365, 1171 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C21H22FN2O4S 417.1284,
found 417.1285.
Methyl 3-(2-ethoxy-2-oxoethyl)-1-tosyl-1H-indole-7-carboxylate (3ka): 12h, EtOAc/PE = 1/10,
302mg, 73%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.61ꢀ7.51 (m, 5H), 7.33 (t, J
= 7.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 4.14 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.63 (s, 2H), 2.34 (s,
3H), 1.22 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 170.0, 168.9, 144.7, 134.7,
132.7, 132.2, 129.4, 128.2, 126.9, 125.8, 123.8, 122.7, 122.1, 117.6, 61.1, 52.6, 31.0, 21.5, 14.1;
ATR-IR: ν 2982, 1727, 1595, 1368, 1171 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
C21H22NO6S 416.1168, found 416.1165.
Methyl 3-(2-morpholino-2-oxoethyl)-1-tosyl-1H-indole-7-carboxylate (3kb): 12h, EtOAc/PE =
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1/1~1/2, 319mg, 70%, pale yellow oil. H NMR (400 MHz, CDCl3) δ (ppm): 7.65 (dd, J = 8.0,
1.2 Hz, 1H), 7.65 (d, J = 8.0, 1.2 Hz, 2H), 7.55 (dd, J = 7.2, 0.8 Hz, 1H),7.40 (s, 1H), 7.34 (t, J =
7.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 3.70 (s, 2H), 3.64ꢀ3.32 (m, 8H), 2.35 (s, 3H);
13C NMR (100 MHz, , CDCl3) δ (ppm): 168.8, 167.9, 144.9, 134.9, 132.5, 132.2, 129.6, 127.3,
126.8, 126.0, 123.9, 122.7, 122.2, 118.1, 66.7, 66.4, 52.6, 46.5, 42.1, 30.7, 21.6; ATR-IR: ν 2922,
1727, 1595, 1365, 1173 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C23H25N2O6S 457.1433,
found 457.1431.
Ethyl 2-(5,7-difluoro-1-tosyl-1H-indol-3-yl)acetate (3la): 12h, EtOAc/PE = 1/10~1/6, 357mg,
91%, pale yellow solid. Mp:93ꢀ94°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.96 (s, 1H), 7.78
(d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (td, J = 9.6, 2.0
Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.85 (s, 2H), 2.36 (s, 3H), 1.20 (t, J = 6.8 Hz, 3H); 13C NMR
(150 MHz, DMSOꢀd6) δ (ppm): 170.6, 158.5 (dd, JC,F = 238.7, 10.5 Hz), 148.8 (dd, JC,F = 250.5,
13.8 Hz), 146.2, 135.3 (dd, JC,F = 10.5, 3.8 Hz), 134.8, 130.8, 129.9, 127.5, 118.4 (d, JC,F = 11.9
Hz), 115.6, 61.0, 30.1, 21.5; ATR-IR: ν 2983, 1740, 1597, 1362, 1164 cmꢀ1; HRMS (ESIꢀTOF)
m/z [M+H]+ calcd for C19H18F2NO4S 394.0925, found 394.0918.
2-(5,7-difluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3lb): 12h, EtOAc/PE = 1/1,
361mg, 83%, pale yellow solid. Mp:185ꢀ188°C;1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.92 (s,
1H), 7.78 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (td, J =
9.2, 2.0 Hz, 1H), 3.84 (s, 2H), 3.57ꢀ3.45 (m, 8H), 2.36 (s, 3H);13C NMR (150 MHz, DMSOꢀd6) δ
(ppm): 168.2, 158.5 (dd, JC,F = 239.7, 11.4 Hz), 148.8 (dd, JC,F = 249.3, 12.5 Hz), 146.1, 135.7 (d,
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JC,F = 6.5 Hz), 134.9, 130.8, 129.5, 127.5, 118.4 (d, JC,F = 11.7 Hz), 116.9, 103.0 (dd, JC,F = 23.6
Hz), 101.1 (dd, JC,F = 30.5, 23.9 Hz), 66.5, 66.5, 46.2, 29.5, 21.5; ATR-IR: ν 2963, 1637, 1603,
1364, 1170 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C21H21F2N2O4S 435.1190,
found435.1190.
Ethyl 2-(7-chloro-5-fluoro-1-tosyl-1H-indol-3-yl)acetate (3ma): 16h, EtOAc/PE = 1/10~1/5,
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340mg, 83%, pale yellow solid. Mp:82ꢀ84°C; H NMR (400 MHz, DMSOꢀd6) δ (ppm): 8.05 (s,
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1H), 7.72 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 8.4, 2.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.32 (dd, J
= 9.2, 2.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.88 (s, 2H), 2.38 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H);
13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 170.6, 158.4 (d, JC,F = 239.3 Hz), 145.7, 136.3, 135.6
(d, JC,F = 9.9 Hz), 131.5, 130.6, 128.5, 127.3, 119.0 (d, JC,F = 13.2 Hz), 115.0 (d, JC,F = 29.9 Hz),
115.0 (d, JC,F = 5.0 Hz), 105.8 (d, JC,F = 23.6 Hz), 61.0, 30.1, 21.5, 14.5; ATR-IR: ν 2987, 1739,
1596, 1365, 1171 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C19H18ClFNO4S 410.0629,
found 410.0630.
2-(7-chloro-5-fluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3mb): 16h, EtOAc/PE
= 2/1, 359mg, 80%, pale yellow solid. Mp:199ꢀ200°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm):
8.0 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.31
(dd, J = 8.8, 2.0 Hz, 1H), 3.87 (s, 2H), 3.60ꢀ3.47 (m, 8H), 2.38 (s, 3H); 13C NMR (150 MHz,
DMSOꢀd6) δ (ppm): 168.2, 158.3 (d, JC,F = 242.0 Hz), 145.7, 136.3, 136.1 (d, JC,F = 10.4 Hz),
131.1, 130.6, 128.5, 127.3, 118.9 (d, JC,F = 11.3 Hz), 116.3 (d, JC,F = 2.9 Hz), 114.9 (d, JC,F = 28.7
Hz), 106.0 (d, JC,F = 23.4 Hz), 66.6, 66.5, 46.2, 42.2, 29.4, 21.5; ATR-IR: ν 2972, 1641, 1604,
1346, 1170 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C21H21ClFN2O4S 451.0895, found
451.0894.
2-(4-fluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3nb): 24h, EtOAc/PE = 1/1~1/2,
216mg, 52%, pale yellow solid. Mp:204ꢀ206°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.87 (d,
J = 8.8 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.35ꢀ7.29 (m, 1H),
7.03ꢀ6.99 (m, 1H), 3.84 (s, 2H), 3.59ꢀ3.45 (m, 8H), 2.34 (s, 3H);13C NMR (150 MHz, DMSOꢀd6)
δ (ppm): 168.6, 156.4 (d, JC,F = 246.3 Hz), 146.2, 137.0 (d, JC,F = 9.8 Hz), 134.4, 130.8, 127.2,
126.2 (d, JC,F = 5.9 Hz), 125.5, 119.8 (d, JC,F = 19.5 Hz), 115.7, 110.0, 109.3 (d, JC,F = 18.6 Hz),
66.6, 66.6, 46.0, 42.2, 30.4, 21.5; ATR-IR: ν 2959, 1641, 1591, 1373, 1177 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C21H22FN2O4S 417.1284, found 417.1287.
2-(4-chloro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3ob): 24h, EtOAc/PE = 1/1~1/2,
91mg, 21%, pale yellow solid. Mp:216ꢀ218°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.91 (d,
J = 7.6 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.73 (s, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz,
1H), 7.25 (d, J = 7.6 Hz, 1H), 3.94 (s, 2H), 3.60ꢀ3.34 (m, 8H), 2.33 (s, 3H);13C NMR (100 MHz,
CDCl3) δ (ppm): 169.0, 145.3, 136.4, 134.8, 130.0, 127.1, 126.9, 126.5, 125.8, 125.4, 124.4, 115.8,
112.5, 66.9, 66.6, 46.3, 42.2, 31.5, 21.6; ATR-IR: ν 2958, 1637, 1591, 1371, 1172 cmꢀ1; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C21H22ClN2O4S 433.0989, found 433.0987.
2-(4,5-difluoro-1-tosyl-1H-indol-3-yl)-1-morpholinoethan-1-one (3pb): 16h, EtOAc/PE =
1/1~1/2, 340mg, 78%, pale yellow solid. Mp:166ꢀ168°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm):
7.87 (d, J = 8.0 Hz, 2H), 7.75ꢀ7.72 (m, 2H), 7.43ꢀ7.35 (m, 3H), 3.86 (s, 2H), 3.60ꢀ3.45 (m, 8H),
2.34 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 168.3, 146.4 (dd, JC,F = 240.2, 10.1 Hz),
145.5, 143.6 (dd, JC,F = 249.0, 14.1 Hz), 134.7, 132.4 (d, JC,F = 6.9 Hz), 130.1, 126.9, 126.3, 120.7
(dd, JC,F = 15.5 Hz), 114.2 (d, JC,F = 20.9 Hz), 109.5 (t, JC,F = 5.5 Hz), 66.9, 66.6, 46.3, 42.3, 30.5,
21.6; ATR-IR: ν 2960, 1637, 1591, 1373, 1170 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
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C21H21F2N2O4S 435.1190, found 435.1187.
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Ethyl 2-(1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)acetate (3qa): 100°C, 24h, EtOAc/PE = 1/15,
259mg, 72%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.54 (dd, J = 1.6, 4.8 Hz, 1H),
8.26 (dd, J = 1.6, 8.8 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.27ꢀ7.25 (m, 3H), 4.21 (q, J
= 7.2 Hz, 2H), 3.86 (s, 2H), 2.37 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm): 170.7, 147.7, 146.0, 145.4, 135.0, 130.1, 128.5, 127.7, 126.8, 120.9, 119.3, 116.3, 61.1,
29.2, 21.6, 14.2; ATR-IR: ν 2981, 1732, 1597, 1366, 1168 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+
calcd for C18H19N2O4S 359.1066; Found 359.1066.
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1-Morpholino-2-(1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (3qb): 12h, EtOAc/PE =
1/4, 324mg, 81%, white solid. Mp:136ꢀ137°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 8.50 (d,
J = 4.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 8.4
Hz, 2H), 7.37 (dd, J = 4.8, 5.6 Hz, 1H), 3.82 (s, 2H), 3.56ꢀ3.44 (m, 8H), 2.33 (s, 3H); 13C NMR
(100 MHz, DMSOꢀd6) δ (ppm): 168.4, 148.0, 146.3, 146.2, 134.4, 130.8, 128.4, 128.0, 127.2,
121.1, 120.0, 118.5, 66.5, 46.2, 42.2, 28.2, 21.5; ATR-IR: ν 3100, 1651, 1601, 1369, 1168 cmꢀ1;
HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C20H22N3O4S 400.1331; Found 400.1326.
Ethyl 2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (3ra): 24h, EtOAc/PE = 1/20, 241mg,
67%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.45 (dd, J = 1.6, 4.4 Hz, 1H), 8.09 (d,
J = 8.8 Hz, 2H), 7.88 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 (s, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.20 (dd, J =
4.4, 8.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.69 (d, J = 0.8 Hz, 2H), 2.38 (s, 3H), 1.27 (t, J = 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3 δ (ppm): 170.3, 147.3, 145.1, 145.1, 135.5, 129.6, 128.3,
128.0, 124.6, 122.8, 118.7, 111.6, 61.2, 31.4, 21.6, 14.2; ATR-IR: ν 2981, 1732, 1596, 1370, 1173
cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C18H19N2O4S 359.1066; Found 359.1062.
1-Morpholino-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (3rb): 24h, EtOAc/PE =
1/2, 248mg, 62%, white solid. Mp:134ꢀ136°C; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm): 8.36 (d,
J = 3.6 Hz, 1H), 8.00ꢀ7.96 (m, 3H), 7.81 (s, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.29 (dd, J = 4.8, 7.8
Hz, 1H), 3.85 (s, 2H), 3.56ꢀ3.44 (m, 8H), 2.34 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm):
168.4, 147.1, 145.9, 145.1, 135.2, 130.4, 129.8, 127.9, 124.9, 123.5, 119.4, 114.47, 66.5, 66.5,
46.3, 42.2, 29.9, 21.5; ATR-IR: ν 2963, 1665, 1589, 1353, 1158 cmꢀ1; HRMS (ESIꢀTOF) m/z
[M+H]+ calcd for C20H22N3O4S 400.1331; Found 400.1329.
Ethyl
2-(5-((pyrrolidin-1-ylsulfonyl)methyl)-1-tosyl-1H-indol-3-yl)acetate
(3sa):
A
threeꢀnecked round bottom flask charged with a magnetic stir bar, 1l (6.0 g, 11.5 mmol), 2 (2.0 g,
11.5 mmol), Pd(OAc)2 (78 mg, 0.35 mmol), P(oꢀtol)3 (213 mg, 0.70 mmol), DIPEA (3.6 g, 27.8
mmol) was added anhydrous DMA (50 mL), then equipped with a condenser, evacuated and
backfilled with N2. The reaction mixture was stirred overnight at 100°C under nitrogen
atmosphere and then was added water (5 mL) and stirred for another 1 minute. After cooling to
room temperature, the mixture was stilled for 2h and filtered. The solid was washed successively
with ethyl acetate (20 mL) and ethanol (10 mL), and then was dissolved in ethyl acetate (20 mL)
while stirring at 80°C. After cooling to room temperature, the mixture was filtered to obtain a
1
white solid (4.4 g, 76%). Mp:216ꢀ218°C; H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.92 (d, J =
8.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.76 (s, 1H), 7.56 (s, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.38 (d,
J = 8.4 Hz, 2H), 4.47 (s, 2H), 4.09 (d, J = 7.2 Hz, 2H), 3.78 (s, 2H), 3.12ꢀ3.08 (m, 4H), 2.31 (s,
3H), 1.75ꢀ1.72 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 170.7,
146.1, 134.43, 134.38, 130.8, 130.7, 128.1, 127.1, 126.3, 125.6, 122.8, 116.2, 113.5, 61.0, 53.6,
48.0, 30.5, 25.7, 21.5, 14.5; ATR-IR: ν 2978, 1721, 1594, 1327, 1177 cmꢀ1; HRMS (ESIꢀTOF)
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m/z [M+H]+ calcd for C24H29N2O6S2 505.1467; Found 505.1461.
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2-(5-((pyrrolidin-1-ylsulfonyl)methyl)-1-tosyl-1H-indol-3-yl)ethan-1-ol (3sa-1): To a solution
of 3la (4.2 g, 8.3 mmol) in DMA (30 mL) was added anhydrous CaCl2 (1.4 g, 12.6 mmol) and
NaBH4 (1.9 g, 50 mmol). The reaction mixture was stirred for 24h at 40 °C. Then the mixture was
adjusted pH to 2~3 with 1M HCl solution at 0°C, and then added water (60 mL). After stilled for
2h, the mixture was filtered. The solid was washed with ethyl acetate (20 mL) and ethanol (10
mL), and then was dissolved in ethyl acetate (20 mL) while stirring at 80°C. After cooling to room
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temperature, the mixture was filtered to obtain a white solid (3.6 g, 95%). Mp:204ꢀ206°C; H
NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.89 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.61 (s,
2H), 7.38ꢀ7.35 (m, 3H), 4.77 (t, J = 5.4 Hz, 1H), 4.48 (s, 2H), 3.67 (q, J = 5.6 Hz, 2H), 3.11ꢀ3.08
(m, 4H), 2.78 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H), 1.75ꢀ1.72 (m, 4H); 13C NMR (150 MHz, DMSOꢀd6)
δ (ppm): 145.8, 134.5, 131.4, 130.6, 127.8, 127.1, 125.4, 124.8, 122.7, 120.8, 113.5, 60.7, 53.6,
48.0, 28.5, 25.7, 21.5; ATR-IR: ν 3496, 3104, 1594, 1317, 1171 cmꢀ1; HRMS (ESIꢀTOF) m/z
[M+Na]+ calcd for C22H26N2O5S2Na 485.1181; Found 485.1174.
2-(5-((pyrrolidin-1-ylsulfonyl)methyl)-1H-indol-3-yl)ethan-1-ol (3sa-2): To a solution of 3la-1 (3.3
g, 7.1 mmol) in MeOH (30 mL) was added KOH (1.2 g, 21.3 mmol). The reaction mixture was
stirred for overnight at 70 °C. The mixture was adjusted pH to 7 with 1M HCl solution at 0°C, and
then MeOH was removed under reduced pressure. The residue mixture was extracted with ethyl
acetate (50 mL×2). The organic layer was combined and then washed with saturated NaCl solution
(60 mL), dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/PE = 1:1) to obtain a white solid
(2.1g, 96%). Mp:186ꢀ188°C; 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 10.87 (s, 1H), 7.56 (s, 1H),
7.31 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 1.2 Hz, 1H), 4.66 (t, J = 5.4
Hz, 1H), 4.45 (s, 2H), 3.64 (q, J = 6.6 Hz, 2H), 3.12ꢀ3.09 (m, 4H), 2.84 (t, J = 7.4 Hz, 2H),
1.77ꢀ1.73 (m, 4H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 136.3, 127.8, 124.2, 124.0, 121.4,
119.7, 112.0, 111.5, 62.1, 54.7, 48.1, 29.3, 25.8; ATR-IR: ν 3497, 3273, 2934, 1627, 1302, 1113
cmꢀ1; HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C15H20N2O3SNa 331.1092; Found 331.1093.
N,N-dimethyl-2-(5-((pyrrolidin-1-ylsulfonyl)methyl)-1H-indol-3-yl)ethan-1-amine
(Almotriptan): To a solution of 3la-2 (1.8 g, 5.8 mmol) in CH3CN (30 mL) was added TEA (708
mg, 7.0 mmol) at 0 °C. After stirring for 10mins, the mixture was slowly added MeSO2Cl (802 mg,
7.0 mmol) and then warmed to room temperature. After stirring for another 20mins, the mixture
was added dimethylamine (40% in water, 3.9g, 35 mmol) in one portion and then heated to 60 °C.
The solvent was removed under reduced pressure after 5h and the residue was added ethyl acetate
(80 mL). The organic layer was then washed with saturated NaCl solution (50 mL×2), dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was
crystallized with acetone to obtain a white solid (1.5g, 78%). Mp:110ꢀ112°C; 1H NMR (400 MHz,
DMSOꢀd6) δ (ppm): 10.86 (s, 1H), 7.56 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H),
7.12 (dd, J = 8.4, 1.2 Hz, 1H), 4.46 (s, 2H), 3.12ꢀ3.09 (m, 4H), 2.81 (t, J = 8.0 Hz, 2H), 2.51 (t, J =
8.0 Hz, 2H), 2.21 (s, 6H), 1.76ꢀ1.73 (m, 4H); 13C NMR (150 MHz, DMSOꢀd6) δ (ppm): 136.3,
127.6, 124.2, 123.7, 121.3, 119.7, 113.1, 111.6, 60.5, 54.8, 48.1, 45.6, 25.8, 23.6; ATR-IR: ν 2849,
1624, 1317, 1146 cmꢀ1; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C17H26N3O2S 336.1746; Found
336.1744.
Acknowledgments
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We are grateful for the financial support from NSFC (81502930) and STCSM (15QB1404400)
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H and 13C NMR spectra for all new compounds (PDF)
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