Scale-up synthesis of antidepressant drug vilazodone

Article abstract of DOI:10.1021/op300171m

A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel-Crafts acylation of 1-tosyl-1H-indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH₄/CF ₃COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2- carboxylate hydrochloride, one-step deprotection and esterolysis, and the final ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity. This convenient and economical procedure is remarkably applicable for scale-up production.

Full text of DOI:10.1021/op300171m

Article
pubs.acs.org/OPRD
Scale-Up Synthesis of Antidepressant Drug Vilazodone
Bin Hu, Qiao Song, and Yungen Xu*
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
ABSTRACT: A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel−Crafts acylation of
1-tosyl-1H-indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH4/CF3COOH system coupled
with ethyl 5-(piperazin-1-yl)-benzofuran-2-carboxylate hydrochloride, one-step deprotection and esterolysis, and the final
ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity. This convenient and economical
procedure is remarkably applicable for scale-up production.
carbonitrile (2a) furnishes the product 3-(4-chlorobutyl)-1H-
indole-5-carbonitrile (3a) in a low yield (26%), and the
resulting solid 3a is difficult to purify chromatographically.2 We
postulated that the significantly low yield and laborious
purification process reported in the literature might result
from the over-reduction of indole to indoline by a variety of
hydride sources in the presence of various acids, such as Et3SiH
in CF3COOH (TFA),4 NaBH4 in carboxylic acid or TFA,5
NaCNBH3 in acetic acid or TFA,6 or Me2SiHCl in Lewis acids,
INTRODUCTION
Vilazodone (Figure 1), a dual selective serotonin reuptake
inhibitor (SSRI) and serotonin 5-HT1A receptor partial agonist,
■
7
like InCl3 (Scheme 2). The partial protonation of N-
Figure 1. Vilazodone (1).
unprotected or N-alkylindoles in acid media might underlie
the over-reduction of the compound 2a. In order to
demonstrate this hypothesis, we tried different reducing agents
under acid media to reduce the molecule 2a. As indicated in
Table 1, the compound 2a was indeed over-reduced into
indoline by most of reductants, and accordingly the product 3a
was obtained at a very low yield, which simultaneously required
laborious separation procedures. For instance, a large portion of
compound 2a would be reduced to the molecule 3b (the
indoline structure), while a small quantity of compound 2a was
converted to the desired product 3a in the conditions of the
NaBH4/TFA system.
Finally, the intermediate 5a is synthesized from 3a and
commercially available 4 (the synthesis is also published8) in
32% yield. Although 5a could be obtained by this method in
moderate yield, the process obviously was not amenable to
industrial manufacturing due to the involvement of column
chromatography. Furthermore, the costly catalyst 1-methyl-2-
chloropyridinium iodide (Mukaiyama reagent) used in the
literature to synthesize the target molecule vilazodone might
further impede large-scale production. Thus all these undesired
results prompted us to search for an alternate route.
is a novel antidepressant drug recently approved by the Food
and Drug Administration (FDA) for the treatment of major
depressive disorder (MDD).1 The reported synthetic ap-
proaches,2 however, proceed with complicated workups,
laborious purification procedures, fairly expensive or unfriendly
catalysts, such as sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al) and 1-methyl-2-chloropyridinium iodide
(Mukaiyama reagent), and merely 3.5% overall yield. Although
the further modifications of the above procedures have also
been published in many patents,3 all these approaches suffer
from several drawbacks, including low overall yields,
complicated purification process, and the employment of
some expensive, unstable, or environmentally unfriendly
reagents and catalysts. Thus, there still remains a high unmet
need for a high-yield process applicable to the multikilogram
production of vilazodone. Herein we described the develop-
ment of a scalable synthesis of vilazodone (1) in a fairly high
overall yield.
RESULTS AND DISCUSSION
■
Process Development for the Preparation of 1,
Vilazodone. In contrast, herein we identified an efficient
synthetic route to vilazodone, starting from N-protected 5-
cyanoindole since indoles bearing strong electron-withdrawing
groups, such as p-toluenesulfonyl or phenylsulfonyl functional
groups, are resistant to C-3 protonation and thus effectively
inert to over-reduction (Scheme 3).9 The synthesis of N-
protected 5-cyanoindole was quite convenient to proceed with
Initial Synthesis of 1, Vilazodone. The synthesis of 3-
acylindoles is often complicated by the fact that indole displays
ambident reactivity leading to competing substitution at
nitrogen. For example, the synthesis of 3-(4-chlorobutanoyl)-
1H-indole-5-carbonitrile 2a (73%) (Scheme 1) in a mixture of
isobutyl-AlCl2 and 4-chlorobutyryl chloride would unavoidably
produce N-substituted indoles, such as 1-(4-chlorobutanoyl)-
1H-indole-5-carbonitrile (2b), which was difficult to separate
chromatographically.
Additionally, the following selective deoxygenation of the
keto function group of 3-(4-chlorobutanoyl)-1H-indole-5-
Received: June 28, 2012
Published: August 29, 2012
© 2012 American Chemical Society
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Scheme 1. Initial Synthesis of 1, Vilazodone
Scheme 2. Over-Reduction of Indole to Indoline under the Acidic Conditions
First, the Friedel−Crafts reaction would selectively substitute
at C-3 position of indole ring without any N-substituted
byproduct. The product 2 could readily be prepared through
recrystallization in n-propanol. Moreover, the electron-with-
drawing effect of protecting groups, such as tosyl group or
phenylsulfonyl group, would prevent the over-reduction of
indole to indoline by reducing agents under acidic conditions,
and therefore the selective deoxygenation of the keto group was
accomplished with decent yields under mild conditions
(Scheme 3).
Table 1. Reduction of Compound 2a with Reducing Agents
under Different Acid Conditions
a
b
entry
subject
conditions
products
ratio
yield
1
2
3
4
5
6
2a
2a
2a
2a
2a
2a
NaBH4/TFA
3a:3b
1:4
31%
--
c
NaBH4/HOAc
NaBH3CN/TFA
NaBH3CN/HOAc
HSi(C2H5)3/TFA
Red-Al/THF
--
--
d
3a:3b
>1:10
>1:10
1:8
56%
22%
69%
--
d
3a:3b
3a:3b
--
--
a
Conditions were typically the reducing agents dissolved in acid
For further optimization of this condition, we had explored a
variety of reducing agents under different acid media to reduce
the keto group of N-protected indole 2. The results,
summarized in Table 2, indicated that most of the reducing
agents under acidic conditions could selectively deoxygenize
the ketone group without any over-reduction byproducts.11
Compared with acetic acid (HOAc), the trifluoroacetic acid
(TFA) displayed much better characteristics for the accom-
plishments of the initial reduction of the ketone carbonyl by the
stronger trifluoroacetoxyborohydride, acid-catalyzed protona-
tion of the resultant alcohol, and loss of water. Finally, NaBH4/
TFA system was adopted by us thanks to its excellent yield
(95%) and relevant low cost.
solutions at 0 °C to which was added compound 2a in CH2Cl2
b
solution, and the reaction mixture was stirred at rt for 6 h. Isolated
c
total yield of indole and indoline derivatives. “--” represents that no
d
product is produced. Minute amount of 3a is formed.
an excellent yield (98%).10 This simple protection provided
several major benefits.
Scheme 3. Alternative Synthesis of the Key Intermediate 3
The important intermediate 3-(4-chlorobutanoyl)-1-tosyl-
1H-indole-5-carbonitrile (2) was prepared by stirring a mixture
of 1-tosyl-1H-indole-5-carbonitrile and 4-chlorbutyryl chloride
in the presence of the catalyst AlCl3 at the ambient temperature
for 8 h. The reaction mixture was then poured into ice water,
followed by extraction with CH2Cl2. The combined organic
phase was washed with brine, dried with anhydrous sodium
sulfate, filtered, concentrated under reduced pressure, and
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Table 2. Reduction of Compound 2 with Reducing Agents under Acid Conditions
a
Conditions were typically the reducing agents dissolved in acid solutions at 0 °C to which was added compound 2a in CH2Cl2 solution, and the
b
c
d
reaction mixture was stirred at rt for 6 h. Isolated yield. “+” means only product 3 is produced. “--” represents that no product is obtained.
Scheme 4. Scale-Up Synthesis of 1, Vilazodone
Table 3. Reaction Condition Optimization of Ammonolysis in the Synthesis of Vilazodone
a
entry
subject
conditions
yield
b
1
2
3
4
5
6
7
8
6
6
6
6
6
6
6
5
Mukaiyama reagent/NH3(g)
CDI/NH3(g)
72%
81%
75%
70%
<5%
<5%
23%
EDCI, HOBt/NH3(g)
PyBOP/NH3(g)
SOCl2/NH3(g)
C2Cl2O2/NH3(g)
POCl3/NH3(g)
c
NH3(g)
--
a
Conditions were typically as follows: the compound 6 was dissolved in DMF at rt, to which were added coupling agents, and then NH3(g) was
introduced for 30 min; or the compound 6 was suspended in DCM at 0 °C, to which were added different chlorinating agents. The mixture was
b
stirred at rt for 2 h, and then NH3(g) was introduced for 15 min; or compound 5 was dissolved in MeOH, to which NH3(g) was introduced. The
c
yield is cited from ref 2a. “--” represents that no vilazodone is obtained.
purified via recrystallisation from n-propanol to yield 2 (90%)
with analytical purity. The subsequent selective deoxygenation
of 2 was carried out in the NaBH4/CF3COOH system. Initially,
NaBH4 was added slowly into the CF3COOH solution under
the protection of nitrogen gas, which was followed by the
addition of a solution of 2 in CH2Cl2. After the reaction mixture
was stirred at room temperature for 6 h, it was poured into ice
water and extracted with CH2Cl2. The combined organic phase
was washed successively with Na2CO3-saturated aqueous
solution and brine, dried with anhydrous sodium sulfate,
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filtered, and concentrated. The crude product was recrystallized
from methanol to afford 3 in 95% yield with analytical purity.
In the synthesis of the intermediate 5, the Finkelstein
conditions12 were employed since iodine is a good leaving
group. This led cleanly to compound 5 and meanwhile
shortened the reaction time significantly. We have also
evaluated a range of acid scavengers (TEA, K2CO3, pyridine,
DIPEA, NMM) and their different combinations. Surprisingly,
we had noted that the addition of both TEA and K2CO3 led
cleanly to product 5. Therefore, this optimized process consists
of stirring a mixture of the intermediate 3, compound 4, TEA,
K2CO3, and a catalytic amount of KI in DMF for 16 h at 85 °C
(Scheme 4). The reaction mixture was then poured into ice
water, and the resulting precipitate was filtered and dried under
vacuum to furnish off-white solid 5. The obtained solid was
then dissolved in ethyl acetate (EtOAc) and converted to the
corresponding hydrochloride salt after addition of HCl-
saturated EtOAc solution in 78% yield.
It is worth noting that compound 5 could be transformed
into molecule 6 through one-step esterolysis and deprotection
of tosyl group in a NaOH/MeOH system with excellent yield
(97%), which would not require additional procedures at the
cost of lowering the yield or boosting the expenditure after
introducing a protecting group. A mixture of 5 and NaOH in
methanol was heated to reflux for 4 h and then cooled. The
reaction mixture was concentrated under reduced pressure, and
the residue was dissolved in water. 15% aqueous hydrochloric
acid was then added until complete precipitation (pH ≈ 7); the
precipitate was filtered and dried under vacuum to afford 6
(97%) which was pure enough for the following step.
Finally, a range of experiments was carried out to optimize
the aminolysis reaction in synthesizing vilazodone. As
illustrated in Table 3, most condensing agents furnished the
final product vilazodone in good yields, while the chlorinating
agents gave poor results and the direct aminolysis failed to
initiate the reaction. Thus, N,N′-carbonyldiimidazole (CDI)
was finally employed as coupling agent in replacement of
Mukaiyama reagent to synthesize vilazodone for its low price
and environmentally friendly characteristics. The target
compound vilazodone (1) was produced in good yield as
well (81%). First, CDI was added into a solution of 6 in
anhydrous DMF. After the reaction mixture was stirred for 1 h
at rt, NH3(g) was introduced for 30 min. The mixture was
poured into ice water, and the precipitate was filtered and dried
under vacuum to yield a crude product of vilazodone in free
base form, which was followed by a further salt switch to
hydrochloride through the addition of HCl-saturated EtOAc
solution. Then the product hydrochloride was further purified
by recrystallization from an ethanol/methanol (1:1) solution.
EXPERIMENTAL SECTION
■
General Methods. All chemicals and solvents were either
purchased or purified by standard techniques and used without
any further purification. TLC was carried out using Merck 25
DC-AlufolienKieselgel GF254 silica gel plates. Melting points
were recorded on an RY-1 melting point apparatus and were
uncorrected. MS spectra were acquired on Agilent 1100 series
LC/MSD Tarp (SL). The 1H NMR spectra were recorded on a
BRUKER AV-300 or AV-500 NMR spectrometer using TMS as
the internal standard. The HRMS spectra were acquired on a
Waters Micros Q-TOF apparatus. Product purities were
determined by HPLC conducted on an Agilent 1200 system
using a reverse-phase C18 column, and MeOH−H2O was used
as the mobile phase.
1-Tosyl-1H-indole-5-carbonitrile. The 1-tosyl-1H-indole-
5-carbonitrile was prepared similarly to the reported procedure
of ref 6. Mp: 116−118 °C (lit.13 116−118 °C). 1H NMR (300
MHz, CDCl3): δ = 8.08 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.78
(d, J = 8.3 Hz, 2H), 7.70 (d, J = 3.6 Hz, 1H), 7.55 (dd, J = 8.6
Hz, J = 1.4 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 3.6
Hz, 1H), 2.36 (s, 3H).
3-(4-Chlorobutanoyl)-1-tosyl-1H-indole-5-carbonitrile
(2). To a solution of AlCl3 (7.2 kg, 54 mol) in CH2Cl2 (120 L)
were added 4-chlorobutyryl chloride and a solution of 1-tosyl-
1H-indole-5-carbonitrile (8 kg, 27 mol) in CH2Cl2 (20 L). The
reaction mixture was stirred at rt for 8 h. After completion of
the reaction, the reaction mixture was poured into ice water
(150 L) and extracted with CH2Cl2 (3 × 120 L). The
combined organic layer was washed successively with Na2CO3-
saturated aqueous solution and brine, dried overnight with
anhydrous Na2SO4, filtered and concentrated to afford white
crude product 2 (10.2 kg). The crude product was recrystal-
lized from 1-propanol (150 L) to give analytical purity product
1
2 (9.7 kg, 90%) as white crystal. Mp 154−156 °C. H NMR
(300 MHz, CDCl3): δ = 8.71 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H),
8.03 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.62 (dd, J =
8.7 Hz, J = 1.4 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 3.69 (t, J =
6.3 Hz, 2H), 3.13 (t, J = 6.3 Hz, 2H), 2.40 (s, 3H) 2.21−2.30
(m, 2H). IR (KBr): 3310, 2946, 2227, 1663, 1608, 1540, 1458,
1389, 1173, 1134, 1086, 989, 823, 702, 672 cm−1. HRMS
(ESI): m/z [M + H]+ calcd for C20H18ClN2O3S, 401.0721;
found, 401.0722.
3-(4-Chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile (3).
To a stirred solution of CF3COOH (150 L) under the
protection of nitrogen at 0 °C was added NaBH4 (11 kg, 300
mol) slowly. A solution of 2 (8 kg, 20 mol) in CH2Cl2 (200 L)
was then added to this mixture under 15 °C. The reaction
mixture was stirred for 6 h at ambient temperature, poured into
ice water (500 L) and extracted with CH2Cl2 (3 × 150 L). The
combined organic layer was washed successively with Na2CO3-
saturated aqueous solution and brine (2 × 250 L), dried
overnight with anhydrous Na2SO4, filtered and concentrated to
afford white crude product 3 (7.8 kg). The crude product was
recrystallized from methanol (300 L) to give 3 (7.3 kg, 95%) as
white crystal. Mp: 110−112 °C. 1H NMR (300 MHz, CDCl3):
δ = 8.06 (d, J = 8.6 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J = 8.3 Hz,
2H), 7.56 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 7.25 (d, J = 8.3 Hz,
2H), 3.57 (s, 2H), 2.70 (s, 2H), 2.36 (s, 3H), 1.68−1.91 (m,
4H). MS (ESI, 70 eV): m/z = 385 [M − H]−. IR (KBr): 3114,
2225, 1458, 1371, 1175, 1129, 811, 667, 590 cm−1. HRMS
(ESI): m/z [M + Na]+ calcd for C20H19ClN2NaO2S, 409.0748;
found, 409.0744.
CONCLUSION
■
Our five-step approach furnished vilazodone with an overall
yield of 52.4% and was, to the best of our knowledge, the most
efficient route to date to synthesize the target molecule
vilazodone in an economical and convenient manner.
Furthermore, all intermediates and vilazodone could be
prepared with readily available, inexpensive and environ-
mentally friendly reagents and solvents via simple and
straightforward workups, rendering this new process highly
amenable to the large-scale production of vilazodone.
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Ethyl 5-(4-(3-(5-Cyano-1-tosyl-1H-indol-3-yl)butyl)-
piperazin-1-yl)benzofuran-2-carboxylate Hydrochloride
(5). A mixture of 3 (5 kg, 13 mol), 4 (4 kg, 13 mol), K2CO3
(3.6 kg, 26 mol), TEA (3.6 L, 26 mol), catalytic amount of KI
(0.2 kg, 1.3 mol) and DMF (150 L) was heated to 85 °C for 16
h and cooled. After cooling, the reaction mixture was poured
into ice water (200 L) and the precipitate was filtered and dried
under vacuum to give off-white crude product 5 (6.9 kg). To a
solution of the crude product in EtOAc (100 L) was added
HCl-saturated EtOAc solution until complete precipitation (pH
= 2−3). The precipitate was filtered and dried under vacuum to
eV): m/z = 442 [M + H]+. IR (KBr): 3458, 3128, 2216, 1674,
1597, 1400, 934 cm−1. 13C NMR (75 MHz, DMSO-d6): 22.9,
23.6, 26.8, 46.9 (2C), 50.9 (2C), 55.4, 100.1, 108.5, 109.8,
112.2, 112.7, 115.3, 118.5, 121.0, 123.6, 124.1, 125.1, 126.9,
127.7, 138.0, 146.7, 149.5, 149.6, 160.0. HRMS (ESI): m/z [M
+ H]+ calcd for C26H28N5O2, 442.2238; found, 442.2234.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xu_yungen@hotmail.com. Tel: +86(25)83271244.
Fax: +86(25)83271512.
1
give 5 (6.7 kg, 78%) as off-white solid. Mp: 194−196 °C. H
Notes
NMR (300 MHz, DMSO-d6): δ = 8.23 (s,1H), 8.06 (d, J = 8.6
Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.73 (d, J = 9.5
Hz, 1H), 7.64 (s, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.36 (s, 1H),
7.32 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.76 (d, J = 11.0 Hz,
2H), 3.57 (d, J = 11.0 Hz; 2H), 3.31 (t, J = 11.9 Hz, 2H), 3.18
(bs, 4H), 2.73 (s, 2H), 2.31 (s, 3H), 1.65−1.1.88 (m, 2H)
1.41−1.65 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). IR (KBr): 3427,
2220, 1724, 1458, 1361, 1300, 1166, 816, 676, 600, 537 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C35H37N4O5S,
625.2479; found, 625.2478.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are very grateful to Yun Shi and Lu Lu for their helpful and
informative discussions.
REFERENCES
■
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5-(4-(3-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-
benzofuran-2-carboxylic Acid (6). To a mixture of 5 (5 kg,
7.6 mol) was added NaOH (1.2 kg, 30 mol) in MeOH (50 L),
and the mixture was heated to reflux for 4 h and then cooled.
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and the residue was dissolved in water (50 L). The pH of the
solution was adjusted to about 7.0 by the addition of 15%
aqueous hydrochloric acid. After the complete precipitation, the
precipitate was filtered and dried under vacuum to furnish 6
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1
(3.25 kg, 97%) as off-white product. Mp: 192−194 °C. H
NMR (300 MHz, DMSO-d6): δ = 11.50 (bs, 1H), 8.11 (bs,
1H), 7.60−7.51 (m, 3H), 7.43 (s, 1H), 7.40 (s, 1H), 7.25 (s,
2H), 7.12 (d, J = 7.5 Hz, 1H), 3.40−3.07 (m, 8H), 2.77 (s,
2H), 2.29 (s, 2H), 1.60−1.81 (m, 4H). MS (ESI, 70 eV): m/z =
441 [M − H]−. IR (KBr): 3411, 2217, 1579, 1560, 1472, 1397,
1216, 805, 685, 563 cm−1. HRMS (ESI): m/z [M + H]+ calcd
for C26H27N4O3, 443.2078; found, 443.2076.
5-(4-(3-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-
benzofuran-2-carboxamide (1). To a solution of 6 (3 kg,
11.3 mol) in anhydrous DMF (150 L) at 15 °C was added CDI
(1.6 kg, 10.2 mol). The reaction mixture was stirred at ambient
temperature for 1 h, followed by the introduction of NH3(g)
for 30 min. The mixture was then poured into ice−water (180
L). The precipitate was filtered and dried under vacuum to
yield 2.7 kg of vilazodone in the form of free base. The free base
was then dissolved in hot isopropanol (30 L), and HCl-
saturated EtOAc solution was added until complete precip-
itation (pH = 2−3). The precipitate was filtered and dried
under vacuum to furnish the crude product of vilazodone
hydrochloride 1 as off-white solid. The product of vilazodone
hydrochloride was then recrystallized from an ethanol−
methanol solution (1:1; 10 L) to give the final pure product
vilazodone hydrochloride as white needles (2.4 kg, 81%).
HPLC analysis: 99.7%. Mp: 234−236 °C (became charred). 1H
NMR (500 MHz, DMSO-d6): δ = 11.49 (s, 1H), 11.81 (bs,
1H), 8.10 (s, 1H), 7.61 (brs, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.52
(d, J = 8.2 Hz, 1H), 7.45 (d, J = 0.65 Hz, 1H), 7.41 (dd, J = 8.4
Hz, J = 1.6 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.27 (d, J = 2.4
Hz, 1H), 7.21 (dd, J = 9.1 Hz, J = 2.4 Hz, 1H), 3.78−3.70 (m,
2H), 3.58−3.52 (m, 2H), 3.23−3.21 (m, 6H), 2.78 (t, J = 7.5
Hz, 2H), 1.85−1.78 (m, 2H), 1.61−1.75 (m, 2H). MS (ESI, 70
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Organic Process Research & Development
Article
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(11) In order to demonstrate that there are no indoline byproducts,
N-tolylsulfonyl indoline structure 3c was synthesized from molecule
3b through a similar procedure to synthesize 1-tosyl-1H-indole-5-
carbonitrile, and detailed comparison was made through NMR, MS
and TLC characteristics between products 3 and 3c. The character-
ization data of 3c: 1H NMR 7.73−7.69 (m, 3H), 7.52 (dd, J1 = 9 MHz,
J2 = 3 MHz, 1H), 7.33−7.27 (m, 3H), 4.06 (t, J = 9 MHz, 1H), 3.69−
3.63 (m, 1H), 3.50 (t, J = 6 MHz, 2H), 3.25−3.18 (m, 1H), 2.41 (s,
3H), 1.76−1.28 (m, 6H); MS (ESI, 70 eV) m/z = 389 [M + H]+.
(12) Baughman, T. W.; Sworen, J. C.; Wagener, K. B. Tetrahedron
2004, 60, 10943.
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1557
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