N-Chlorophthalimide as a mild and efficient chlorination reagent in the Gassman ortho alkylation of aromatic amines. Synthesis of 3-(methylthio)oxindoles

Article abstract of DOI:10.1016/j.tetlet.2014.08.044

A practical modification of the Gassman 3-(methylthio)oxindole synthesis is reported. In our method, substituted anilines and 2-(methylthio)acetamide were reacted under mild reaction conditions, in the presence of N-chlorophthalimide as a chlorinating agent to give α-amidosulfides, which, in the next step of the process, were cyclized to give 3-(methylthio)oxindoles. The method was successfully applied for the synthesis of the key intermediate, 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide, in the process of the preparation of nepafenac, a commonly used ophthalmic drug.

Full text of DOI:10.1016/j.tetlet.2014.08.044

Tetrahedron Letters 55 (2014) 5423–5425
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-Chlorophthalimide as a mild and efficient chlorination reagent
in the Gassman ortho alkylation of aromatic amines. Synthesis
of 3-(methylthio)oxindoles
a
b
Marcin Cybulski a, , Adam Formela , Izabela Fokt
⇑
a Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland
b The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 February 2014
Revised 29 July 2014
Accepted 13 August 2014
Available online 19 August 2014
A practical modification of the Gassman 3-(methylthio)oxindole synthesis is reported. In our method,
substituted anilines and 2-(methylthio)acetamide were reacted under mild reaction conditions, in the
presence of N-chlorophthalimide as a chlorinating agent to give a-amidosulfides, which, in the next step
of the process, were cyclized to give 3-(methylthio)oxindoles. The method was successfully applied for
the synthesis of the key intermediate, 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide, in the
process of the preparation of nepafenac, a commonly used ophthalmic drug.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Gassman reaction
3-(Methylthio)oxindoles
N-Chlorophthalimide
The indole system is one of the most common heterocycles in
nature.1 The indole moiety is present in biologically active alka-
loids such as the plant-derived, so called vinca alkaloids, vinblas-
tine, and vincristine, as well as in many synthetic medicinal
compounds.2–4 The synthesis of differently substituted indole rings
has long-inspired organic chemists.5–8
The choice of the method used depends on the type and avail-
ability of the starting material, type of substituents in such sub-
strates, safety, and practicality, especially when a multigram
amount of product needs to be prepared.
agents reported in the literature such as tert-butyl hypochlorite
or chlorine15 are difficult to handle, especially when a multigram
amount of the substituted indole needs to be synthesized. The
Gassman method is a one-pot chemical process, and because of
their low stability, none of the intermediates are isolated.
We previously developed a new method for the synthesis of
nepafenac, a non-steroidal anti-inflammatory drug, commonly
used to treat eye pain, redness, and swelling in patients recovering
from cataract surgery.17 The key step of the process was the
development of an efficient method for the synthesis of an
Numerous methods for the synthesis of indoles have been
developed, among them the Gassman synthesis. In the Gassman
method, N-chloroanilines react with b-keto sulfides or a-carboalk-
oxy sulfides to yield azasulfonium salts, which when treated with a
base led to 3-methylthioindoles or 3-(methylthio)oxindoles,
respectively (Scheme 1).
Subsequent reduction of 3-methylthioindoles or 3-methylthio-
oxindoles obtained using Raney-Nickel as the catalyst led to the
appropriate indoles or oxindoles.9–12
A major limitation of this method is the stability of N-chloroani-
lines formed during the first step of the process, which strongly
depends on the type and position of the substituents on the aro-
matic ring. In all reported conditions applied for the Gassman reac-
tion, temperatures of À65 °C or lower, as well as anhydrous
solvents and an inert atmosphere are required.13–16 Chlorinating
a-amidosulfide intermediate. While using classical conditions for
Gassman ortho alkylation of aromatic amines, we obtained a mix-
ture of 2-amino-5-chlorobenzophenone and 2-(2-amino-3-ben-
zoyl-5-chlorophenyl)-2-(methylthio)acetamide along with the
required
2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetam-
ide.17 While searching for a milder, more stable, and easy to handle
(on a large scale) source of chlorine for the Gassman ortho-
alkylation of aniline, we found that N-chlorophthalimide was
suitable. In this Letter, we present our studies on the limitations
and usefulness of N-chlorophthalimide for the synthesis of
a-amidosulfides. The a-amidosulfides obtained can be used for
the synthesis of 3-(methylthio)oxindole via very efficient cycliza-
tion under mild acidic conditions (Table 1), and also as building
blocks in other processes. Table 1 also includes the previously pub-
lished yield of product 4a, and the overall yields of 5a–f were
obtained using the original Gassman one-pot method. The stability
of N-chlorophthalimide and its mild reactivity allowed us to carry
out all the processes in ACS-grade solvents (no need for additional
⇑
Corresponding author. Tel.: +48 22 456 39 40; fax: +48 22 456 39 00.
E-mail address: m.cybulski@ifarm.eu (M. Cybulski).
http://dx.doi.org/10.1016/j.tetlet.2014.08.044
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5424
M. Cybulski et al. / Tetrahedron Letters 55 (2014) 5423–5425
1) t-BuOCl
O
S
S
O
OR2
_
OR2
2)MeS
OR2
Et3N
Δ or H+
X
X
X
X
O
S+
O
N
NH
R1
NH
R1
N
R1
R1
Scheme 1. Mechanism of the Gassman synthesis of oxindoles from substituted anilines.15,20
Table 1
3-(Methylthio)oxindole synthesis in the presence of N-chlorophthalimide
Step I
Step II
Overall yield (%)
Overall yield
Reference data (%)
Substrate
Product
Yield (%)
Reference data (%)
Substrate
Product
Yield (%)
1a
1b
1c
1d
1e
1e
4a
4b
4c
4d
4e
4f
59
41
55
22
8415
—
—
—
—
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
97
98
92
85
75
95
57
40
51
19
10
16
7815
3416
7719
1212
13
Traces15
6116
17 (mixture with 5f)
—
drying) without an inert atmosphere. All the reactions were per-
formed over a temperature range of À20 °C to À8 °C, which is
higher than when tert-butyl hypochlorite or chlorine was used
(À65 °C and lower). To study the usefulness of N-chlorophthali-
mide in such a process, several novel (4b–f) as well as known
amide (4a) and their cyclized analogs (5a–f) were prepared under
the conditions previously described17 (Scheme 2). Starting from
para-substituted methyl (1b), chloro (1c), and nitro (1d) we
obtained the corresponding substituted 2-(methylthio)acetamides.
No such compounds were reported in the literature. For a meta-
nitro-substituted aniline (1e), Gassman reported the formation of
5f as the only product.12 Using our method, we were able to obtain
both regioisomers 5e and 5f. This is as a result of the intramolecu-
lar attack of the generated ylide on either the ortho or para posi-
tions of aniline. For the first time, we were able to obtain
oxindole 5e with a nitro substituent at position 6. Similar to the
original Gassman conditions (2% yield in the original Gassman
paper12), in our method, we were not successful when anisidine
with a strong electron-donating para-methoxy group was used as
the substrate.
In conclusion our results show that the present modification
offers an attractive alternative to other chlorinating agents avail-
able for the preparation of oxindoles via the Gassman procedure.
In the reports of Gassman,10–12,16 substituted phenyl-2-(methyl-
thio)acetates, which were obtained in the first step of the process,
were not isolated because of their instability and were therefore
immediately cyclized into oxindoles. In our method, by using 2-
methylacetamide as the starting material in the first step of the
process, we obtained stable substituted phenyl-2-(methyl-
thio)acetamides, which allowed them to be isolated and fully char-
acterized. Under acidic conditions such compounds easily cyclize
into the corresponding oxindoles in high yields. Although the over-
all yield of our two-step process is comparable to that reported by
Gassman for the direct process of oxindole preparation, the ease of
manipulation (higher temperature, non-anhydrous solvents, and
an easy-to-handle chlorinating agent) of our route might be attrac-
tive to chemists. We did not optimize the conditions of the process,
therefore, it is our belief that further optimization may improve the
yields further. The use of N-chlorophthalimide allowed us, for the
first time using the Gassman procedure, to obtain an oxindole
derivative with a nitro group at position 6 of the indole ring.
General experimental procedures (GP)
ortho alkylation (GP1)
A vigorously stirred suspension of aniline 1a–e (8.9 mmol) and
2-(methylthio)acetamide (2)18 (0.94 g, 8.9 mmol) in CH2Cl2
(40 mL) was cooled to À20 °C. A solution of N-chlorophthalimide
(3) (1.62 g, 8.9 mmol) in CH2Cl2 (55 mL) was added dropwise,
while the temperature was maintained between À20 °C and
À15 °C. The obtained mixture was stirred at À20 °C to À15 °C for
2 h, and then was allowed to warm to ꢀÀ8 °C. Et3N (1.35 mL,
9.7 mmol) was added and the mixture was washed with 1 M
KOH aqueous solution (3 Â 20 mL) and then with H2O until neu-
tral, and dried over anhydrous MgSO4. The solvents were removed
and the residue was purified by column chromatography over sil-
ica gel with EtOAc–hexanes (gradient) as eluent.
O
NH2
NH2
R2
S
R3
N Cl
S
NH2
R2
R1
O
O
3
+
S
O
O
a), b)
Step I
c)
NH2
R1
R3
R1
R3
Step II
N
2
R2
H
1a R1 = R2 = R3 = H
4a R1 = R2 = R3 = H
5a R1 = R2 = R3 = H
5b
1 = R3 = H, R2 = CH3
1 = R3 = H, R2 = CH3
R
1 = R3 = H, R2 = CH3
5c R1 = R3 = H, R2 = Cl
5d R1 = R3 = H, R2 = NO2
5e
1b
4b
R
R
1c R1 = R3 = H, R2 = Cl
1d R1 = R3 = H, R2 = NO2
1e R1 = NO2, R2 = R3 = H
4c R1 = R3 = H, R2 = Cl
4d R1 = R3 = H, R2 = NO2
R1 = NO2, R2 = R3 = H
R1 = NO2, R2 = R3 = H
5f R1 = R2 = H, R3 = NO2
4e
4f R1 = R2 = H, R3 = NO2
Scheme 2. Synthesis of various substituted 3-(methylthio)oxindoles. Step I: (a) N-chlorophthalimide (3), CH2Cl2, (b) Et3N, KOH (aq); Step II: (c) HCl (aq).

M. Cybulski et al. / Tetrahedron Letters 55 (2014) 5423–5425
5425
2-(2-Aminophenyl)-2-(methylthio)acetamide (4a)
Supplementary data
Yield 59%, mp 95–96 °C.
1H NMR (600 MHz, DMSO-d6): d = 7.54 (br s, 1H, NH), 7.22 (br s,
1H, NH), 7.20 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 6.90 (m, 1H), 6.64 (dd,
1H, J = 7.9 Hz, J = 1.1 Hz), 6.52 (ddd, 1H, J = 7.9 Hz, J = 7.7 Hz,
J = 1.5 Hz), 5.18 (br s, 2H, NH2), 4.56 (s, 1H, CHS), 1.96 (s, 3H, SMe).
13C NMR (600 MHz, DMSO-d6): d = 171.5, 146.9, 129.3, 128.1,
119.8, 116.1, 115.5, 50.9, 14.5.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.
044.
References and notes
HRMS (ESI): calcd for C9H12N2OSNa [M+Na]+: 219.0568; found:
219.0565.
1. Van Order, R. B.; Lindwall, H. G. Chem. Rev. 1942, 30, 69.
2. Wu, Y. J. In Heterocyclic Scaffolds II: Reaction and Applications of Indoles; Gribble,
G. W., Ed.; Springer-Verlag: Berlin Heidelberg, 2010; pp 1–30.
3. de Sa Alves, F. R.; Barreiro, E. J.; Manssour, F.; Carlos, A. Mini-Rev. Med. Chem.
2009, 9, 782.
3-(Methylthio)oxindole formation (GP2)
4. Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Kumar, A.; Choi, E. H.
Molecules 2013, 18, 6620.
5. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
6. Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195.
7. Miller, M.; Tsang, W.; Merritt, A.; Procter, D. J. Chem. Commun. 2007, 498.
8. Miller, M.; Vogel, C. J.; Tsang, W.; Merrit, A.; Procter, D. J. Org. Biomol. Chem.
2009, 7, 589.
9. Gassman, P. G.; Gruetzmacher, G. J. Am. Chem. Soc. 1973, 95, 588.
10. Gassman, P. G.; Van Bergen, T. J. J. Am. Chem. Soc. 1973, 95, 591.
11. Gassman, P. G.; Van Bergen, T. J. J. Am. Chem. Soc. 1973, 95, 590.
12. Gassman, P. G.; Gruetzmacher, G.; Van Bergen, T. J. J. Am. Chem. Soc. 1974, 96,
5512.
A suspension of
a-amidosulfide 4a–f in 2 M HCl (10 mL/
4 mmol) was prepared and stirred at room temperature while
the progress of the reaction was monitored by TLC. After the reac-
tion was complete, the obtained solid product was filtered, washed
with H2O until neutral and air dried.
3-(Methylthio)indolin-2-one (5a)
13. Wierenga, W.; Griffin, J.; Warpehoski, M. A. Tetrahedron Lett. 1983, 24, 2437.
14. Wright, S. W.; McClure, L. D.; Hageman, D. L. Tetrahedron Lett. 1996, 37, 4631.
15. Gassman, P. G.; Van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508.
16. Gassman, P. G.; Van Bergen, T. J. J. Am. Chem. Soc. 1973, 95, 2718.
17. Cybulski, M.; Formela, A.; Mucha, M.; Klos, K.; Roszczynski, J.; Winiarski, J. Lett.
Org. Chem. 2012, 9, 461.
18. Mori, Y.; Fujiwara, S.; Miyachi, T.; Kitanishi, H.; Oya, M.; Yamamoto, K.; Suzuki,
M. Chem. Pharm. Bull. 1983, 31, 1505.
19. Gassman, P. G.; Gilbert, D. P.; Luh, T. Y. J. Org. Chem. 1977, 42, 1340.
20. Li, J. J. In Name Reactions, 4th ed.; Li, J. J., Ed.; Springer-Verlag: Berlin
Heidelberg, 2009; pp 251–252.
Yield 97%, mp 132–133 °C, Lit.12 126–127 °C
1H NMR (600 MHz, DMSO-d6): d = 10.50 (br s, 1H, NH), 7.16–
7.28 (m, 2H), 6.98 (dd, 1H, J = 7.7 Hz, J = 7.7 Hz), 6.82 (d, 1H,
J = 7.7 Hz), 4.49 (s, 1H, CHS), 1.96 (s, 3H, SMe).
13C NMR (600 MHz, DMSO-d6): d = 176.1, 142.5, 128.7, 126.6,
124.8, 121.8, 109.4, 45.3, 11.8.
HRMS (ESI): calcd for C9H9NOSNa [M+Na]+: 202.0303; found:
202.0294.