2-Trifluoroacetyl aminoindoles as useful intermediates for the preparation of 2-acylamino indoles

Article abstract of DOI:10.1016/j.tetlet.2011.01.051

A three-step method was developed to convert N-1 unprotected 3-substituted indoles to 3-substituted 2-acylaminoindoles. Established indole chlorination chemistry was employed to generate stable 2-trifluoroacetylamino indoles, which were subsequently deprotected and selectively acylated.

Full text of DOI:10.1016/j.tetlet.2011.01.051

Tetrahedron Letters 52 (2011) 1292–1295
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-Trifluoroacetyl aminoindoles as useful intermediates for the preparation
of 2-acylamino indoles
John E. Mangette a, , Xuemei Chen a, Ravi Krishnamoorthy a, A. Samuel Vellekoop a, Adam J. Csakai a,
⇑
Fatoumata Camara a, William D. Paquette a, Hong-Jun Wang a, Hidenori Takahashi b, Roman Fleck b,
Gregory P. Roth b,
a AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
b Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-step method was developed to convert N-1 unprotected 3-substituted indoles to 3-substituted
2-acylaminoindoles. Established indole chlorination chemistry was employed to generate stable 2-triflu-
oroacetylamino indoles, which were subsequently deprotected and selectively acylated.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 November 2010
Revised 12 January 2011
Accepted 13 January 2011
Available online 20 January 2011
Keywords:
2-Aminoindole
Acylaminoindole
Chloroindolenine
2-Aminoindole acylation
During the course of a recent lead optimization program, it was
of interest to prepare indole analogs with an acylamino group at
the indole 2-position. This class of compounds and the potential
precursor 2-aminoindoles are well documented in the literature.
However, their utility, limited by a reported lack of stability,1 has
been primarily as intermediates en route to a host of natural prod-
ucts2 and to various tricyclic aromatic compounds.3 Fewer reports
are available describing simpler 2-aminoindoles with potential
therapeutic activity as, for example, inhibitors of 5-lipoxygenase4
or poly(adenosine 50-diphosphate ribose) polymerase (PARP),5 or
as antibacterial agents.1c Not withstanding these limitations, a
multitude of preparative methods have been reported. Intramolec-
ular amidations, used extensively in the natural product work, tend
to employ either chlorination/displacement via the Witkop proce-
dure2a–c,6 or the copper-catalyzed amidation of 2-iodo-indoles.2d–h
Other methods include Curtius rearrangement of 2-carboxy in-
doles7 and catalytic reduction of o-nitrobenzyl cyanides.3b–f,8 More
closely related to the current work is the nitration/nitro reduction
procedure of Gribble, which required trapping of the labile 2-amin-
oindole by acylation,1a,b and the more recent copper-catalyzed
amidation by selective C–H activation of 1-methylindoles reported
by Li.9
For the current work, several key factors influenced the route
choice. Retention of ester functionality in the substrate precluded
Curtius chemistry, while eliminating the need for protection of
the indole nitrogen was desired. Of the utmost importance was
developing a route that would avoid decomposition of the 2-amin-
oindole intermediates. These requirements were accommodated
using the established Witkop tert-butylhypochlorite/triethylamine
conditions. Herein we report a unique adaptation of this chemistry
using the conjugate base of trifluoroacetamide as a nucleophile to
prepare useful, stable trifluoroacetyl 2-aminoindole intermediates
2 (Scheme 1). Deprotection of 2 and acylation of the intermediate
2-aminoindole hydrochloride salt allowed for preparation of the
targeted amides 4. As a potentially useful route for a more diverse
amine functionalization, this protocol was advantageous in that it
allowed for late stage installation of the amino group followed by
rapid analog preparation without decomposition of the potentially
labile intermediates. As one of the few examples of an indole chlo-
rination followed by intermolecular displacement amination,4,10
which is limited to 3-substituted indoles, this procedure is comple-
mentary to the methods of Gribble and Li which are useful for 3-H
indoles, but require either substitution or protection of the N-1
nitrogen.
As shown in Table 1, initial efforts focused on determining the
scope of the chlorination/amidation chemistry to prepare com-
pounds 2.11 While various functionalities on the core or side chain
were tolerated, yields were good for substrates with a functional-
ized alkyl chain or methyl group at the 3-position (entries 1,
⇑
Corresponding author. Tel.: +1 518 512 2172; fax: +1 518 512 2081.
E-mail address: john.mangette@amriglobal.com (J.E. Mangette).
Present address: Sanford-Burnham Medical Research Institute, Orlando, FL 32827,
USA.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.051

J. E. Mangette et al. / Tetrahedron Letters 52 (2011) 1292–1295
1293
R
O
R
1. tBuOCl,NEt 3
THF, –78 °C
ClOtBu
Cl
R
R
CF3
O
R
NH
O
2.
N
N
H
R'
H
NEt3
R'
N
NaHN
CF3
N
R'
F3C
NHNa
R'
H
1
2
15-crown-5
–78 °C to 0 °C
1
HCl
5
1,4-dioxane
MeOH
R
O
re-aromatize
H
CF3
R
N
O
R
O
NH
R"COCl
R"
H
N
N
NH3+Cl –
CF3
NH
R'
R'
H
pyridine
DMAP
CH2Cl2
N
N
H
6
2
H
R'
R'
3
4
Scheme 2.
Scheme 1.
initial chlorination (entry 15). Indole substrate 1k (entry 13, see
Scheme 3), while giving a low yield of the desired product 2k,
afforded 7 as the major product, a result of chlorination and dis-
3–5), but variable for 3-phenyl indole (entry 6) and substrates with
an electron withdrawing group on the indole core (entries 7–12).
Considering the expected pathway for product formation via the
reactive chloroindolenine intermediate 5 (Scheme 2), the lower
yields are consistent with reduced reactivity toward chlorination
due to greater steric bulk at the 3-position or reduced electron
density of the indole core.
This point is perhaps best illustrated for methyl 3-indole car-
boxylate. With an electron withdrawing substituent at the site of
chlorination, the tert-butyl hypochlorite/triethylamine conditions
failed to give any reaction (entry 11). Alternative conditions using
N-chlorosuccinimide and N,N-dimethyl piperazine10 were required
(entry 12). Unfortunately, the latter set of conditions, while provid-
ing the desired product, also gave many more by-products and a
relatively low yield. Similar results were obtained when tested
on the more reactive indole 1a (entry 2).
placement at the
a
-position. This shift in reactivity was complete
for 1l where
a-trifluoroacetylamino ester 8 was the only isolated
product.12
With key intermediates 2 in hand, conversion to the desired
amides 4 was accomplished through a facile removal of the triflu-
oroacetyl group with 4 N HCl in 1,4-dioxane/methanol, followed by
a regioselective acylation of the intermediate 2-aminoindole.13 As
shown in Table 2, yields for the two-step conversion to 4 were gen-
erally good.14
A few literature reports indicated that acylation should favor
reaction at the amino group instead of at the indole nitrogen.15
For the current protocol, acylation regioselectivity was confirmed
by direct reaction of the chloroindolenine intermediate of 1a with
amide conjugate bases of cyclopentanecarboxamide and 4-cyanob-
enzamide (see Scheme 4). The major products prepared in this
manner, 4b and 4d, were identical by 1H NMR to the products from
the three-step procedure from Scheme 1. Although more direct, the
procedure from Scheme 4 generated more complex reaction mix-
tures with yields of 4b (27%) and 4d (24%) that were lower than
the overall yields from the three-step procedure (57%).16
Intermediates 2 were generally stable under ambient condi-
tions for several months, although some decomposition was noted
after longer periods, especially for 2d. Most examples of 4 showed
good stability in solution and in the concentrated form. Exceptions
were 4a, 4b, and 4e, which were stable in solution (deuterochloro-
form or DMSO-d6) for up to 6 weeks, but showed minor decompo-
sition after 1–2 weeks as concentrated solid or foam products.
Compound 4j, on the other hand decomposed rapidly in deutero-
chloroform and showed some decomposition in DMSO-d6 after
1 week, but showed no decomposition as a solid. The longer term
stability of compounds 4 and the circumstances of decomposition
are of continued interest.
A number of substrates failed to provide 2-trifluoro acetylamino
indoles as the main products. Indole, for example, gave 3-chloroin-
dole as the only product, resulting from re-aromatization following
Table 1
Synthesis of 2-(N-20,20,20-trifluoroacetyl)-amino indoles
R1
R1
O
1. tBuOCl,Et3N
R2
N
CF3
R2
2.
O
H
N
N
H
H
NaHN
CF3
1
2
15-crown-5
Entry
1
R1
R2
2
Isolated percent yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1j
1k
1l
1m
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CONMe2
(CH2)2NBn2
CH3
H
H
H
H
H
H
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2j
2k
2l
2m
86
35b
73
63
72
In summary, late stage amination of unprotected, 3-substituted
indoles was developed through the use of stable trifluoroacetyl
Ph
59 (72)
41(61)
29(41)
63(70)
40(44)
0
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
CO2CH3
5-CN
6-CN
5-CO2Me
O
O
F3COCHN
6-CO2Me
H
H
H
H
H
R
CO2CH3
26b
27
R
N
1. tBuOCl,Et3
2.
CH2CONMe2
CH2CO2Me
H
0
O
N
H
0c
N
H
NaHN
CF
3
a
Parenthetical yields are based on recovered starting material.
Chlorination was carried out with N-chlorosuccinimide and N,N-dimethylpi-
1k, R = NMe2
1l, R = OMe
7
, R = NMe2 (72%)
8, R = OMe (91%)
15-crown-5
b
perazine in dichloromethane.10
c
3-Chloroindole was the sole product.
Scheme 3.

1294
J. E. Mangette et al. / Tetrahedron Letters 52 (2011) 1292–1295
Table 2
Synthesis of 2-(N-acyl)-amino indoles
1. HCl
R1
R1
O
O
1,4-dioxane
MeOH
N
R3
N
CF3
H
H
2. R3COCl
pyridine
CH2Cl2
N
N
H
R2
R2
H
4
2
Entry
2a
R1
R2
4
R3
Isolated percent yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2e
2e
2f
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CONMe2
(CH2)2CONMe2
(CH2)2CONMe2
(CH2)2NBn2
(CH2)2NBn2
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
Me
60
66
51
66
54
61
86
73
77
96
73
93
76
72
59
72
87
74
62
c-Pentyl
tert-Butyl
p-CN-Ph
p-Cl-Ph
p-CH3-Ph
Me
Ph
p-CN-Ph
Ph
p-CN-Ph
CH3
Ph
Me
Me
Ph
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
(CH2)2CO2Me
CO2Me
5-CN
6-CN
5-CO2Me
6-CO2Me
H
H
2g
2h
2i
2j
2j
Me
Me
Me
Ph
CO2Me
a
Compound 2d failed to give the desired products upon attempted acylation with several different acid chlorides.
4. Landwehr, J.; George, S.; Karg, E.-M.; Poeckel, D.; Steinhilber, D.; Troschuetz, R.;
Werz, O. J. Med. Chem. 2006, 49, 4327–4332.
5. US 20050054631.
CO2Me
CO2Me
6. Ohno, M.; Spande, T. F.; Witkop, B. J. Am. Chem. Soc. 1970, 92, 343–348.
7. (a) Hiremath, S. P.; Mruthyunjayaswamy, B. H. M.; Purohit, M. G. Indian J. Chem.
1978, 16B, 789–792; (b) Mor, M.; Spadoni, G.; Di Giacomo, B.; Diamantini, G.;
Bedini, A.; Tarzia, G.; Plazzi, P. V.; Rivara, S.; Nonno, R.; Lucini, V.; Pannacci, M.;
Fraschini, F.; Stankov, B. M. Bioorg. Med. Chem. 2001, 9, 1045–1057; (c)
Murakami, Y.; Watanabe, T.; Sakai, M.; Yokoyama, Y. Chem. Pharm. Bull. 1988,
36, 3732–3735.
8. (a) Walker, G. N. J. Am. Chem. Soc. 1955, 77, 3844–3850; (b) Snyder, H. R.;
Merica, E. P.; Force, C. G.; White, E. G. J. Am. Chem. Soc. 1958, 80, 4622–4625.
9. Shuai, Q.; Deng, G.; Chua, Z.; Bohle, D. S.; Li, C.-J. Adv. Synth. Catal. 2010, 352,
632–636.
O
1. tBuOCl,Et3N
2.
N
R
H
N
O
N
H
H
NaHN
R
1a
15-crown-5
4b, R =
4d, R =
10. Bergman, J.; Engqvist, R.; Ståhlhandske, C.; Wallberg, H. Tetrahedron 2003, 59,
1033–1048.
11. Representative procedure: tert-Butylhypochlorite (0.130 mL, 0.125 g,
1.15 mmol) was added dropwise to a solution of 1a (0.213 g, 1.05 mmol) and
triethylamine (0.160 mL, 0.116 g, 1.15 mmol) in anhydrous tetrahydrofuran
(15 mL) cooled to ꢀ78 °C. The mixture was stirred at this temperature for
45 min. In a separate flask, a solution of 2,2,2-trifluoroacetamide (0.352 g,
3.11 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to a
suspension of 60% sodium hydride (0.120 g, 2.99 mmol) in anhydrous
tetrahydrofuran (10 mL) cooled to 0 °C. This mixture was allowed to stir at
0 °C for 10 min and allowed to warm to room temperature. The solution of
sodium (2,2,2-trifluoroacetyl)amide was added to the chloroindolenine
solution. 15-Crown-517 ether (0.410 mL, 0.455 g, 2.06 mmol) was added, and
the mixture was allowed to warm to 0 °C. Aqueous workup with saturated
ammonium chloride and ethyl acetate was followed by flash chromatography
(90:10 hexanes/ethyl acetate) to afford 2a (0.282 g, 86%) as a white solid: mp
99–100 °C; 1H NMR (300 MHz, DMSO-d6) d 11.41 (br s, 1H), 11.23 (br s, 1H),
7.51 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.10 (td, J = 7.2, 0.9 Hz, 1H), 7.00
(td, J = 7.5, 0.9 Hz, 1H), 3.55 (s, 3H), 2.90 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 7.8 Hz,
2H); 13C NMR (125.7 MHz, CDCl3) d 176.7, 155.1 (q, JC–F = 38.9 Hz), 132.6,
128.9, 126.1, 122.2, 120.3, 117.3, 115.8 (q, JC–F = 285.8 Hz), 111.2, 101.0, 52.3,
CN
Scheme 4.
protected intermediates, allowing subsequent deprotection and
regioselective acylation. It is anticipated that this protocol might
be used for more diverse 2-aminoindole functionalization.
References and notes
1. (a) Roy, S.; Gribble, G. W. Heterocycles 2006, 70, 51–56; (b) Roy, S.; Roy, S.;
Gribble, G. W. Tetrahedron Lett. 2008, 49, 1531–1533; (c) US 2875212.
2. (a) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 1999, 121, 11964–11975; (b) Cardoso, A. S. P.; Marques, M.
M. B.; Srinivasan, N.; Prabhakar, S.; Lobo, A. M. Tetrahedron 2007, 63, 10211–
10225; (c) Okada, M.; Sato, I.; Cho, S. J.; Dubnau, D.; Sakagami, Y. Tetrahedron
2006, 62, 8907–8918; (d) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc.
1998, 120, 6417–6418; (e) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545–
563; (f) Snider, B. B.; Wu, X. Org. Lett. 2007, 9, 4913–4915; (g) Toumi, M.; Couty,
F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027–5030; (h) Coste, A.; Toumi, M.;
Wright, K.; Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10,
3841–3844.
3. (a) Doss, S. H.; Mohareb, R. M.; Elmegeed, G. A.; Luoca, N. A. Pharmazie 2003, 58,
607–613; (b) WO 2008055233.; (c) WO 2009004329.; (d) Matsumoto, T.;
Yoshida, D.; Tomita, H. Agric. Biol. Chem. 1981, 45, 2031–2035; (e) US
20090082374.; (f) Forbes, I. T.; Morgan, H. K. A.; Thompson, M. Synth.
Commun. 1996, 26, 745–754.
33.7, 17.1; HRMS (ESI) m/z calcd for
315.0953.
C
14H13F3N2O3 + H+ 315.0957, found
12. Following the procedure in Ref. 11, 1k afforded compounds 7 and 2k both as
white solids. Compound 7: mp 203–204 °C; 1H NMR (500 MHz, DMSO-d6) d
11.22 (s, 1H), 9.74 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1H), 7.32 (d, J = 2.5 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.06
(d, J = 7.0 Hz, 1H), 2.89 (s, 3H), 2.84 (s, 3H); 13C NMR (125.7 MHz, DMSO-d6) d
168.3, 155.6 (q, JC–F = 36.4 Hz), 136.2, 125.7, 125.5, 121.5, 119.2, 118.4, 115.8
(q, JC–F = 288.1 Hz), 111.7, 107.8, 47.7, 36.4, 35.4; HRMS (ESI) m/z calcd for
C
14H14F3N3O2 + H+ 314.1116, found 314.1114. Compound 2k: mp 76–77 °C; 1
H
NMR (500 MHz, CDCl3) d 12.48 (s, 1H), 10.11 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H),
7.37 (d, J = 8.0 Hz, 1H), 7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.16 (td, J = 7.0, 1,0 Hz, 1H),

J. E. Mangette et al. / Tetrahedron Letters 52 (2011) 1292–1295
1295
3.87 (s, 2H), 3.21 (s, 3H), 3.00 (s, 3H); 13C NMR (125.7 MHz, CDCl3) d 172.3,
154.7 (q, JC–F = 38.6 Hz), 131.5, 130.7, 125.4, 121.5, 120.0, 116.1, 115.4
(q, JC–F = 287.3 Hz), 110.9, 92.4, 38.1, 35.6, 27.5; HRMS (ESI) m/z calcd for
14. The hydrochloride salts 3 were stable over the timeframe for their generation,
isolation, and use in the acylation step, which was usually no more than 24 h.
Although no effort was made to determine their long-term stability, as
indicated in Ref. 1c, salt formation from 2-aminoindoles tends to significantly
increase their stability.
15. (a) Glennon, R. A.; von Strandtmann, M. J. Heterocycl. Chem. 1975, 12, 135–138;
(b) Venugopalan, B.; Desai, P. D.; de Souza, N. J. J. Heterocycl. Chem. 1988, 25,
1633–1639; (c) Winters, G.; Di Mola, N.; Berti, M.; Arioli, V. Farmaco Ed. Sci.
1979, 34, 507–517; (d) Wamhoff, H.; Wehling, B. Chem. Ber. 1975, 108, 2107–
2114.
16. Optimization of the direct reaction of amides as shown in Scheme 4 was
unfruitful since deprotonation of amides of varying N–H acidity, and
difficulties with solubility and nucleophilicity of the resulting salts,
necessitated continual reoptimization; the use of sodium (2,2,2-
trifluoroacetyl) amide, which was readily formed with sodium hydride, had
good solubility in THF and proved to be a good nucleophile in the presence of
15-crown-5 ether, eliminated these difficulties and allowed for diversification
in the final step with more routine acylation chemistry.
17. 15-Crown-5 ether, a selective sequestration agent of the sodium cation, was
used to increase the nucleophilicity of the trifluoroacetyl amide anion. This
gave drastically improved yields of 2. As an example, the yield of 2a without
15-crown-5 was 14%.
C
14H14F3N3O2 + H+ 314.1116, found 314.1122.
13. Representative procedure: Hydrogen chloride (4 N in 1,4-dioxane, 0.46 mL,
1.85 mmol) was added to suspension of trifluoroacetamide 2i (0.068 g,
a
0.18 mmol) in methanol (2 mL) at room temperature. The reaction mixture
was heated at 80 °C and monitored by TLC. After 5 h, the reaction was cooled
and concentrated under vacuum. The residue was dissolved in methylene
chloride (2 mL), and pyridine (0.075 mL, 0.073 g, 0.92 mmol) and acetyl
chloride (0.017 mL, 0.018 g, 0.24 mmol) were added. The reaction mixture
was stirred at room temperature for 16 h. After that time, the reaction mixture
was partitioned between ethyl acetate and water. The organic layer was
washed with 10% sodium bicarbonate aqueous solution, dried over sodium
sulfate, filtered, and concentrated under vacuum. The residue was purified by
flash chromatography (silica, gradient from 20:80 to 60:40 ethyl acetate/
hexanes) to afford 4q (0.051 g, 87%) as a white solid: mp 178–179 °C; 1H NMR
(500 MHz, CDCl3) d 10.45 (s, 1H), 9.59 (s, 1H), 8.03 (s, 1H), 7.80 (d, J = 8.0 Hz,
1H), 7.38 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 2.96–2.94 (m, 2H), 2.71–
2.69 (m, 2H), 2.31 (s, 3H); 13C NMR (125.7 MHz, CDCl3) d 176.7, 169.5, 168.3,
135.8, 131.4, 130.6, 122.3, 121.4, 116.1, 113.2, 97.5, 52.4, 52.0, 34.2, 24.3, 17.3;
HRMS (ESI) m/z calcd for C16H18N2O5 + H+ 319.1294, found 319.1302.