Synthesis of N-aminoindole ureas from ethyl 1-amino-6-(trifluoromethyl)-1H-indole-3-carboxylate

Article abstract of DOI:10.1055/s-2001-10784

Two routes to the synthesis of ethyl 6-(trifluoromethyl)-1H-indole-3-carboxylate are described. N-Amination of this key intermediate with O-(diphenylphosphinyl)hydroxylamine and subsequent reactions with aryl isocyanates, using pyridine as solvent, gave t

Full text of DOI:10.1055/s-2001-10784

222
LETTER
Synthesis of N-Aminoindole Ureas from Ethyl 1-Amino-6-(trifluoromethyl)-
1H-indole-3-carboxylate
Michel Belley,* John Scheigetz, Pascal Dubé, Sarah Dolman
Merck Frosst Centre for Therapeutic Research, Department of Medicinal Chemistry, 16711 Route Transcanadienne, Kirkland,
Québec, H9H 3L1, Canada
Fax (514) 428-4900; E-mail: belley@merck.com
Received 13 December 2000
Abstract: Two routes to the synthesis of ethyl 6-(trifluoromethyl)-
1H-indole-3-carboxylate are described. N-Amination of this key in-
termediate with O-(diphenylphosphinyl)hydroxylamine and subse-
quent reactions with aryl isocyanates, using pyridine as solvent,
gave the corresponding N-aminoindole ureas 1-4 in good yields.
Key words: aminations, indoles, cyclizations, urea formation, iso-
cyanates
The synthesis of N-aminoindoles has been well docu-
mented and many of their derivatives have been reported
to have interesting biological activities.1 For example, be-
sipirdine and some of its analogs are potent acetylcho-
linesterase inhibitors developed for the treatment of
Alzheimer’s disease.2 However, the synthesis and phar-
macological properties of N-aminoindole ureas continues
to be virtually unexplored, with only one example cited in
the literature.3 Herein we wish to report a concise synthe-
sis of compounds 1-4 (Figure 1) which are representatives
of this new class of N-aminoindole ureas.
Figure 1
The synthesis of ureas 1-4 was initially envisioned to start
from commercially available 6-(trifluoromethyl)-1H-in-
dole (7)4. Unfortunately, high costs of the starting material
Scheme 1
7 prompted for a more economical preparation, which
could be achieved in three steps with an overall yield of
75% (Scheme 1). Thus, 3-amino-4-bromobenzotrifluo-
nyl)-5-(trifluoromethyl)-2-ethynylaniline (81% yield)
was observed; with DBU in acetonitrile (reflux, 1.5 h), the
N-(ethoxycarbonyl) derivative of 7 was obtained in 54%
yield.
ride was treated with ethyl chloroformate and pyridine in
THF to give the carbamate 5. Coupling with (trimethyl-
silyl)acetylene in the presence of bis(triphenylphos-
phine)palladium dichloride and copper iodide, using the
procedure described by Yamanaka,5 yielded the acetylene
derivative 6, which could be cyclized to 7 with sodium
ethoxide in ethanol.5 The choice of the reaction conditions
for this cyclization step is critical. When 6 was treated
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in etha-
nol (reflux, 1 h), only desilylation of 6 to N-(ethoxycarbo-
The indole nitrogen was then protected as a tert-butyldi-
methylsilyl amine6 to give 8. Carboxylation in the 3-posi-
tion using carbon monoxide, palladium acetate and sodi-
um persulfate7 afforded the acid 9 (37% yield), but
subsequent esterification with hydrogen chloride in etha-
nol failed to give the desired ester 10.
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LETTER
Synthesis of N-Aminoindole Ureas
223
Ethyl 6-(trifluoromethyl)-1H-indole-3-carboxylate 10 (Table 1). This was not surprising since Somei had previ-
was finally obtained using the procedure of Amat6 with a ously reported no N-amination for 3-acetylindole,3 proba-
slight modification (Scheme 1). When the bromination of bly due to the decreased reactivity of indoles containing
8 was performed as described by Amat on a milligram an electron-withdrawing substituent in position 3. Better
scale with NBS at 78 °C, 11 was obtained in 66% yield. yields for the N-amination of 10 were obtained with
However, upon scaling up, the yield decreased signifi- O-(diphenylphosphinyl)hydroxylamine12 using the proce-
cantly to 20%. Better and reproducible yields could be ob- dure of Klotzer.13 Optimization of the reaction conditions
tained by performing the brominations with bromine in led to the identification of lithium hexamethyldisilazanide
DMF8 (71% yield) or with pyridinium bromide as the base of choice for this amination, providing 15 with
perbromide9 in pyridine at 0 °C (87% yield). Transmetal- a reproducible yield of 80%.14
lation of the corresponding bromoindole with tert-butyl-
lithium and reverse addition to ethyl chloroformate gave
the ester 12 (60% yield), which was noted to slowly hy-
Table 1 N-Amination of indole 10
drolyze to 10 on silica gel or on standing at room temper-
ature. Higher yields of 10 (87%) were possible when the
crude reaction mixture containing 12 was treated with tet-
rabutylammonium fluoride in THF.10
A more expedient route to the indole 10 was subsequently
found (Scheme 2). The best-published synthesis of 6-(tri-
fluoromethyl)-1H-indole (7), described by Kalir and Pel-
ah,4a involved an aromatic nucleophilic substitution on
3-nitro-4-chlorobenzotrifluoride by the anion of ethyl cy-
anoacetate to yield the cyanoester 13. Ester hydrolysis and
decarboxylation of 13 followed by a reductive cyclization
afforded 7 in three steps in 38% overall yield. We won-
dered whether the reductive cyclization could be per-
a determined by HPLC
formed on the intermediate cyanoester 13 directly, thus
furnishing 10 in two steps. After much investigation, we
found that the best conditions to effect the reductive cy-
clization of 13 involved the use of AcOH or
AcOH:EtOAc mixtures as solvents and an amount of 10%
Pd/C corresponding to half the weight of 13.
The addition reaction between an amine and an isocyanate
is the most common method for preparing ureas.3,15 In an
attempt to form the N-aminoindole urea of 15, we initially
prepared 1-indole isocyanate 16a in situ via the treatment
of 15 with triphosgene16 or di-tert-butyl dicarbonate.17
Unfortunately, subsequent reaction of this isocyanate with
4-methylaniline afforded 1 in low yields (maximum
35%), with the two symmetrical ureas 17 and 18 resulting
as the major products. Equally disappointing was the re-
action between the trichloroacetamide 16b18 and 4-meth-
ylaniline in the presence of sodium carbonate using
Isobe’s19 procedure, where none of the desired urea could
be detected.
Scheme 2
N-Amination of indoles is usually performed using the
method of Somei, with hydroxylamine-O-sulfonic acid
and potassium hydroxide in anhydrous DMF.1a, 2, 3, 11 Un-
Figure 2
fortunately, these conditions were found to give poor con-
version of the indole 10 to the desired N-aminoindole 15
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224
M. Belley et al.
LETTER
We then turned our attention to the addition of N-aminoin- 1 in four steps in 42% overall yield. The key steps, com-
dole 15 to p-tolyl isocyanate. Our initial attempts using mon to both syntheses, involved the N-amination of an in-
this strategy gave very low yields of urea 1, with dole with O-(diphenylphosphinyl)hydroxylamine and its
N,N’-di-p-tolyl urea 17 as the major product. These poor subsequent reaction with an aryl isocyanate in pyridine.
results could be attributed to the low nucleophilicity of the The biological profile of these new compounds is current-
amino group in 15. A more thorough examination of the ly being investigated.
reaction conditions, however, revealed DMF or pyridine
as the solvent of choice for this urea formation, with
yields above 70% (Table 2). The reaction was found to
Experimental procedures
Ethyl 6-(trifluoromethyl)-1H-indole-3-carboxylate 10 from 11: 1.7
M t-Butyllithium in pentane (23 mL, 39 mmol) was added dropwise
to a solution of 1-(t-butyldimethylsilyl)-3-bromo-6-(trifluorometh-
yl)indole (11) (7.0 g, 18.5 mmol) in THF (63 mL) at -78 C, and the
work well with other aryl isocyanates, giving yields rang-
ing from 60 to 92% in pyridine (Table 3).20
resulting solution was stirred at that temperature for 30 min. It was
then cannulated into a solution of ethyl chloroformate (1.86 mL,
Table 2 Preparation of 1 by reaction of aminoindole 15 with p-tolyl
isocyanate
19.4 mmol) in THF (63 mL) at -100 C. The reaction mixture was
allowed to warm to 0 C over an hour, at which point a 1 M solution
of tetrabutylammonium fluoride in THF (22 mL) was added. After
15 minutes, the mixture was quenched with sat. NH4Cl (70 mL) and
extracted with i-PrOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated in vacuo to give a green solid.
A pink-white solid (3.93 g, 83% yield) was obtained after purifica-
tion by flash chromatography with EtOAc:toluene 10:90. 1H NMR
(300 MHz, acetone-d6) 11.40 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H),
8.24 (s, 1H), 7.90 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.34 (q, J = 7.1
Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (400 MHz, acetone-d6)
164.8, 136.5, 135.3, 129.6, 127.5, 124.8, 122.6, 118.5, 110.6,
109.1, 60.1, 14.8; IR (KBr) 3200, 2980, 1680, 1440, 1330, 1230,
1160, 1120, 1050 cm-1; MS (APCI, neg.) 256 (M-1, 100%), 228,
184; Anal. calcd. for C12H10NO2F3: C, 56.02; H, 3.92; N, 5.45;
found: C, 56.08; H, 4.46; N, 5.47.
Ethyl 6-(trifluoromethyl)-1H-indole-3-carboxylate 10 from 13: To
ethyl 2-cyano-2-(2-nitro-4-(trifluoromethyl)phenyl)acetate (13) (50
mg; 0.165 mmol) in a 4:1 mixture of EtOAc:AcOH (2.5 ml) was
added 25 mg of 10% Pd/C. The solution was stirred at room temper-
ature under 1 atmosphere of H2 and the reaction was followed by
HPLC (Nova Pak C18 column, gradient 20 to 90% CH3CN in aq.
NH4OAc 2 g/L, 1 mL/min, detection at 239 nm). After 4 hours, the
hydrogen was removed and the solution was stirred overnight at
room temperature under air. The mixture was filtered through celite,
the cake washed with ethanol and the filtrate concentrated under
vacuum to give 53 mg of crude product. A trituration in 5% toluene
in hexanes gave the desired product (34 mg, 81% yield) as a white
solid. Yields on larger scale were slightly lower (66%), principally
due to adsorption of compound 10 on Pd/C.
Table 3 Reaction of N-aminoindole 15 with isocyanates
Ethyl 1-amino-6-(trifluoromethyl)-1H-indole-3-carboxylate 15:
Lithium hexamethyldisilazanide (4.7 mL, 4.7 mmol) was added
dropwise to 10 (1.0 g, 3.9 mmol) in 1-methyl-2-pyrrolidinone (40
mL) at 10 C, followed by O-(diphenylphosphinyl)hydroxylamine
(1.09 g, 4.7 mmol) at 0 C. The reaction was allowed to warm to
room temperature and was followed by HPLC (30:70 ethyl ace-
tate:hexane, Porasil column). After 6 hours, the ratio of 10:15 re-
mained constant at 1:4. The mixture was then quenched with 2 N
HCl (20 mL) and extracted with i-PrOAc (200 mL). The organic
layer was washed with brine, dried over Na2SO4 and concentrated
in vacuo. The products were purified by flash chromatography on
silica gel eluting with EtOAc:hexane 30:70. A yellow-white solid
(1.06 g) containing 10 and 15 in a ratio of 1:4 was isolated. Pure 15
was obtained after purification by HPLC on a
Porasil column
In summary, two synthetic pathways to the N-aminoin-
dole ureas 1-4, from commercially available materials,
have been described. The first route, from 6-(trifluorome-
thyl)-1H-indole (7), gave 1 in six steps with an overall
yield of 46%, while the second route, starting from the
less expensive 3-nitro-4-chlorobenzotrifluoride, afforded
(EtOAc:hexane 30:70). 1H NMR (300 MHz, acetone-d6) 8.25 (d,
J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 7.49 (dd, J = 1.2, 8.4 Hz,
1H), 6.10 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H);
13C NMR (500 MHz, acetone-d6) 164.6, 139.0, 137.5, 133.2,
128.1, 122.8, 122.5, 118.7, 108.8, 105.4, 60.2, 14.8; IR (KBr) 3350,
3310, 3120, 1680, 1520, 1320, 1270, 1200, 1150, 1100, 1040 cm-1;
Synlett 2001, No. 2, 222–225 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Aminoindole Ureas
225
MS (APCI, neg) 184 (100%), 197, 256, 271 (M-1), 331 (M+AcO-);
Anal. calcd. for C12H11F3N2O2: C, 52.95; H, 4.07; N, 10.29; found:
C, 53.10; H, 4.33; N, 10.06; mp 115.3 °C.
amino)carbonyl)amino)-1H-indole) was given without any
detail on the experimental procedure.
(4) Available from Lancaster. Reported synthesis: a) Kalir, A.,
Pelah, Z. Isr. J. Chem. 1966, 4, 155, b) Raucher, S., Koolpe,
G. A. J. Org. Chem. 1983, 48, 2066.
(5) a) Sakamoto, T., Kondo, Y., Yamanaka, H. Heterocycles
1986, 24, 1845, b) Sakamoto, T., Shiraiwa, M., Kondo, Y.,
Yamanaka, H. Synthesis 1983, 312, c) Sakamoto, T., Kondo,
Y., Yamanaka, H. Heterocycles 1986, 24, 31
(6) Amat, M., Hadida, S., Sathyanarayana, S., Bosch, J. J. Org.
Chem. 1994, 59, 10.
(7) Itahara, T. Chem. Lett. 1982, 1151
(8) Bocchi, V., Palla, G. Synthesis 1982, 1096.
(9) a) Vaillancourt, V., Albizati, K. F. J. Am. Chem. Soc. 1993,
115, 3499, b) Erickson, K. L., Brennan, M. R., Namnum, P. A.
Synth. Commun. 1981, 11, 253.
(10) Excess ethyl chloroformate should be avoided; it leads to the
formation of the N-(ethoxycarbonyl) derivative of 10.
(11) a) Somei, M., Matsubara, M., Kanda, Y., Natsume, M. Chem.
Pharm. Bull. 1978, 26, 2522, b) Somei, M., Natsume, M.
Tetrahedron Lett. 1974, 461, c) Lee, T. B., Goehring, K. E.
U.S. Patent 5459274, 1995; Chem. Abstr. 1995, 124, 145914.
(12) Prepared according to Colvin, E. W., Kirby, G. W., Wilson, A.
C. Tetrahedron Lett. 1982, 23, 3835.
(13) a) Klötzer, W., Baldinger, H., Karpitschka, E. M., Knoflach,
J. Synthesis 1982, 592, b) Harger, M. J. P. J. Chem. Soc.,
Perkin Trans. 1 1981, 3284, c) Sosnovsky, G., Purgstaller, K.
Z. Naturforsch 1989, 44b, 582.
Ethyl 1-((((4-(methylthio)phenyl)amino)carbonyl)amino)-6-(triflu-
oromethyl)-1H-indole-3-carboxylate (3): To a solution of the
N-aminoindole 15 (93 mg, 0.34 mmol) in pyridine (4.5 ml) was add-
ed 4-(methylthio)phenyl isocyanate (96 L, 2.0 eq) and the result-
ing mixture was stirred at 80 °C under nitrogen for 5 hours. The
reaction was quenched with sat. NH4Cl and the product extracted
with ethyl acetate, washed with brine and dried over Na2SO4. Con-
centration under reduced pressure gave 214 mg of crude product,
which was adsorbed onto 2 g silica gel before purification by flash
chromatography on silica gel eluting with EtOAc:toluene 30:70. A
second purification, using the same procedure, but with acetone:tol-
uene 10:90, was necessary to provide pure 3 (101 mg, 68% yield) as
a yellow solid. 1H NMR (300 MHz, acetone-d6) 9.34 (s, 1H), 8.87
(s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.83 (s, 1H), 7.56 (d,
J = 8.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H),
4.35 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13
C
NMR (500 MHz, acetone-d6) 164.1, 154.5, 139.5, 137.5, 137.4,
132.9, 128.5, 127.9, 122.8, 120.5, 119.3, 119.2, 108.1, 108.1, 107.4,
60.3, 16.3, 14.6; IR (KBr) 3270, 1695, 1645, 1535, 1315, 1190,
1035 cm-1; MS (APCI, pos.) 392, 438 (M+1), 455 (100%); Anal.
calcd. for C20H18F3N3O3S: C, 54.92; H, 4.15; N, 9.61; S, 7.33;
found: C, 54.86; H, 4.37; N, 9.32; S, 7.45; mp 226.5 °C.
Acknowledgement
(14) When sodium hydride or DBU was used as the base to effect
the N-amination of 10 with O-(diphenylphosphinyl)-
hydroxylamine, we found that the aminoindole 15 reverted
back to the starting material 10 over time in the reaction
mixture. This was not happening with KHMDS or LiHMDS
and we are currently investigating the mechanism of this retro-
amination. It should also be noted that recycling of the 1:4
mixture did not improved the ratio of 10:15.
The authors would like to thank the Natural Sciences and Enginee-
ring Research Council of Canada (NSERC), for an industrial
research grant given to S. Dolman, and Renee Aspiotis, for critical
comments on the manuscript.
References and Notes
(15) For examples, see a) Josey, J. A., Tarlton, C. A., Payne, C. E.
Tetrahedron Lett. 1998, 39, 5899, b) Xin, Z., Pei, Z., von
Geldem, T., Jirousek, M. Tetrahedron Lett. 2000, 41, 1147, c)
Roshchin, A. I., Bumagin, N. A. Chem. Heterocycl. Compd.
1999, 35, 171.
(16) Majer, P., Randad, R. S. J. Org. Chem. 1994, 59, 1937.
(17) Knölker, H. J., Braxmeier, T., Schlechtingen, G. Synlett 1996,
502.
(18) Prepared in 60% yield by treating 15 with trichloroacetyl
chloride and i-Pr2NEt in THF at 0 °C.
(19) Yamamoto, N., Isobe, M. Chem. Lett. 1994, 2299.
(20) Similar results were also obtained with the 4:1 mixture of
15:10 obtained in the previous step, thus avoiding the HPLC
purification of 15.
(1) a) Andersen, K., Perregaard, J., Arnt, J., Nielsen, J. B.,
Begtrup, M. J. Med. Chem. 1992, 35, 4823, b) Schatz, F.,
Jahn, U., Wagner-Jauregg, T., Zirngibl, L., Thiele, K.
Arzneim. Forsch. 1980, 30, 919 and references cited therein.
(2) Martin, L. L., Davis, L., Klein, J. T., Nemoto, P., Olsen, G. E.,
Bores, G. M., Camacho, F., Petko, W. W., Rush, D. K., Selk,
D., Smith, C. P., Vargas, H. M., Winslow, J. T., Effland, R. C.,
Fink, D. M. Bioorg. Med. Chem. Lett. 1997, 7, 157 and
references cited therein.
(3) Somei, M., Matsubara, M., Natsume, M. In Hukusokan
Kagaku Toronkai Koen Yoshishu, 8th; Pharm. Inst., Tohoku
Univ.; Sendai, Japan 1975; pp 219-223 (written in Japanese);
Chem. Abstr. 1976, 84, 164705. In this presentation, many
examples of N-amination of indoles with hydroxylamine-
O-sulfonic acid and potassium hydroxide in anhydrous DMF
were provided. However, indoles bearing an acetyl group in
position 3 could not be N-aminated using this method (which
is contrary to what was reported in Chem. Abstr.). It was also
stated that N-aminoindoles react with isocyanates to yield
N-aminoindole ureas, but only one example (1-(((phenyl-
Article Identifier:
1437-2096,E;2001,0,02,0222,0225,ftx,en;S09400ST.pdf
Synlett 2001, No. 2, 222–225 ISSN 0936-5214 © Thieme Stuttgart · New York