A scalable Nenitzescu synthesis of 2-methyl-4-(trifluoromethyl)-1H-indole- 5-carbonitrile

Article abstract of DOI:10.1002/jhet.571

2-Methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4-nitro-3-(tr

Full text of DOI:10.1002/jhet.571

May 2011
A Scalable Nenitzescu Synthesis of 2-Methyl-4-(trifluoromethyl)-
1H-indole-5-carbonitrile
733
Eric E. Boros,* Istvan Kaldor, and Philip S. Turnbull
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709
*E-mail: eric.e.boros@gsk.com
Received April 6, 2010
DOI 10.1002/jhet.571
Published online 28 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
2-Methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile is a key intermediate in the synthesis of selec-
tive androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis
of the title compound starting from 4-nitro-3-(trifluoromethyl)phenol and tert-butyl acetoacetate was
developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of
2-trifluoromethyl-1,4-benzoquinone. Conversion of the known Nenitzescu indole product to a novel tri-
flate intermediate followed by palladium-catalyzed cyanation afforded a penultimate carbonitrile. Re-
moval of the C-3 tert-butyl ester group on the indole through a decarboxylative pathway completed the
synthesis of the title compound in six steps (27% overall yield) from 4-nitro-3-(trifluoromethyl)phenol
(five steps, 37% overall yield from tert-butyl acetoacetate).
J. Heterocyclic Chem., 48, 733 (2011).
INTRODUCTION
mild conditions. In addition, a telescoped procedure for the
key Nenitzescu reaction (without isolation of the benzoqui-
none intermediate) is described, together with characteriza-
tion of novel intermediates and the title compound (2).
There is significant current interest in the design and
development of selective androgen receptor modulators
(SARMs) as therapeutic agents for the treatment of sar-
copenia and the improvement of muscle function in
humans [1]. A novel series of indoles discovered in
these laboratories (e.g., 1: Ar ¼ aryl; heteroaryl) were
recently disclosed as nonsteroidal modulators of the
androgen receptor [2]. In the course of this drug discov-
ery effort, a practical synthesis of 2-methyl-4-(trifluoro-
methyl)-1H-indole-5-carbonitrile (2), a key synthetic in-
termediate in the preparation of 1, was required.
The original medicinal chemistry route to 2 [2] entailed
an indole ring synthesis from propynyl intermediate 3 [3].
This approach, although efficient, required use of propyne
gas for incorporation of the alkyne moiety and very high
temperatures for the cyanodechlorination reaction (copper
cyanide) and removal of the pivaloyl group (180–250ꢀC).
Consequently, a more convenient and scalable synthesis
of 2 was needed for large-scale applications.
RESULTS AND DISCUSSION
The Nenitzescu reaction [4] involves condensation of
1,4-benzoquinones with enamino esters to afford
diversely functionalized 5-hydroxyindole-3-carboxylates
(Scheme 1). In the case of 2-substituted-1,4-benzoqui-
nones, the Nenitzescu reaction typically affords 6-substi-
tuted-5-hydroxyindoles (R1 at C-6 of the indole) or mix-
tures of 6- and 7-substituted products [5,6]; however,
there are exceptions.
Interestingly, Littell and Allen [5] discovered that the
Nenitzescu reaction of 2-trifluoromethyl-1,4-benzoqui-
none (R1 ¼ CF3) with 3-aminocrotonates (R2 ¼ Me)
selectively affords the 4-substituted-5-hydroxyindole
products (CF3 at C-4 of the indole). This regioselectivity
was attributed to the powerful inductive influence of the
trifluoromethyl group on the 1,4-benzoquinone and the
lack of a competing resonance effect with this substitu-
ent. Consequently, addition of the enamine methine car-
bon occurs selectively at the 3-position of the 1,4-benzo-
quinone. Aside from the work of Littell and Allen [5],
this particular Nenitzescu synthesis of 4-trifluoromethy-
lindoles appears to be relatively unexploited in the fields
of medicinal and process chemistry.
A Nenitzescu-based synthesis of 2 was developed that is
amenable to multigram scale operations under relatively
C
V
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E. E. Boros, I. Kaldor, and P. S. Turnbull
Vol 48
Scheme 1. Nenitzescu synthesis of 5-hydroxyindole-3-carboxylates.
Scheme 3. Synthesis of 2 from Nenitzescu indole 7.
Based on this precedence, the Nenitzescu reaction
appeared to have all the attributes for an efficient syn-
thesis of 2. In addition to being highly convergent, the
Nenitzescu synthesis would incorporate the trifluoro-
methyl substituent at the desired 4-position of the indole
along with a 5-hydroxy substituent. The latter might eas-
ily be converted to a triflate group and later substituted
with a cyano substituent under palladium-catalyzed con-
ditions. Removal of the ester moiety at C-2 of the indole
through a decarboxylative pathway would then complete
the synthesis of the title compound. This approach to
the novel intermediate 2 was subsequently reduced to
practice as outlined in Schemes 2 and 3.
gram scales for conversion of 4–5, including ceric am-
monium nitrate, sodium (meta)periodate (NaIO4), and
manganese (II) oxide (MnO2). All of these reagents
gave satisfactory results; however, we favored the use of
MnO2 [9] for scale-up because of its low cost.
Adding a solution of 4 in 2.5M sulfuric acid to a stirred
suspension of manganese dioxide in dilute sulfuric acid
effected clean conversion to 5. The manganese salts were
easily removed by filtration, and extraction of both the fil-
ter cake and filtrate with dichloromethane afforded (after
drying over MgSO4) a clear solution of 5 (estimated yield
¼ 78%) which could be used directly in the next step.
1,1-Dimethylethyl (2Z)-3-amino-2-butenoate 6 [10]
was prepared in quantitative yield by treatment of tert-
butyl acetoacetate [11] with 28–30 wt % ammonium hy-
droxide in MeOH. Addition of the dichloromethane so-
lution of 5 to an ethanol solution of 6 at ambient tem-
perature resulted in spontaneous Nenitzescu reaction to
afford 7. The reaction was mildly exothermic (10–15ꢀC
temperature rise on 0.3 mol scale) and was complete
within 1 h. A solvent switch from dichloromethane/etha-
nol to chloroform and filtration of the resulting precipi-
tate afforded the known indole 7 as a white solid in
64% yield (based on 3-aminocrotonate 6). Indole 7 was
used without further purification.
Conversion of 4-amino-3-(trifluoromethyl)phenol (4)
to 2-trifluoromethyl-1,4-benzoquinone (5) and Nenit-
zescu reaction of 5 with 1,1-dimethylethyl (2Z)-3-
amino-2-butenoate (6) are illustrated in Scheme 2. Com-
pound 4 was prepared in quantitative yield [7] by hydro-
genation of 4-nitro-3-(trifluoromethyl)phenol [8] in etha-
nol over palladium on carbon at atmospheric pressure.
Initially, oxidation of 4 [5] with sodium dichromate in a
biphasic mixture of 20% sulfuric acid and hexanes
afforded 5 as a crystalline solid in 33% isolated yield.
The low yield of 5 was in accordance with the
reported synthesis [5], and the material sublimed readily
under relatively low-vacuum conditions. The toxicity
associated with chromium salts and the volatility of 5
prompted us to explore alternative reagents for the oxi-
dation step and a procedure that avoided isolation of 5
(i.e., a telescoped conversion of 4 ! 7). A number of
oxidizing agents were evaluated qualitatively on milli-
Synthesis of the title compound (2) from indole 7 is
illustrated in Scheme 3. We opted to perform triflate for-
mation prior to tert-butyl ester removal in order to
maintain protection of the indole’s potentially reactive
C-3 position. Initially, reaction of 7 with triflic anhy-
dride and 2,6-lutidine in dichloromethane at 0ꢀC gener-
ated the novel triflate 8; however, the reaction was
accompanied by formation of several unidentified by-
products. Alternatively, reaction of 7 with N-phenyl-
bis(trifluoromethane)sulfonimide and Hunig’s base in
acetonitrile at reflux gave a much cleaner reaction mix-
ture. The sulfonamide by-product was removed from the
reaction mixture on workup (dilute sodium hydroxide
wash), and the product (8) was crystallized from tert-
butyl methyl ether in 75% yield.
Scheme 2. Nenitzescu indole synthesis of 7.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
A Scalable Nenitzescu Synthesis of
2-Methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile
735
MHz, dimethylsulfoxide-d6) d 1.45 (s, 9H), 2.37 (s, 3H), 6.76
(d, 1H, J ¼ 9 Hz), 7.33 (d, 1H, J ¼ 9 Hz), 9.68 (br s, 1H),
11.55 (s, 1H); Anal. Calcd. for C15H16F3NO3: C, 57.14; H,
5.11; N, 4.44. Found: C, 56.80; H, 5.02; N, 4.34.
Limited examples of palladium-catalyzed couplings of
zinc cyanide with ortho-trifluoromethyl substituted aryl
halides and aryl triflates are described in the patent liter-
ature [12]. We explored coupling of 8 with zinc cyanide
using tris[dibenzylideneacetone]-di-palladium(0) catalyst
and 1,10-bis(diphenylphosphino)-ferrocene ligand in wet
1-methyl-2-pyrrolidinone (NMP) [13]. Heating the batch
to 125ꢀC effected a 50% conversion of 8 to the desired
5-cyanoindole 9 during which time the reaction stalled
and turned very dark both observations consistent with
catalyst deactivation. Interestingly, if the reaction was
performed under the same conditions, but at lower tem-
perature (80ꢀC), the results were dramatically improved.
Under these conditions, the reaction mixture maintained
a light amber appearance and was complete within a
few hours. The novel nitrile product (9) was obtained in
85% yield following workup and trituration with tert-
butyl methyl ether.
1,1-Dimethylethyl 2-methyl-4-(trifluoromethyl)-5-{[(tri-
fluoromethyl)-sulfonyl]oxy}-1H-indole-3-carboxylate (8). A
stirred solution of 7 (62 g, 0.197 mol), N, N-diisopropyl ethyla-
mine (DIEA) (56 mL, 0.321 mol), and PhN(Tf)2 (78 g, 0.218
mol) in CH3CN (300 mL) was heated at reflux temperature for 2
h. The reaction mixture was cooled to ambient temperature,
diluted with EtOAc, and washed with water; the layers were sep-
arated and the aqueous phase was extracted with EtOAc. The
combined EtOAc layers were washed with 0.1N NaOH, 2M
H3PO4, and water. The EtOAc layer was dried over MgSO4, fil-
tered, and concentrated, and the resulting material crystallized
from tert-butyl methyl ether (MTBE) to afford 8 as a white crys-
1
talline solid (66 g, 75% yield), mp 161–163ꢀC; H NMR (400
MHz, dimethylsulfoxide-d6) d 1.48 (s, 9H), 2.48 (s, 3H), 7.29 (d,
1H, J ¼ 9 Hz), 7.77 (d, 1H, J ¼ 9 Hz), 12.39 (s, 1H); 13C NMR
(101 MHz, dimethylsulfoxide-d6) d 13.6, 28.4, 81.0, 109.3, 112.6
(q, JCF ¼ 33 Hz), 115.8, 117.45, 120.3 (q, JCF ¼ 321 Hz), 122.8
Completion of the synthesis entailed removal of the
tert-butyl ester group of 9 with para-toluenesulfonic
acid in refluxing toluene [5]. Following workup and
crystallization from toluene, the novel indole 2 was
obtained in 87% yield as an off-white crystalline solid.
In summary, a scalable synthetic pathway to the novel
indole 2, an important intermediate in the preparation of
nonsteroidal androgen receptor modulators (1), was
achieved in six steps and 27% overall yield from 4-
nitro-3-(trifluoromethyl)phenol (five steps and 37% over-
all yield from tert-butyl acetoacetate). This chemistry
was subsequently adapted to kilo-lab preparations of the
title compound. The medicinal chemistry synthesis of 3
and the structure activity relationships of SARMs
derived from 2 are planned for future publications.
(q, JCF ¼ 2 Hz), 123.6 (q, JCF ¼ 275 Hz), 135.5, 141.2 (q, JCF
¼
2 Hz), 145.5, 165.0; ESMS (negative mode): m/z 446 (MꢁH)ꢁ;
Anal. Calcd. for C16H15F6NO5S: C, 42.96; H, 3.38; N, 3.13; S,
7.17. Found: C, 42.94; H, 3.46; N, 3.23; S, 7.12.
1,1-Dimethylethyl 5-cyano-2-methyl-4-(trifluoromethyl)-
1H-indole-3-carboxylate (9). To a stirred solution of 8 (20.2
g, 45.2 mmol) in NMP (150 mL) was added deionized water
(8 mL), and N2 was passed through the solution for 10 min.
1,10-Bis(diphenylphosphino)ferrocene (2.49 g, 4.49 mmol) and
tris(dibenzylidineacetone)-dipalladium(0) (2 g, 2.18 mmol)
were added, and the solution was stirred under N2 atmosphere
at rt for 15 min. Zinc cyanide (3.95 g, 33.6 mmol) was added
and the mixture was stirred an additional 10 min at rt. The
reaction mixture was heated to 80ꢀC and maintained at this
temperature for 3 h. After cooling to 35ꢀC, the mixture was
diluted with MTBE and washed with water. The aqueous layer
was extracted with MTBE, and the combined MTBE layers
were washed with water and dried over MgSO4. The organic
phase was filtered and the MTBE filtrate was stirred over
decolorizing charcoal for 15 min. The charcoal mixture was
filtered through a plug of silica gel (75 g), and the filtrate was
concentrated at reduced pressure. The remaining material was
triturated with hot MTBE, then diluted with iso-octane, cooled
to ꢁ15ꢀC and filtered to afford 9 as a beige solid (12.5 g, 85%
yield), mp 220–222ꢀC (dec); 1H NMR (400 MHz, dimethyl-
sulfoxide-d6) d 1.49 (s, 9H), 2.50 (s, 3H), 7.70 (1H, d, J ¼ 8
Hz), 7.77 (1H, d, J ¼ 8 Hz), 12.54 (s, 1H); ESMS (negative
mode): m/z 323 (MꢁH)ꢁ; Anal. Calcd. for C16H15F3N2O2: C,
59.26; H, 4.66; N, 8.64. Found: C, 59.26; H, 4.70; N, 8.46.
2-Methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (2). A
rapidly stirred mixture of 9 (12.5 g, 38.54 mmol), para-tolue-
nesulfonic acid monohydrate (0.71 g, 3.7 mmol), and toluene
(110 mL) was heated at reflux for 1 h. The mixture was cooled
to ambient temperature, diluted with EtOAc, and washed with
saturated NaHCO3 solution. The organic phase was dried over
MgSO4, filtered, and concentrated at reduced pressure; the
remaining material was crystallized from toluene to provide 2
as an off-white solid (7.5 g, 87% yield), mp 191–192ꢀC; 1H
NMR (400 Mz, dimethylsulfoxide-d6) d 2.45 (s, 3H), 6.43 (br
EXPERIMENTAL
1,1-Dimethylethyl 5-hydroxy-2-methyl-4-(trifluoromethyl)-
1H-indole-3-carboxylate (7). A solution of 4 [7] (70 g, 0.40
mol) in 2.5M H2SO4 (720 mL) was added dropwise to a stirred
suspension of MnO2 (78 g, 0.9 mol) in 2.5M H2SO4 (720 mL)
with external cooling; the reaction mixture temperature was
maintained between 6ꢀC and 8ꢀC during this addition. After
stirring an additional 30 min, the mixture was filtered and the
cake washed several times with CH2Cl2. The organic phase of
the filtrate was separated, dried over MgSO4, filtered through a
small plug of silica gel and concentrated to a volume of about
300 mL at atmospheric pressure (to avoid sublimation of 5).
The resulting CH2Cl2 solution of 5 (about 0.31 mol, 78%
yield) was added dropwise to a stirred solution of 6 [10] (47.6
g, 0.3 mol) in EtOH (100 mL) at room temperature (rt) (inter-
nal temperature rose to þ35ꢀC during this addition). After stir-
ring the reaction mixture for 1 h at ambient temperature, the
solvent was removed by rotovap and replaced with CHCl3.
The stirred mixture was cooled to 0ꢀC and indole 7 [5] was
collected by filtration as an off-white solid (62 g, 66% yield
from 6) and used without further purification; 1H NMR (400
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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E. E. Boros, I. Kaldor, and P. S. Turnbull
Vol 48
[6] Patrick, J. B.; Saunders, E. K. Tetrahedron Lett 1979, 20, 4009.
[7] Filler, R.; Novar, H. J Org Chem 1961, 26, 2707.
s, 1H), 7.58 (d, 1H, J ¼ 8 Hz), 7.69 (d, 1H, J ¼ 8 Hz), 12.07
(br s, 1H); 13C NMR (101 MHz, dimethylsulfoxide-d6) d 13.9,
99.3 (q, JCF ¼ 3 Hz), 99.7 (q, JCF ¼ 3 Hz), 115.5, 118.4,
121.6 (q, JCF ¼ 32 Hz), 124.7 (q, JCF ¼ 275 Hz), 125.9, 126.1
(q, JCF ¼ 2 Hz), 139.5, 142.9; ESMS (negative mode): m/z
223 (MꢁH)ꢁ; Anal. Calcd. for C11H7F3N2ꢂ(0.2 H2O): C,
58.00; H, 3.27; N, 12.30. Found: C, 58.04; H, 3.05; N, 12.34.
[8] 4-Nitro-3-(trifluoromethyl)phenol was purchased from
Alfa Aesar/Lancaster Synthesis (100
L08228).
g @ $8.00/g; catalog #
[9] For oxidations of 4-aminophenol derivatives to 1,4-benzo-
quinones with manganese (II) oxide, see: (a) Malesani, G.; Galiano,
F.; Ferlin, M. G.; Masiero, S. J Heterocycl Chem 1980, 17, 563; (b)
Buttrus, N. H.; Cornforth, J., Sir; Hitchcock, P. B.; Kumar, A.; Stuart,
A. S. J Chem Soc Perkin Trans 1 1987, 851.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet