Metal-free synthesis of fluorinated indoles enabled by oxidative dearomatization

Article abstract of DOI:10.1002/anie.201511149

Nitrogen heterocycles are found in a majority of approved small-molecule pharmaceuticals, and the number of approved fluorinated drugs is increasing each decade. Therefore, new approaches for accessing fluorinated nitrogen heterocycles are of great significance. A novel, scalable, and metal-free method for accessing a wide range of fluorinated indoles is described. This oxidative-dearomatization-enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore, the indole products contain a 3-trifluoroacetyl group, which can be exploited to access a plethora of useful functional groups.

Full text of DOI:10.1002/anie.201511149

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International Edition: DOI: 10.1002/anie.201511149
German Edition: DOI: 10.1002/ange.201511149
Synthetic Methods
Metal-Free Synthesis of Fluorinated Indoles Enabled by Oxidative
Dearomatization
Edon Vitaku, David T. Smith, and Jon T. Njardarson*
Abstract: Nitrogen heterocycles are found in a majority of
approved small-molecule pharmaceuticals, and the number of
approved fluorinated drugs is increasing each decade. There-
fore, new approaches for accessing fluorinated nitrogen
heterocycles are of great significance. A novel, scalable, and
metal-free method for accessing a wide range of fluorinated
indoles is described. This oxidative-dearomatization-enabled
approach assembles 2-trifluoromethyl NH-indole products
from simple commercially available anilines with hexafluoro-
acetylacetone in the presence of an organic oxidant. The nature
of the aniline N-capping group is critical for the success of this
new reaction. Furthermore, the indole products contain a 3-
trifluoroacetyl group, which can be exploited to access
a plethora of useful functional groups.
Figure 1. Blockbuster drugs containing nitrogen heterocycles and fluo-
rinated substituents.
N
itrogen heterocycles are structural components of a large
number of bioactive natural and unnatural compounds. Our
recent analysis revealed that 59% of all US FDA (FDA =
Food and Drug Administration) approved small-molecule
drugs contain at least one nitrogen heterocycle.[1] Addition-
ally, the fluorine atom is undoubtedly one of the most
successful additions to the drug discovery toolkit in the last
few decades, as its incorporation impacts solubility, lipophi-
licity, and metabolic activity, among other drug properties.[2]
Fluorinated drugs make up 11% of small-molecule drugs, and
around 20% of drugs in the current decade.[3] The combina-
tion of fluorine substituents with nitrogen heterocycles has
resulted in numerous blockbuster drugs, five of which are
shown in Figure 1. As such, we are interested in the develop-
ment of robust methods for forming fluorinated nitrogen
heterocycles from simple building blocks.
Indoles[4] are one of the most common nitrogen hetero-
cycles found in pharmaceuticals,[1] and they have been
referred to as “privileged structures” in drug discovery.[5]
Inspired by the oxidative dearomatization[6] reaction used in
our synthesis of vinigrol,[7] we decided to apply this approach
to the synthesis of 2-trifluoromethyl substituted indoles.[8]
Recently, our group has been interested in using strategic
dearomatization/rearomatization cascades to result in a net
À
C H functionalization, a strategy we used to form fused
oxygenated aromatic heterocycles.[9] Based on the insights of
the hypervalent iodine[10] mediated oxidative dearomatization
Scheme 1. a) Oxidative dearomatization inspired approach to indoles.
b) Nenitzescu indole reaction.
[*] E. Vitaku, D. T. Smith, Prof. Dr. J. T. Njardarson
Department of Chemistry and Biochemistry, University of Arizona
1306 E. University Blvd., Tucson, AZ 85721 (USA)
E-mail: njardars@email.arizona.edu
mechanism, we postulated that strategically substituted ani-
lines (Scheme 1a) could be dearomatized to create quinone
imines (2). We then expected that these cationic acceptors
would electronically guide soft nucleophiles, such as hexa-
fluoroacetylacetone (hfacac; 3), to add ortho to the resulting
Homepage: http://jon.oia.arizona.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201511149.
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quinone imine. The nucleophilic addition product (4) would
amides (entries 9 and 10) were compatible, but suffered lower
conversion. Hydrogen or alkyl substituents (entries 4–6)
failed to give any desired product, as did acylated anilines
(entries 7 and 8).
À
then rearomatize, thus resulting in a net C H functionaliza-
tion (5). Furthermore, we anticipated that this aromatic
intermediate would undergo a cyclization event (6), with the
expectation that the nitrogen atom substituent could be
removed in the same pot to afford 2-trifluoromethyl-3-
trifluoroacetyl NH-indole products (7). From a mechanistic
perspective, the Nenitzescu reaction[11] is the closest of the
indole syntheses to our proposal. However, in the Nenitzescu
reaction (Scheme 1b), para-benzoquinones (8) are used as
electrophiles, and 3-aminocrotonates (9) are used as nucleo-
philes. Consequently, the indole nitrogen atom is a part of the
nucleophile, whereas in our approach it is built into the
electrophile.
Since our goal was to access indoles in one pot, we were
pleased that the carbamates worked great, as they can be
installed easily and be removed cleanly using a variety of
industrially attractive approaches. Therefore, Boc was chosen
as the ideal capping group for all investigations. We obtained
an X-ray crystal structure of the Boc-dihydroindole (12a;
Scheme 2), which reveals that the trifluoroacetyl and the
trifluoromethyl groups are oriented anti to each other and the
hydroxy group of the aminal is engaged in a hydrogen bond
with the carbonyl group of the Boc substituent. Addition of
trifluoroacetic acid (TFA) to the crude reaction mixture at
room temperature afforded the desired fluorinated NH in-
dole in an excellent yield upon isolation.
We soon established that Boc-functionalized aniline
(Table 1) could be dearomatized[12] as proposed by employing
Table 1: Critical nature of the nitrogen-capping group.
Entry
Substrate
R
Consumption [%]
Yield [%][a–c]
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11 f
11g
11h
11i
Boc
Troc
Fmoc
H
Me
100
100
100
100
100
100
14
0
34
75
100
>99 (64)
>99 (55)
>99 (47)
0
0
0
0
0
Bn
COCH3
COCF3
Ms
9
10
11
34 (30)
75 (46)
>99 (73)
11j
11k
Ts
Scheme 2. One-pot synthesis of fluorinated indoles.[21] Thermal ellip-
P(O)(OEt)2
soids shown at 50% probability.
[a] Reaction conditions: substrate (0.25 mmol, 1.0 equiv), PIDA
(0.50 mmol, 2.0 equiv), hfacac (0.75 mmol, 3.0 equiv), TFE (1.0 mL).
[b] Yield is based on conversion as determined by 1H NMR spectroscopy.
[c] Yield within parentheses is that of the product isolated after
chromatography. Boc=tert-butoxycarbonyl, Fmoc=9-fluorenylmethoxy-
carbonyl, Ms=methanesulfonyl, Troc=2,2,2-trichloroethoxylcarbonyl,
Ts =4-toluenesulfonyl.
Further investigations revealed the scope of this new
indole synthesis (Table 2). To best aid future users of this
method we chose to investigate substrates containing halides
(F, Cl, Br and I), alkyl (methyl), aryl (phenyl), electron-
withdrawing groups (nitro and methyl ester) and electron-
donating groups (alkoxy) in both ortho- and meta-positions, as
well as phenol alkyl substituents (methyl, benzyl, allyl and
propargyl). These studies revealed that alkyl, aryl, and halide
substituents in both ortho- and meta-positions worked well
(yields ranging from 57–88%), with the exception of ortho-
iodo substitution (37% yield). Phenol alkyl substituents gave
uniformly excellent yields (90–99%). Electron-withdrawing
groups show a distinctive limitation to the method, with only
the methyl ester in the ortho-position working, albeit in low
yield (21%). In the latter cases, the starting N-Boc aniline
underwent Boc-removal to give the corresponding free
aniline, thus not undergoing dearomatization, because
hfacac reacts with the oxidant instead. When stronger hyper-
valent iodine reagents (PIFA and iodosylbenzene) were used
in hopes of alleviating this limitation, no improvements were
observed.
phenyliodine(III) diacetate (PIDA) as our hypervalent iodine
oxidant, and hfacac as our nucleophile in the polar non-
nucleophilic solvent trifluoroethanol (TFE).[13] When struc-
turally similar 1,3-dicarbonyl compounds (acetylacetone,
trifluoroacetylacetone, methyl acetoacetate, and dimethyl
malonate) were used instead of hfacac, we either observed
reactions between the oxidant and the nucleophile, or
oligomerization of the quinone imine intermediates.[14] Thus,
it is remarkable how well-matched hfacac is as a nucleophile
in this novel indole approach.[15] To better understand the
electronic and steric impacts of the aniline nitrogen substitu-
ent, we evaluated ten commonly used nitrogen-capping
groups (Table 1) using our optimized reaction conditions
(see the Supporting Information).[16] Our studies revealed
that carbamate substituents (entries 1–3) and phosphorami-
date (entry 11) were best suited for this reaction. Sulfon-
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Table 2: Substrate scope.[a,b]
[a] Reaction conditions:[21] substrate (1.25 mmol, 1.0 equiv), PIDA (2.50 mmol, 2.0 equiv), hfacac (3.75 mmol, 3.0 equiv), TFE (5.0 mL), RT, 30 min,
then TFA (12.50 mmol, 10.0 equiv), RT, 12 h. Thermal ellipsoids shown at 50% probability. [b] Yield of isolated product is given.
Methoxy-substituted substrates worked poorly, with only
the ortho substitution working (8%), because of competing
oligomerization of highly unstable quinone imines. To over-
come the problem presented by alkoxy-substituted indoles,
we used a trifluoroethoxy group,[17] which resulted in the
formation of the desired indoles in good yields (45% and
70%, for ortho- and meta- substitution, respectively). The
acetate group in the meta-position also works well, however, it
gives a mixture of the desired indole and de-acetylated indole
Scheme 3. Large-scale synthesis of the indole 13.
in a 1:1 ratio (64%).
To demonstrate the scalability of this new methodology,
we performed a 25 mmol scale reaction on our generic
substrate (11a), thus giving the desired indole 13 in 89% yield
(Scheme 3). This result is comparable to that obtained on
1.25 mmol scale as shown in Table 2.
An added benefit to this indole method is the resultant
trifluoroacetyl functionality,[18] which can be utilized for
a diverse variety of synthetic transformations.[19] This utility
is showcased in Table 3, where the free (13) and N-benzyl (19)
indoles are subjected to conditions which make possible
reactivity associated with both ketones and esters. Reaction
steps a, f, and g utilize the trifluoroacetyl group as a traditional
ketone to give reduction, conversion into the chiral imine, and
addition, respectively. When reaction conditions that utilize
the trifluoromethyl component as a leaving group are applied,
ester-like reactivity is observed. Highlighting this are ester-
ifications in steps c and h, and hydrolysis in step e. It is
remarkable that by changing the carbonate counterion from
sodium to cesium (step d versus c), both N-alkylation and
esterification occurred in one pot. Based on previous
research,[20] along with our own observations, trace water
mediates the reaction via a carboxylate intermediate, which
then reacts with benzyl bromide to afford the ester. When 13
is subjected to the same hydrolysis conditions as 19, all
fluorines are lost and the indole-2-carboxylic acid (17) is
generated. This serendipitous transformation provides a high-
yielding metal-free route to indole-2-carboxylic acids.
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Table 3: Trifluoroacetyl group as a versatile synthon.
Reaciton consitions:[21] a) NaBH4, NaHCO3, MeOH, RT, 97%; b) NaOH, 1:10 THF/H2O, reflux, 91%; c) BnBr, Cs2CO3, wet DMF, 908C, 92%; d) BnBr,
Na2CO3, DMF, 908C, 86%; e) NaOH, 1:10 THF/H2O, reflux, 97%; f) (S)-(À)-2-methyl-2-propanesulfinamide, Ti(OiPr)4, THF, reflux, 98% (1:1 E/Z);
g) Phenylacetylene, Cu(OAc)2, K2CO3, DMSO, 708C, 89%; h) BnBr, Cs2CO3, wet DMF, 908C, 85%. Thermal ellipsoids shown at 50% probability.
DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide, THF=tetrahydrofuran.
[4] For reviews of indole syntheses, see: a) U. Pindur, R. Adam, J.
Heterocycl. Chem. 1988, 25, 1 – 8; b) S. Cacchi, G. Fabrizi, Chem.
Rev. 2005, 105, 2873 – 2920; c) G. R. Humphrey, J. T. Kuethe,
Chem. Rev. 2006, 106, 2875 – 2911; d) D. F. Taber, P. K. Tiruna-
hari, Tetrahedron 2011, 67, 7195 – 7210; e) S. Cacchi, G. Fabrizi,
Chem. Rev. 2011, 111, PR215 – PR283; f) M. Platon, R. Amar-
deil, L. Djakovitch, J. C. Hierso, Chem. Soc. Rev. 2012, 41, 3929 –
3968.
In summary, we report a new, one-pot, scalable and metal-
free synthesis of 2-trifluoromethyl-3-trifluoroacetyl NH-
indoles from N-Boc anilines and hfacac. This new reaction
is regioselective, and works well with akyl, aryl, halide, and
other moderately electron-donating groups as substituents on
the parent aniline. We have further demonstrated the
versatility of the trifluoroacetyl group, wherein it undergoes
both ketone-like and ester-like chemistry.
[5] F. R. de Sa Alves, E. J. Barreiro, C. A. M. Fraga, Mini-Rev. Med.
Chem. 2009, 9, 782 – 793.
[6] For recent reviews on oxidative dearomatization of phenols, see:
a) L. PouysØgu, D. Deffieux, S. Quideau, Tetrahedron 2010, 66,
2235 – 2261; b) S. P. Roche, J. A. Porco, Angew. Chem. Int. Ed.
2011, 50, 4068 – 4093; Angew. Chem. 2011, 123, 4154 – 4179;
c) Q. P. Ding, Y. Ye, R. H. Fan, Synthesis 2013, 1 – 16.
Acknowledgements
Financial support for this work was provided by The
University of Arizona. We thank Dr. Sue Roberts, Dr.
Jonathan J. Loughrey, Isaac Chogii, Pradipta Das, and
Brandon R. Smith for X-ray crystallographic collection and
analysis.
[7] Q. Yang, J. T. Njardarson, C. Draghici, F. Li, Angew. Chem. Int.
Ed. 2013, 52, 8648 – 8651; Angew. Chem. 2013, 125, 8810 – 8813.
[8] For selected recent examples of 2-trifluoromethyl indole syn-
theses, see: a) L. Cao, D. Shen, J. M. Wei, J. Chen, H. M. Deng,
M. Shao, J. M. Shi, H. Zhang, W. G. Cao, Eur. J. Org. Chem.
2014, 2460 – 2467; b) B. Zhang, A. Studer, Org. Lett. 2014, 16,
1216 – 1219; c) X. C. Dong, Y. M. Hu, T. B. Xiao, L. Zhou, RSC
Adv. 2015, 5, 39625 – 39629; For selected recent examples of C2-
trifluoromethylation of indoles, see: d) M. S. Wiehn, E. V.
Vinogradova, A. Togni, J. Fluorine Chem. 2010, 131, 951 – 957;
e) Y. N. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S.
Su, D. G. Blackmond, P. S. Baran, Proc. Natl. Acad. Sci. USA
2011, 108, 14411 – 14415; f) T. D. Senecal, A. T. Parsons, S. L.
Buchwald, J. Org. Chem. 2011, 76, 1174 – 1176.
[9] a) E. Vitaku, J. T. Njardarson, Tetrahedron Lett. 2015, 56, 3550 –
3552; For other examples, see: b) D. BØrard, A. Jean, S. Canesi,
Tetrahedron Lett. 2007, 48, 8238 – 8241; c) C. Sabot, B. Commare,
M. A. Duceppe, S. Nahi, K. C. Guerard, S. Canesi, Synlett 2008,
3226 – 3230; d) D. BØrard, L. Racicot, C. Sabot, S. Canesi, Synlett
2008, 1076 – 1080; e) D. BØrard, M. A. Giroux, L. Racicot, C.
Sabot, S. Canesi, Tetrahedron 2008, 64, 7537 – 7544; f) T. Dohi,
Y. J. Hu, T. Kamitanaka, N. Washimi, Y. Kita, Org. Lett. 2011, 13,
4814 – 4817; g) T. Dohi, Y. Toyoda, T. Nakae, D. Koseld, H.
Kubo, T. Kamitanaka, Y. Kita, Heterocycles 2015, 90, 631 – 644.
[10] For recent reviews, see: a) V. V. Zhdankin, P. J. Stang, Chem.
Rev. 2008, 108, 5299 – 5358; b) V. V. Zhdankin, Hypervalent
Keywords: dearomatization · fluorine · indoles ·
nitrogen heterocycle · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2243–2247
Angew. Chem. 2016, 128, 2283–2287
[1] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257 – 10274.
[2] a) H. J. Bçhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Muller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637 –
643; b) K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013 – 1029; c) K.
Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886;
d) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359 – 4369; e) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320 – 330; f) R. Filler, R. Saha, Future Med. Chem.
2009, 1, 777 – 791; g) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J.
Donnelly, N. A. Meanwell, J. Med. Chem. 2015, 58, 8315 – 8359.
[3] E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014, 57,
2832 – 2842.
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Iodine Chemistry, Wiley, Hoboken, 2013, pp. 145 – 336; c) T.
[15] It is reminiscent of how uniquely hfacac served as a metal ligand
Dohi, Y. Kita, in Iodine Chemistry and Applications, Wiley,
Hoboken, 2014, pp. 103 – 157; d) G. Maertens, C. Lꢀhomme, S.
Canesi, Front. Chem. 2015, 2, 115.
for our strained ring expansion program. For details, see: L. A.
Batory, C. E. McInnis, J. T. Njardarson, J. Am. Chem. Soc. 2006,
128, 16054 – 16055.
[16] Isolation of the resulting dihydroindoles by chromatography
resulted in loss of material because of their sensitivity to silica
gel.
[17] We have used the trifluoroethoxy group to help with the
oxidative dearomatization step in our total synthesis of vinigrol.
For deprotection of this group, see: Q. Yang, J. T. Njardarson,
Tetrahedron Lett. 2013, 54, 7080 – 7082.
[18] These indoles readily form their corresponding hydrate. For
conversion rate determined by NMR spectroscopy, see the
Supporting Information.
[19] a) C. B. Kelly, M. A. Mercadante, N. E. Leadbeater, Chem.
Commun. 2013, 49, 11133 – 11148; b) M. J. OꢀConnor, K. N.
Boblak, A. D. Spitzer, P. A. Gucciardo, A. M. Baumann, J. W.
Peter, C. Y. Chen, R. Peter, A. A. Mitton, D. A. Klumpp,
Tetrahedron Lett. 2010, 51, 4984 – 4987; c) T. Wang, S. Ye, Org.
Lett. 2010, 12, 4168 – 4171; d) H.-F. Cui, L. Wang, L.-J. Yang, J.
Nie, Y. Zheng, J.-A. Ma, Tetrahedron 2011, 67, 8470 – 8476; e) T.
Wang, L.-T. Shen, S. Ye, Synthesis 2011, 3359 – 3363; f) T. Wang,
S. Ye, Org. Biomol. Chem. 2011, 9, 5260 – 5265; g) G.-W. Zhang,
W. Meng, H. Ma, J. Nie, W.-Q. Zhang, J.-A. Ma, Angew. Chem.
Int. Ed. 2011, 50, 3538 – 3542; Angew. Chem. 2011, 123, 3600 –
3604.
[11] a) C. D. Nenitzescu, Bull. Soc. Chim. Romania 1929, 11, 37 – 43;
b) G. R. Allen, Org. React. 1973, 20, 337 – 454.
[12] Aniline dearomatizations are rare compared to those of phenols.
For recent examples, see: a) H. Liu, Y. Z. Xie, Y. H. Gu,
Tetrahedron Lett. 2011, 52, 4324 – 4326; b) H. A. Liu, X. M.
Wang, Y. H. Gu, Org. Biomol. Chem. 2011, 9, 1614 – 1620; c) N.
Bodipati, R. K. Peddinti, Org. Biomol. Chem. 2012, 10, 4549 –
4553; d) T. Tian, W. H. Zhong, S. Meng, X. B. Meng, Z. J. Li, J.
Org. Chem. 2013, 78, 728 – 732; e) P. Schaal neØ Lennartz, H.
Baars, G. Raabe, I. Atodiresei, C. Bolm, Adv. Synth. Catal. 2013,
355, 2506 – 2512; f) T. Hashimoto, H. Nakatsu, Y. Takiguchi, K.
Maruoka, J. Am. Chem. Soc. 2013, 135, 16010 – 16013; g) A.
Pialat, B. Liegault, M. Taillefer, Org. Lett. 2013, 15, 1764 – 1767;
h) S. C. Wang, Z. Q. Ni, Y. J. Wang, Y. H. Pang, Y. J. Pan,
Tetrahedron 2014, 70, 6879 – 6884; For examples of nitrogen
heterocycle syntheses, see: i) H. Tohma, H. Watanabe, S.
Takizawa, T. Maegawa, Y. Kita, Heterocycles 1999, 51, 1785 –
1788; j) P. Huang, X. L. Fu, Y. J. Liang, R. Zhang, D. W. Dong,
Aust. J. Chem. 2012, 65, 121 – 128; k) Z. S. Yu, L. J. Ma, W. Yu,
Synlett 2012, 1534 – 1540; l) L. Fra, A. Millan, J. A. Souto, K.
Muniz, Angew. Chem. Int. Ed. 2014, 53, 7349 – 7353; Angew.
Chem. 2014, 126, 7477 – 7481; and ref. [9g].
[20] A. Delgado, J. Clardy, Tetrahedron Lett. 1992, 33, 2789 – 2790.
[21] CCDC 1434643 (12a), 1434644 (15d), 1434645 (15l), 1434646
(18), and 1434647 (22) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[13] For a review on fluorinated solvents in oxidative dearomatiza-
tion reactions, see: T. Dohi, N. Yamaoka, Y. Kita, Tetrahedron
2010, 66, 5775 – 5785.
[14] Cyclic 2-substituted 1,3-dicarbonyls have been previously used
as nucleophiles added to para-substituted phenol ethers by
oxidative dearomatization mediated by PIFA. For details, see: Y.
Kita, H. Tohma, K. Hatanaka, T. Takada, S. Fujita, S. Mitoh, H.
Sakurai, S. Oka, J. Am. Chem. Soc. 1994, 116, 3684 – 3691.
Received: December 1, 2015
Published online: January 8, 2016
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