Transformation of anionically activated trifluoromethyl groups to heterocycles under mild aqueous conditions

Article abstract of DOI:10.1021/ol200326u

The (hetero)aromatic trifluoromethyl group is present in many biologically active molecules and is generally considered to be chemically stable. In this paper, a convenient one-step synthesis of C-C linked aryl-heterocycles or heteroaryl-heterocycles in good to excellent yields via the reaction of anionically activated trifluoromethyl groups with amino nucleophiles containing a second NH, OH, or SH nucleophile in 1 N sodium hydroxide is reported. The method has high functional group tolerability and is potentially useful in parallel synthesis.

Full text of DOI:10.1021/ol200326u

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1804–1807
Transformation of Anionically Activated
Trifluoromethyl Groups to Heterocycles
under Mild Aqueous Conditions
Jennifer X. Qiao,* Tammy C. Wang, Carol Hu, Jianqing Li, Ruth R. Wexler, and
Patrick Y. S. Lam
Research & Development, Bristol-Myers Squibb Company, Princeton,
New Jersey 08543, United States
Jennifer.qiao@bms.com
Received February 2, 2011
ABSTRACT
The (hetero)aromatic trifluoromethyl group is present in many biologically active molecules and is generally considered to be chemically stable. In
this paper, a convenient one-step synthesis of C-C linked aryl-heterocycles or heteroaryl-heterocycles in good to excellent yields via the
reaction of anionically activated trifluoromethyl groups with amino nucleophiles containing a second NH, OH, or SH nucleophile in 1 N sodium
hydroxide is reported. The method has high functional group tolerability and is potentially useful in parallel synthesis.
The aromatic trifluoromethyl (CF3) group is extensively
present in biologically active molecules because of its
unique physical properties and chemical stability.1 As a
result, hundreds of CF3-containing compounds are com-
mercially available. Recently, it has been reported that the
CF3 group can be readily incorporated via either Qing-
modified Chan-Lam coupling from arylboronic acids2 or
Buchwald-modified Hiyama coupling from aryl chlorides.3
Incorporation of the CF3 group into a lead molecule may
increase lipophilicity, resulting in enhanced binding activ-
ity or selectivity, and/or chemical or metabolic stability.
However, subsequent analoging from the CF3 group in an
advanced lead molecule is challenging because aromatic
CF3 groups are generally considered inert to organic
transformations. Nevertheless, the CF3 group in phenols,
anilines, or NH-containing heterocycles, when appropri-
ately positioned, can be anionically activated, i.e., the CF3
functionality can be conjugated with ionizable NH or OH
groups. The anionically activated CF3 group has been
reported to undergo several transformations,4-7 such as
formation of 2-hydroxybenzoic acid,4 tertiary amides,5 and
heterocycles such as benzothiazoles and benzoxazoles.6
These heterocycles were obtained in low to moderate yields
from the anions and dianions generated in situ with strong
bases such as n-BuLi.
In a previous in-house structure-activity relationship
(SAR) study, we transformed an anionically activated
aromatic CF3 moiety in a lead molecule to functional
groups such as carboxylic acid, esters, nitrile, amides,
(1) (a) Boehm, H.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Mueller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637–
643. (b) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214–
231. (c) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432–5446. (d)
Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996. (e) Muller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. (f) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320–330. (g) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369.
(2) (a) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060–5063 and
refrences cited therein. (b) For a recent review on Chan-Lam coupling,
see: Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829-856.
(4) (a) Jones, R. G. J. Am. Chem. Soc. 1947, 69, 2346–2350. (b)
Belcher, R.; Stacey, M.; Sykes, A.; Tatlow, J. C. J. Chem. Soc. 1954,
3846–3851.
(5) O’Mahony, G.; Pitts, A. K. Org. Lett. 2010, 12, 2024–2027.
(6) (a) Wydra, R. L.; Patterson, S. E.; Strekowski, L. J. Heterocycl.
Chem. 1990, 23, 803–805. (b) Kiselyov, A. S.; Hojjat, M.; Van Aken, K.;
Strekowski, L. Heterocycles 1994, 37, 775–782.
(7) (a) Kiselyov, A. S.; Strekowski, L. Org. Prep. Proced. Int. 1996, 3,
289–318 and references cited therein. (b) Strekowski, L.; Lin, S.;
Nguyen, J.; Redmore, N. P.; Mason, J. C.; Kiselyov, A. S. Heterocycl.
Commun. 1995, 5-6, 331–334. (c) Kobayashi, Y.; Kumadaki, I. Acc.
Chem. Res. 1978, 5, 197–204.
(3) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679–1681 and references cited
therein.
r
10.1021/ol200326u
Published on Web 03/07/2011
2011 American Chemical Society

and nitrogen-containing heterocyclic compounds.8 A com-
mon theme runs throughout these reactions and the afore-
mentioned literature examples: the activated CF3 group
eliminates HF with the assistance of a base, to generate a
key quinodifluoromethide intermediate that is susceptible
to nucleophilic addition. Repetitive base-induced HF
elimination and addition of nucleophiles leads to the
replacement of all three fluorine atoms in the CF3 group
by the nucleophiles. This implies that in drug design, one
either can utilize an anionically activated CF3 to design
suicide substrates9 or avoid an activated CF3 in a drug
molecule to prevent the potential formation of the active
difluoromethide intermediate in vivo.
Table 1. Formation of Heterocycles from 2-CF3-Phenol 1 and
5-CF3-Uracil 2
C-C linked aryl-heterocycle or heteroaryl-hetero-
cycle structure motifs with a general structure of I are used
extensively as building blocks to construct numerous
pharmaceutical agents with a diverse range of biological
properties. The most popular approaches to construct I
involve either condensation of an aromatic/heteroaro-
matic carboxylic acid or its derivatives to form the second
heterocyclic ring, or Suzuki-Miyaura coupling of aro-
matic/heteroaromatic boronic acid or derivatives with the
halide of the second heterocyclic ring. These methods have
limitations, however: some of the condensation reactions
are performed under harsh conditions with strong acids at
hightemperature;someoftheheterocycliccarboxylicacids
are water-soluble and are not easy to handle; while some of
the heteroaromatic boronic acids or derivatives and the
halides of the heterocyclic rings are either expensive or not
readily available. Therefore, there continues to be a need
for alternate mild methods, as illustrated by the many
recent publications.10
Herein, we reportanefficientone-steptransformationof
anionically activated aromatic/heteroaromatic trifluoro-
methyl groups into a variety of nitrogen-containing het-
erocycles in good to excellent yields under mild aqueous
conditions in the absence of organic solvents to form C-C
linked aryl-heterocycles and heteroaryl-heterocycles, a
subset of compounds with general structure I.
Treating the anionically activated aromatic CF3 group
as a masked carboxylic acid group, we synthesized differ-
ent types of heterocycles 3-12 in good to excellent yields
from two commercially available substrates 2-CF3-phenol
1 or 5-CF3-uracil 2 (1.0 equiv) and a list of representative
NH2-containing nucleophiles (1.0-1.4 equiv) in 1 N NaOH
(3-4 equiv) at 40 to 90 °C (Table 1). To the best of our
knowledge, this is the first report of the formation of
a Isolated yield of analytically pure products. b Reaction performed
at 40 °C. c Reaction performed at 90 °C.
azabenzoxazole (entry 6), 1H-pyrimidine (entry 7), 1,3,4-
thiadiazole (entry 8), 1,3,4-oxadiazole (entry 9), and 1,2,4-
oxadiazole (entry 10) from an anionically activated CF3
group. Thus, reaction of 1 with 3-aminopyridin-2-ol and
1,8-diaminonapthalene gave azabenzoxazole 8 and 1H-
pyrimidine9 in68%and 82%yield, respectively. Similarly,
treatment of 2 with thiohydrazide, hydrazide, and hydro-
xyamidine in 1 N NaOH (4 equiv) at 80 °C for two days
afforded the corresponding 1,3,4-thiadiazole 10, 1,3,4-
oxadiazole 11, and 1,2,4-oxadiazole 12 in 68%, 88%,
and 80% yield, respectively. In contrast, compound 12, a
(8) Detailed chemistry and SAR results will be disclosed in due
course.
(9) Betley, J. R.; Cesaro-Tadic, S.; Mekhalfia, A.; Rickard, J. H.;
Denham, H.; Partridge, L. J.; Pluckthun, A.; Blackburn, G. M. Angew.
Chem., Int. Ed. 2002, 5, 775–777.
(10) Examples of recent developments in the synthesis of C-C linked
aryl-heterocycles and heteroaryl-heterocycles: (a) Sardarian, A. R.;
Shahsavari-Fard, Z. Synlett 2008, 1391–1393. (b) Moghaddam, F. M.;
Bardajee, G. R.; Ismaili, H.; Taimoory, S. M. D. Synth. Commun. 2006,
36, 2543–2548. (c) Ma, D.; Xue, P.; Jiang, Y.; Xie, S.; Zhang, X.; Dong,
J. Angew. Chem., Int. Ed. 2009, 48, 4222–4225. (d) Mukhopadhyay, C.;
Datta, A. Heterocycles 2007, 71, 1837–1842. (e) Bahrami, K.; Khodaei,
M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835–6837. (f) Bahrami, K.;
Khodaei, M. M.; Naali, F. Synlett 2009, 569–572.
Org. Lett., Vol. 13, No. 7, 2011
1805

substructure in a series of potential modulators of dopa-
mine D3 receptors, was made as crude in 4 steps from 2,4-
dimethoxypyrimidine-5-carbaldehyde in 10% yield.11
Table 2. Regioisomeric and Other Anionically Activated CF3
Groups in the Formation of Heterocycles 3 and 25-34
Scheme 1. Functional Group Tolerability in the Transforma-
tion of 2-CF3-Phenol 1 and 4-CF3-Imidazoles 13 and 14 to
Benzoxazole 15-24
We next evaluated the functional group tolerability in
the formation of substituted benzoxazoles from either
2-CF3-phenol 1 or imidazole analogues 13 and 14 with
substituted 2-aminophenols as nucleophiles. As shown in
Scheme 1, novel 2-(20-hydroxy)phenylbenzoxazoles 15-24
were obtained in high yields in the presence of a variety of
functional groups, such as amino, nitro, halogen, car-
boxylic acid, cyano, ether, ketone, sulfone, sulfonamide,
and sulfonic acid. The transformation is evidently more
advantageous than the dianion chemistry6 with use
of strong bases, and complementary to the condensation
reactions with acids such as p-TSA.12 In addition, the
functional groups in 15-24 can be transformed into other
groups, further diversifying the structures of C-C linked
aryl-heterocycles and heteroaryl-heterocycles.
Several commercially available anionically activated
aromatic/heteroaromatics CF3 substrates were success-
fully transformed to heterocycles 3 and 25-34 by using
either 2-aminophenol 35 or N,N-dimethylhydrazinecar-
bothioamide 36 as the nucleophile (Table 2). 2- and 4-
CF3-phenol as well as 5-OH-2-CF3-pyridine afforded ben-
zoxazole 3, 25, and 26 in excellent yields. 4-CF3-aniline
afforded 28in 84% yield; 2-CF3-aniline, on the other hand,
reacted much more slowly to give 27 in only 42% yield,
with ca. 50% remaining of 2-CF3-aniline. The anionically
activated CF3 group inamino heterocycles (entries 6 and 7)
can also afford the corresponding benzoxazoles 29 and 30
a Isolated yield of analytically pure products. b Reaction performed
at 90 °C.
in good yields. Previously, 5-(6-methoxybenzo[d]oxazol-2-
yl)pyridin-2-amine, an analogue of 29, was prepared by
using Suzuki-Miyaura coupling of 2-Br-6-MeO-benzox-
azole and the 5-pinacolboronic ester of2-aminopyridine in
32% yield.13 Anionically activated CF3 groups in NH-
containing heterocycles, such as 5-CF3-uracil (entry 8),
(11) Bertani, B.; Cardullo, F.; Dambruoso, P.; Marzorati, P.; Micheli,
F.; Pasquarello, A.; Seri, C.; Tedesco, G. WO2009/043883 A1.
(12) Samota, M. K.; Seth, G. Heteroat. Chem. 2010, 21, 44–50.
(13) Malmstrom, J.; Pyring. D.; Slivo, C.; Sohn, D.; Swahn, B.-M.;
Wensbo, D. WO2007/149030 A1.
1806
Org. Lett., Vol. 13, No. 7, 2011

3-CF3-pyrazole (entry 9), 2-CF3-indole (entry 10), and
4-CF3-imidazole (entry 11), were also transformed to the
corresponding heterocycles 31-34 in good yields. Reac-
tion yields for known compounds were generally better
thanorsimilar to those reported with use ofother synthetic
methods.10,14 Products collected after simple workup were
usually more than 95% pure judged by 1H, 13C NMR, and
orthogonal HPLC. Impure products were purified by
either flash chromatography or recrystallization. In most
cases, the corresponding carboxylic acid side product4 was
not observed.
Scheme 2. Proposed Mechanism for the Formation of Hetero-
cycles Such As Benzoxazole 3 from 1 and 35
Hydroxy, amino group, or NH-containing heterocycles
in products 3-12 and 15-34 can serve as an anchor point
to further diversify the molecular structure. For example,
in the literature, 1-benzyl-3-benzoxazole pyrazole 37 was
assembled by a two-step N-benzylation/Suzuki coupling
sequence from 3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-
2-yl)-1H-pyrazole in 20% yield.15 Complementarily, addi-
tion of 1.0 equiv of 3-CF3-benzyl bromide to the mixture of
entry 9 in Table 2 (crude 32) at 80 °C for 1 h gave 37 in 25%
yield. The other regioisomer was obtained in 13% yield.
The limitation of the methodology is obvious: only
substrates containing an activated CF3 group that can
eliminate HF with the assistance of OH- to form a
quinone methide intermediate 39 may react (see Scheme
2 for the proposed mechanism of NaOH-induced ben-
zoxazole formation of 3). Thus, 3-CF3-phenol and
6-CF3-uracil remained unchanged under the reaction
conditions. When the heterocycle ring formed was not
aromatic, such as in entry 4 of Table 1, a substantial
amount of uncyclized 2-hydroxy-N-(2-hydroxyethyl)-
benzamide 38 was produced, though 38 can be converted
to cyclic 6 with thionyl chloride.10f When using N-methyl-
hydrazine-carbothioamide instead of 36 as the nucleo-
phile, ca. 1:1 mixture of 41 and 42 was observed by
LC-MS, indicating both NHMe and S can act as the
nucleophile in the final ring formation step, different from
the normal condensation reaction wherein thiadiazole 41
would be exclusively formed.
In summary, we developed a one-step, mild, and efficient
transformation of anionically activated (hetero)aromatic
CF3 groups to various nitrogen-containing heterocycles to
form a diverse set of C-C linked aryl-heterocycles or
heteroaryl-heterocycles. The advantages of this method
include the following: mild aqueous conditions and an
organic solvent-free reaction, high functional group toler-
ability, high-yielding reactions with simple workup and
purification procedures, opportunity for further diversifica-
tion on either ring or functional groups, and the potential
for scale-up and parallel synthetic applications.
(14) (a) Heraclio, L.-R.; Horacio, B.-O.; Susana, R.-L.; Rosa, S.;
Norberto, F. Tetrahedron Lett. 2010, 51, 2633–2635. (b) Button, K. M.;
Gossage, R. A. J. Heterocycl. Chem. 2003, 40, 513–517. (c) Johnson.,
S. M.; Connelly, S.; Wilson, I. A.; Kelly, J. W. J. Med. Chem. 2008, 51,
260–270. (d) Chakrabarty, M.; Mukherji, A.; Mukherjee, R.; Arima, S.;
Harigaya, Y. Tetrahedron Lett. 2007, 48, 5239–5242. (e) Lin, S.-Y.;
Isome, Y.; Stewart, E.; Liu, J.-F.; Yohannes, D.; Yu, L. Tetrahedron
Lett. 2006, 47, 2883–2886. (f) Peterson, T.; Falk, K.-E.; Leong, S. A.;
Klein, M. P.; Neilands, J. B. J. Am. Chem. Soc. 1980, 102, 7715–7718.
(15) Curtis, M. P.; Sammons, M. F.; Piotrowski, D. W. Tetrahedron
Lett. 2009, 50, 5479–5481.
Acknowledgment. We thank Mr. Robert Langish from
the BDAS MS group at BMS for performing the HRMS
determinations.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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