Photoredox-Catalyzed Trifluoromethylative Intramolecular Cyclization: Synthesis of CF3-Containing Heterocyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.8b00648

A general photoredox-catalyzed intramolecular cyclization was developed for the synthesis of trifluoromethylated heterocyclic compounds. The reaction proceeded smoothly under mild photocatalytic conditions with high functional group tolerance, allowing the preparation of oxygen-, sulfur-, or nitrogen-containing heterocycles of different sizes. The broad substrate scope demonstrated the complexity-building potential of the strategy.

Full text of DOI:10.1021/acs.orglett.8b00648

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Photoredox-Catalyzed Trifluoromethylative Intramolecular
Cyclization: Synthesis of CF ‑Containing Heterocyclic Compounds
3
Hong Sik Han,†,‡ Eun Hye Oh, Young-Sik Jung,
‡,§
†,‡
and Soo Bong Han*
,†,‡
†Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon
4113, Republic of Korea
3
‡
Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114,
Republic of Korea
§
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
S Supporting Information
*
ABSTRACT: A general photoredox-catalyzed intramolecular cyclization was developed for the synthesis of trifluoromethylated
heterocyclic compounds. The reaction proceeded smoothly under mild photocatalytic conditions with high functional group
tolerance, allowing the preparation of oxygen-, sulfur-, or nitrogen-containing heterocycles of different sizes. The broad substrate
scope demonstrated the complexity-building potential of the strategy.
1
7
8
rifluoromethylated heterocyclic compounds have at-
genation and addition reactions, to form various saturated
ring systems.
T
tracted considerable interest in various fields of chemistry,
owing to both the importance of fluorine and the applications
of heterocycles in the pharmaceutical, agrochemical, and
material industries. In particular, trifluoromethylated non-
aromatic heterocyclic compounds have been widely used in
medicinal chemistry due to the spatial advantage of their
architecture. For example, a novel human CCR2 antagonist
containing a CF -substituted tetrahydropyran ring with
excellent potency in both binding and chemotaxis assays has
2
For instance, a C−H trifluoromethylation of glycals (Scheme
1, a) and a photoredox-catalyzed tandem cyclization (Scheme
1, b) for the formation of CF -containing chromones have
been reported by Ye and by Yang and Chen, respectively.
Moreover, Ding and Hou reported a domino trifluoromethy-
lative cyclization of homopropargylamines to form 5-endodihy-
dropyrrolium ions (Scheme 1, c). In addition, a method to
generate CF -containing isochromenes via alkynol cyclization
9
3
10
3
4
1
1
3
3
5
been reported (Figure 1). In addition, CF -substituted
3
and subsequent trapping by a CF radical has been described
Scheme 1, d). Although these protocols are efficient and
3
12
(
versatile, a mild and general method for the synthesis of
heteroatom (O, N, and S)-containing rings of various sizes is
still highly desirable.
As part of our efforts to construct complex molecules
containing a CF group by multicomponent coupling
3
13
reactions, we designed a photoredox-catalyzed trifluorome-
thylative intramolecular cyclization to form CF -bearing
heterocyclic rings of different sizes (Scheme 2). In the
3
Figure 1. CF -containing nonaromatic heterocycles.
14
3
proposed mechanism, an excited photoredox catalyst is
n
n
15
generated (from M to *M ), which reduces the CF source.
3
piperidine derivatives exhibit high biological activity against
1
6
6
The resulting CF radical can be trapped by an alkyne to form
3
inflammation and Janus kinase. Despite the versatility of
trifluoromethylated compounds, only a few methods have been
a vinyl radical intermediate stabilized by resonance with the
adjacent aromatic ring. The vinyl radical can be oxidized by
17
reported for the preparation of CF -substituted ring systems.
3
Among them, the construction of CF -vinyl heterocycles is
particularly attractive because the olefin functionality provides a
handle for further chemical modifications, such as hydro-
3
Received: February 22, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00648
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of CF -Substituted Vinyl Heterocycles
Table 1. Optimization of Trifluoromethylative
Intramolecular Cyclization
3
a
Scheme 2. Proposed Pathway for Trifluoromethylative
Intramolecular Cyclization
a
Reactions were carried out with 1a (0.10 mmol), CF
source (0.20
3
mmol), catalyst (2.0 mol %), base (0.20 mmol), and solvent (2.0 mL)
at 25 °C under N atmosphere for 12 h. Yields were determined by
H NMR using 1,1,2,2-tetrachloroethane as an internal standard. In
the dark. Without catalyst.
b
2
1
c
d
solvents were screened, and acetonitrile proved to be optimal.
Notably, whereas other solvents were ineffective (entries 9 and
1
0), acetone afforded 3a in 60% yield along with α-CF3-
substituted ketone as the major byproduct (entry 8), which was
presumably formed by attack of residual H O instead of the
2
pendant alcohol. Moreover, no product was formed without
visible light (entry 11). Interestingly, the reactivity dramatically
decreased in the absence of a catalyst (entry 12), supporting the
21
involvement of a photoredox process.
With the optimized reaction conditions in hand, the substrate
scope was examined with alkynols 1a−i (Table 2) bearing
different substituents on the aromatic ring. The reactions of
alkynes containing acetyl (1a)-, p-tosyl (1b)-, and Boc-
protected (1c) amine-substituted aryl groups proceeded
smoothly (76%, 64%, and 78% yields, respectively). Unsub-
stituted (1d) and tert-butyl-substituted alkynols (1e) produced
the corresponding products in moderate (53%) and high (74%)
yields, respectively. Moreover, substrate 1f bearing an ether
substituent efficiently afforded product 3f in 78% yield.
Halogen substituents were also well tolerated to give 3g and
3h in 66% and 60% yields, respectively. Notably, a methyl
group substituent on the tethered chain was not detrimental to
the reaction, and the desired product was obtained in good
Mn+1 to give a vinyl cation, which can be attacked intra-
molecularly by the tethered heteroatom nucleophile (XH) to
give the desired CF -containing heterocycle. It should be noted
3
n
that the catalyst, M , is regenerated in the oxidation step, thus
18
closing the catalytic cycle.
On the basis of this design, we set out to explore the
trifluoromethylative intramolecular cyclization of alkynol 1a
using Umemoto reagent 2a and various photoredox catalysts
under visible light irradiation to form six-membered trifluor-
omethylated cyclic enol ether 3a (Table 1, entries 1−4).
22
yield (73%, 3i).
Encouraged by the successful synthesis of vinyl ether
derivatives, the protocol was extended to the preparation of
cyclic enamines (Table 3). First, various N-protecting groups,
including tosyl (4a), mesyl (4b), Boc (4c), and Cbz (4d), were
examined; pleasingly, all reactions proceeded smoothly to the
corresponding products 5a−d (80%, 60%, 54%, and 57% yields,
respectively). These results demonstrate the strong diversity of
N-nucleophiles with different protecting groups, which can be
applied for the synthesis of complex molecules. Next, our
protocol was tested using alkynamines with various substituents
Gratifyingly, using fac-Ir(ppy) as the catalyst, the desired
3
product was obtained in high yield (79%, entry 4), presumably
owing to the high reducing power of fac-Ir(ppy) compared to
3
19
that of other catalysts. For further optimization, other CF3
sources, namely, Togni I and II reagents, were examined, but
were less effective (40% and 47% yields, respectively; entries 5
2
0
and 6). Moreover, in the absence of base, a mixture of
unidentified byproducts was obtained (entry 7). Next, various
B
DOI: 10.1021/acs.orglett.8b00648
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Organic Letters
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Table 2. Synthesis of CF -Bearing Cyclic Enol Ethers from
Alkynols
Table 3. Synthesis of CF -Bearing Cyclic Enamines from
Alkynamines
3
3
a
a
a
Reactions were carried out with alkynamine (0.20 mmol), Umemoto
reagent 2a (2.0 equiv), Ir(ppy) (2.0 mol %), and Li CO (2.0 equiv)
3
2
3
b
in MeCN (4.0 mL) for 12 h. Isolated yields are shown in parentheses.
X-ray crystal structure was obtained (see the Supporting Informa-
c
tion).
a
Reactions were carried out with alkynol (0.20 mmol), Umemoto
reagent 2a (2.0 equiv), Ir(ppy) (2.0 mol %), and Li CO (2.0 equiv)
3
2
3
interestingly, N-Boc-protected aniline could be used as a
nucleophile to give bicyclic ring 5k (53%), demonstrating the
utility of this strategy for the construction of complex ring
systems.
b
in MeCN (4.0 mL) for 12 h. Isolated yields are shown in parentheses.
c
X-ray crystal structure was obtained (see the Supporting Informa-
tion).
To further highlight the versatility of this transformation, we
attempted to synthesize heterocycles of different sizes. As
shown in Scheme 3, six-, seven-, and eight-membered rings
containing heteroatoms (namely, O, N, or S) were successfully
prepared. In particular, trifluoromethylated seven- and eight-
membered rings containing an oxygen atom were smoothly
obtained in 71% (6a) and 47% (6b) yields, respectively. Our
protocol could also be applied to the synthesis of the seven-
membered nitrogen heterocycle 6c (50%), as well as the CF3-
on the aromatic ring and tosyl-protected amine as the
nucleophile. Aromatic alkynamines bearing an acetyl (4e), p-
tosyl amine (4f), or Boc-protected amine (4g) substituent at
the para position were efficiently transformed into the
corresponding products 5e−g in moderate to high yields
(
45−73%). Moreover, unsubstituted (4h) and halogen-
substituted aromatic rings (4i and 4j) showed moderate
reactivity (50%, 42%, and 41% yields, respectively). Most
C
DOI: 10.1021/acs.orglett.8b00648
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Organic Letters
Letter
Scheme 3. Trifluoromethylated Six-, Seven-, and Eight-
Membered Rings Containing N, O, or S
AUTHOR INFORMATION
■
*
a−c
Corresponding Author
E-mail: sbhan@krict.re.kr.
ORCID
Young-Sik Jung: 0000-0001-9492-6848
Soo Bong Han: 0000-0002-7831-1832
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Korea Research Institute of
Chemical Technology (Grant Nos. KK1803-C00 and KK1706-
G08).
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ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00648.
Experimental procedures and characterization for new
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E
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