A Free-Radical-Promoted Site-Specific Cross-Dehydrogenative-Coupling of N-Heterocycles with Fluorinated Alcohols

Article abstract of DOI:10.1021/acs.orglett.6b02274

A C-C formation of an electron-rich N-heterocycle with fluorinated alcohol is developed. Through this radical-triggered cross-dehydrogenative coupling strategy, a wide range of useful building blocks such as C3 hydroxyfluoroalkylated indoles and pyrroles can be site-specifically synthesized. Mechanistic studies indicate a single-electron-transfer initiated radical cycle would be involved.

Full text of DOI:10.1021/acs.orglett.6b02274

Letter
pubs.acs.org/OrgLett
A Free-Radical-Promoted Site-Specific Cross-Dehydrogenative-
Coupling of N‑Heterocycles with Fluorinated Alcohols
Zhengbao Xu, Zhaojia Hang, Li Chai, and Zhong-Quan Liu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A C−C formation of an electron-rich N-heterocycle with
fluorinated alcohol is developed. Through this radical-triggered cross-
dehydrogenative coupling strategy, a wide range of useful building blocks
such as C3 hydroxyfluoroalkylated indoles and pyrroles can be site-
specifically synthesized. Mechanistic studies indicate a single-electron-
transfer initiated radical cycle would be involved.
he carbon−carbon bond formation using alcohols as
would be feasible for dehydrogenation of fluorinated alcohols
under relatively mild conditions (Scheme 1).
T
hydroxyalkylating reagents is of particular interest in
synthetic chemistry.1 In recent decades, considerable advances
in this area have been made through two main pathways. One is
transition-metal-catalyzed C−C bond construction with alco-
hols, which has been extensively studied by Krische,2 Carreira,3
and Yi,4 et al.5 The other is free-radical-initiated hydroxyalkyla-
tion of alkenes, alkynes, and heteroarenes, which has been well-
explored by Tu,6 Han and Pan,7 us,8 et al.9 However, a long-
recognized challenging problem is that both strategies are not
amenable to trifluoroethanol (TFE) and polyfluorinated
alcohols. Although it would be undeniably important and
valuable for simultaneous introduction of the hydroxyl and
trifluoromethyl or polyfluoroalkyl groups into organic molecules,
direct C−C bond construction using TFE and polyfluorinated
alcohols has very rarely been achieved. Thirty years ago, a first
example of direct C−C bond formation of quinoline with TFE by
γ-irradiation was reported by Sugimori and co-workers (yields
<9%).10 The second C−C formation was accomplished by
reaction of styrene with supercritical TFE (only one example,
yield: 26%).11 Both examples suffered from extremely harsh
reaction conditions and very low yields. Very recently, an
efficient Ru-catalyzed cross-coupling of allenes with fluorinated
alcohols has been developed by Krische and co-workers, which
represents the latter example.12 Nevertheless, this strategy is
limited to primary alcohols and those fluorinated alcohols with at
least two β-hydrogen atoms. Moreover, selective functionaliza-
tion of the α-OH−C(sp3)−H bond in TFE and polyfluorinated
alcohols has remained a great challenge to date.
It is well-known that TFE and polyfluorinated alcohols are
often stable, ample, and manipulable while the corresponding
fluorinated aldehydes are generally unstable, short, and intract-
able. Two main reasons make fluorinated alcohols more difficult
than others in dehydrogenation. One is the larger endothermic
(over 250 °C) and reversibility,13 and the other is the strong
electron-withdrawing effect of the CFn group which enhances the
energetic barrier in β-hydride elimination (ca. 15 kcal/mol).14 Of
particular interest are free-radical-initiated α-OH−C(sp3)−H
bond functionalizations in alcohols/ethers. We hypothesize that
a radical-promoted hydrogen-atom-transfer (HAT) strategy
Scheme 1. Dehydrogenation of Fluorinated Alcohols
Herein, we report a first example of a free-radical-initiated
cross-dehydrogenative-coupling (CDC)15 reaction of fluori-
nated alcohols with N-heterocycles such as indoles and pyrroles.
This method provides an efficient and regiospecific access to a
wide range of hydroxypolyfluoroalkylated indoles and pyrroles.
To test our hypothesis, we initially chose indole and
trifluoroethanol (TFE) as the model compounds (Table 1).
Gratifyingly, 2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol was iso-
lated in 37% yield while using dicumyl peroxide (DCP) as the
radical initiator in TFE solvent (entry 1). It is interesting that the
ratio of TFE and tert-butanol was found to be an important factor
that critically affects the reaction efficiency (Table 1, entries 1−
5). Furthermore, we found that DCP was more efficient than tert-
butyl hydroperoxide (TBHP) and di-tert-butyl peroxide
(DTBP). Finally through a series of optimized reaction
conditions (see Supporting Information (SI)), the desired
product can be isolated in a yield of 74% under the following
conditions: indole (1 equiv, 0.2 mmol), peroxide (2 equiv, 0.4
mmol), t-BuOH/TFE (3/2, 5 mL), CuBr (5 mol %, 0.01 mmol),
140 °C, 12 h.
With the optimized conditions in hand, we investigated the
substrate scope with an array of heterocycles such as indole,
pyrrole, and their derivatives (Scheme 2). First, the steric effect is
investigated (1−5). As a result, the effect of hindrance is not
Received: August 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02274
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Letter
a
Table 1. Modification of the Typical Reaction Conditions
Scheme 2. Site-Specific Radical CDC Reaction of Indole/
a
Pyrrole with Fluorinated Alcohols
b
c
entry
peroxide
solvent (mL)
TFE (5)
t (°C)
yield (%)
1
2
3
4
5
6
7
8
DCP
DCP
DCP
DCP
DCP
DCP
TBHP
DTBP
130
130
130
130
130
140
140
140
37
51
56
69
20
74
21
15
t-BuOH/TFE (1/4, 5)
t-BuOH/TFE (2/3, 5)
t-BuOH/TFE (3/2, 5)
t-BuOH/TFE (4/1, 5)
t-BuOH/TFE (3/2, 5)
t-BuOH/TFE (3/2, 5)
t-BuOH/TFE (2/3, 5)
a
Reaction conditions: indole (1 equiv, 0.2 mmol), peroxide (2 equiv,
0.4 mmol), CuBr (5 mol %, 0.01 mmol), TFE (2 mL), t-BuOH (3
b
mL), 140 °C, 12 h, sealed tube. Measured temperature of the oil bath.
c
Isolated yields.
remarkable. However, while 3-methyl-1H-indole was used as the
substrate, the target molecule is not detected. It indicates that not
a radical process but a polar reaction pathway might be involved
in the C−C formation step. Second, the electronic effect and
functional group tolerance are studied (6−16). Electron-rich
indoles gave moderate to good yields of products (6−8). In
addition, halogenated indoles also afforded the desired products
in good yields (9−12). Gratifyingly, indoles bearing electron-
withdrawing groups such as −CN and −COOMe are also
amenable to this system (13 and 14). Moreover, both alkenyl and
alkynyl groups can be well-tolerated in this reaction (15 and 16).
Next we examined indoles with substituents on the nitrogen
atom (17−26). And we found that a variety of alkyl-, benzyl, and
allyl-substitued indoles all gave the desired products in moderate
yields under the typical conditions. Nevertheless, no product was
observed by using 1-phenyl-1-H-indole. Gratifyingly, pyrrole and
its derivatives are also effective substrates (27−30). It is
noteworthy that C−C bond construction occurred selectively
on the pyrrole core while using 1-(furan-2-ylmethyl)-1H-pyrrole
as the substrate (29). Finally, other fluorinated alcohols are also
investigated. For example, 1,1,1,3,3,3-hexafluoro-2-(1H-indol-3-
yl)propan-2-ol was isolated in moderate yield with 1,1,1,3,3,3-
hexafluoropropan-2-ol (30). Overall, the features of direct
dehydrogenative C−C formation, versatile functional group
tolerance, and site-specificity make this strategy very attractive to
synthetic organic chemists.
In addition, large scale experiments and functional group
transformations are carried out. It was found that this synthetic
method can be conveniently scaled-up to the gram level without
loss of efficiency. Furthermore, diverse trasformations from
hydroxyfluoroalkylated heterocycles to various useful building
blocks can also be smoothly achieved (Figure 1).
As initially hypothesized, HAT from fluorinated alcohol would
generate α-OH C-centered radical, which then adds to
heterocycle yielding C2 hydroxyalkylated product. However, it
is not C2 but C3 alkylated product that is obtained, which
indicates that a Friedel−Crafts pathway might be involved in the
last step. Therefore, a series of control experiments were carried
out (eqs 1 and 2). And we found that both CF3CHO and 1-
ethoxy-2,2,2-trifluoroethan-1-ol gave the corresponding prod-
ucts in excellent yields. As expected, the hemiacetal 1-(tert-
butoxy)-2,2,2-trifluoroethan-1-ol was also detected by GC-MS
(see SI). Next, an array of spin trapping experiments combined
with electron paramagnetic resonance (EPR) detections were
a
Reaction conditions: heterocycle (1 equiv, 0.2 mmol), DCP (2 equiv,
0.4 mmol), CuBr (5 mol %), TFE (2 mL), t-BuOH (3 mL), 140 °C,
12 h, isolated yield, unless otherwise noted. 160 °C. DTBP (3 equiv,
0.6 mmol), CuBr (5 mol %), TFE (3 mL), t-BuOH (2 mL), 140 °C,
15 h. DTBP (3 equiv, 0.6 mmol), CuBr (5 mol %), TFE (3 mL), t-
BuOH (2 mL), 130 °C, 15 h.
b
c
d
carried out to trap the key radical intermediate. Nevertheless, the
α-OH C-centered radical was not observed even though various
spin trapping reagents were screened. It suggests that this radical
B
DOI: 10.1021/acs.orglett.6b02274
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Letter
alcohol to methyl radical leads to methane and CF3CHO,
which is quickly transferred to the hemiacetal in solvent t-BuOH.
Finally, Friedel−Crafts reaction of hemiacetal with an electron-
rich heterocycle affords the final product.
In conclusion, a free radical promoted dehydrogenative C−C
coupling of N-heterocycle with fluorinated alcohol is developed.
Through this strategy, a variety of useful building blocks such as
C3 hydroxyfluoroalkylated indoles and pyrroles can be site-
specifically synthesized on a large scale. Furthermore, this radical-
triggered hydrogen-atom-transfer strategy would open the door
to selective functionalization of the inert α-OH−(sp3)-C−H in
fluorinated alcohol.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 1. Versatile transformations of hydroxyfluoroalkylated hetero-
cycles. Reaction conditions: (1) Y(OTf)3 (10 mol %), allyltrimethylsi-
lane (5 equiv), CH2Cl2, rt; (2) Y(OTf)3 (10 mol %), indole (1.5 equiv),
toluene, 90 °C; (3) Sc(OTf)3 (10 mol %), indole (1.5 equiv), toluene,
80 °C; (4) P(Ph)3 (2 equiv), DEAD (2 equiv), pyrrolidine (2 equiv),
THF, rt; (5) Dess-Martin periodinane (3.7 equiv), CH2Cl2, rt; (6) n-
BuLi (0.8 equiv), PPh3CH3Br (0.8 equiv), THF, rt.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02274.
Full experimental details and characterization data for all
products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
might be very unstable, which would be immediately converted
to the corresponding aldehyde under the present conditions.16
Surprisingly, a β-OH C-centered radical (CF2CH2OH, g =
2.0065, aN = 7.59 G, aH = 13.72 G) was observed by EPR with 2-
methyl-2-nitroso-propane (MNP) as the spin-trapping reagent
(see SI). Furthermore, the signal of Cu(II) (g∥ = 2.1028, g⊥ =
2.0522) was also recorded by EPR (Figure 2).
*E-mail: liuzhq@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is supported by the National Science Foundation of
China (Nos. 21272096, 21472080, 21672089), the Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT15R28), and the Fundamental
Research Funds for the Central Universities (lzujbky-2016-50,
lzujbky-2016-ct02).
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