Direct Copper-Catalyzed C-H Monofluoroalkylation of Benzoxazoles with 1-Fluoro-1-haloalkanes

Article abstract of DOI:10.1002/ejoc.201901929

The first example of direct C–H bond monofluoroalkylation with 1-fluoro-1-haloalkanes with no adjacent functional groups and with β-hydrogens has been developed. This transformation offers a straightforward route for the synthesis of a series of monofluoroalkylated benzoxazoles.

Full text of DOI:10.1002/ejoc.201901929

A Journal of
Accepted Article
Title: Direct Copper-Catalyzed C-H Monofluoroalkylation of
Benzoxazoles with 1-Fluoro-1-haloalkanes
Authors: Wei Li, Andrii Varenikov, and Mark Gandelman
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10.1002/ejoc.201901929
European Journal of Organic Chemistry
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Direct Copper-Catalyzed C-H Monofluoroalkylation of
Benzoxazoles with 1-Fluoro-1-haloalkanes
Wei Li[a], Andrii Varenikov[a] and Mark Gandelman *[a]
Dedication ((optional))
[a]
Dr. W. Li, A. Varenikov, Prof. Dr. M. Gandelman
Schulich Faculty of Chemistry
Technion, The Israel Institute of Technology
Technion City, Haifa, 3200008 (Israel)
E-mail: chmark@tx.technion.ac.il
www: markgandelman.technion.ac.il
Supporting information for this article is given via a link at the end of the document.
Abstract: The first example of direct C-H bond monofluoroalkylation
with 1-fluoro-1-haloalkanes with no adjacent functional groups and
with -hydrogens has been developed. This transformation offers a
of (hetero)arenes, bearing -fluorinated alkyl substituents with
no adjacent functional groups, via direct C-H functionalization.
straightforward route for the synthesis of
monofluoroalkylated benzoxazoles.
a
series of
Selective introduction of fluoroalkyl groups into organic
molecules, especially in (hetero)arenes, is of high importance for
the development of new biomedically active compounds. C-H to
C-F exchange in organic molecules often results in significant
variation in their chemical, physical, and biological properties,
including increase in metabolic stability, lipophilicity, and
bioavailability.[1] As such, a variety of fluoroalkylation reagents
and methodologies have been developed to fulfill the increasing
demand of fluoroalkylated (hetero)arenes for pharmaceutical
and agrochemical chemistry.[2] Compared with methods for
trifluoromethylation,[3]
perfluoroalkylation[4]
and
difluoroalkylation[2d,5] of (hetero)arenes, the direct introduction of
a monofluoroalkyl group (i.e., monofluoroalkylation) is still in a
relatively
underdeveloped
stage.[5]
Selective
Scheme 1. Monofluoroalkylation of (hetero)Arenes.
monofluoroalkylation of (hetero)arenes is mainly performed by
transition metal mediated or catalyzed cross-coupling reactions
of (hetero)aryl based electrophiles or nucleophiles with
fluoro(halo)-organic compounds (Scheme 1a).[6] The direct
monofluoroalkylation of (hetero)arenes via its selective C-H
bond functionalization would be an ideal method. Despite the
recent advances in C-H fluoroalkylation of (hetero)arenes, C-H
monofluoroalkylation remains a formidable challenge and, to the
best of our knowledge, only two examples are reported
(Scheme 1b,c).[7] Moreover, the existing monofluoroalkylation
reactions are limited to the introduction of CH2F group (Scheme
1b) or functionalized fluoromethyl (CFR1R2) unit in which R1 or
R2 are either a sulfonyl or a carbonyl moiety (Scheme 1c).
Recently, we developed an efficient synthesis of geminal
fluoro(halo)alkanes bearing no substituents at the -position.
Chemistry of such compounds was previously unexplored, likely,
due to a lack of efficient approaches to their preparation. We
demonstrated that such electrophiles can be employed in Suzuki
sp3-sp3 and sp3-sp2 cross-coupling reactions to prepare
secondary fluoroalkanes in good yields and enantioselectivities.8
Herein, we reveal, for the first time, that such fluoro(halo)alkanes
can be used in direct catalytic C-H monofluoroalkylation of
(hetero)arenes (Scheme 1d). It opens a door for the preparation
We commenced our studies by exploring reaction conditions
(metals, ligands, bases) for the envisioned direct
monofluoroalkylation of benzoxazole 1a with (3-bromo-3-
fluoropropyl)benzene 2a (Table 1). Benzoxazole patterns have
found a broad application in bioactive compounds, and a direct
method of introduction of mono(fluoro)alkyl function to its core
might be of interest for medicinal chemists.[9] We were pleased
to find that in the presence of a catalytic amount of CuI (15
mol%) in toluene at 110 oC, with NaOtBu as the base and bis[(2-
(N,N-dimethylaminoethyl)]ether L1 as the ligand,[10] the desired
monofluoroalkylation product 2aa was obtained in 47% yield
(entry 1). Replacement of NaOtBu with LiOtBu or KOtBu gave
much lower yield or even resulted in no desired product (entries
2 and 3). Decreasing the reaction temperature from 110 °C to
90 °C resulted in a higher yield (59%, entry 5). Careful survey of
solvents showed that toluene was beneficial for this reaction. For
example, a trace amount of the desired product was observed
when the reaction was carried out in THF, and no reaction
occurred in DMF (entries 6 and 7). We next investigated the
influence of the ligands and copper source. The nature of the
ligand had a strong influence on the reaction outcome
1
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10.1002/ejoc.201901929
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COMMUNICATION
with Cu(OTf)2 giving a slightly better yield (entries 13-15). It is
documented, that Cu(II) could be reduced by the substrate in
situ to give the catalytically active Cu(I) species.[12] Additionally,
Cu(0) exhibited no catalytic activity in our reaction (entry 16). To
our delight, when Cu2Cl2(PPh3)3, a Cu(I) dimer complex, was
applied in the monofluoroalkylation reaction, a significantly
improved yield was obtained (81%, entry 17), while similar
mononuclear phosphine-containing precatalyst showed inferior
results(66%, entry 18). Despite PPh3, ligand L1 was still
necessary for the successful reaction, as no desired product
was formed in its absence (entry 19). The addition of NaI gave
no further increase in yield. When 1-iodo-1-fluoroalkane 2a’ was
applied as an electrophile in the reaction, a much lower yield
was obtained (entry 21). We presumed that the inferior results
observed for 2b, compared to its 1-bromo-1-fluoro analogue 2a,
are, likely, due to the relative instability of the former. This may
lead to release of trace amounts of iodine under the reaction
condition that partially poisons the Cu catalyst. Moreover, no
desired product was formed at all, when 1-chloro-1-fluoroalkane
2a’’ was used (entry 22). The difficulty of stronger C−Cl bond to
undergo an oxidative addition to Cu(I) may account for non-
reactivity of 2a’’. If the molar ratio of 1a and 2a was changed to
2:1, the yield decreased to 35% (entry 23). Lowering of the
catalyst loading to 7.5% decreases yield to 64%(entry 24).
With the optimized reaction conditions in hand, we
investigated the substrate scope of copper-catalyzed
monofluoroalkylation of benzoxazoles (Scheme 2). The reaction
was not sensitive to the electronic properties of the substituents
on the phenyl ring of benzoxazoles. Both electron-donating (Me,
MeO) and electron withdrawing (F, Cl, Br) groups were
compatible, giving the corresponding products 3ba-fa in good
yields. Various 5-arylated benzoxazole derivatives could be
used to give the monofluoroalkylated products, such as 3ga-ia,
selectively and in good yields. 6-substituted benzoxazoles (see
products 3j-k) and naphtho[2,3-d]oxazole (see product 3l)
resulted in products with moderate yield.[13] Unfortunately, other
(hetero)arenes could not be monofluoroalkylated under our
reaction conditions. While the reason for the lack of reactivity of
other (hetero)arenes, yet to be understood, it might be
connected to a relative acidity of C-H activated bond.
Table 1. Optimization of the Reaction Conditions[a]
Entry
[Cu]
Ligand
Base
Yield (%)[b]
1[c]
2[c]
3[c]
4[d]
5
CuI
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
L1
---
NaOtBu
LiOtBu
47
21
trace
52
59
3
CuI
CuI
KOtBu
CuI
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
CuI
6[e]
7[f]
8
CuI
CuI
0
CuI
0
9
CuI
0
10
11
12
13
14
15
16
17
18
19
20[g]
21[h]
22[i]
23[j]
24[k]
CuI
31
55
28
60
63
67
0
CuI
CuI
CuTC*
CuBr·DMS
Cu(OTf)2
Cu
Cu2Cl2(PPh3)3
CuCl(PPh)3
Cu2Cl2(PPh3)3
Cu2Cl2(PPh3)3
Cu2Cl2(PPh3)3
Cu2Cl2(PPh3)3
Cu2Cl2(PPh3)3
Cu2Cl2(PPh3)3
81(79)
66
0
L1
L1
L1
L1
L1
80
31
0
35
64
[a]Unless otherwise noted, the reaction conditions were as follows: 1a (0.1
mmol, 1.0 equiv), 2a (0.2 mmol, 2.0 equiv), [Cu] (15 mol%), ligand (20 mol%),
Base (0.2 mmol, 2.0 equiv), toluene (1 mL), 90 °C, 24 h. [b]Yields determined
by 1H NMR using CH2Br2 as an internal standard and yield within parentheses
is that of the isolated product. [c]110 °C. [d]100 °C. [e]THF was used as a
solvent. [f]DMF was used as a solvent. [g]NaI (0.2 mmol, 2.0 equiv) was
added. [h]2a’ (0.2 mmol, 2.0 equiv) was used instead of 2a. [i]2a’’ (0.2 mmol,
2.0 equiv) was used instead of 2a. [j]1a (0.2 mmol, 2.0 equiv), 2a (0.1 mmol,
1.0 equiv) and NaOtBu (0.1 mmol, 1.0 equiv) was used.[k]7.5 mol% instead of
mol15% [Cu] loading. *TC = thiophene-2-carboxylate
(entries 8-12). When the central oxygen in ligand L1 was
replaced by a sulfur atom or an NH group, the reaction was
completely shut down (entries 8 and 9). Methylated ligand L4
gave a moderate yield of 2aa (entry 10). We assume, that it
indicates
a
necessity of
a
tridentate ligand character.
Interestingly, a pyridine based pincer ligand L5 performed
almost as well as L1 (entry 11). We also tested chiral PyBox
ligand L6 in order to examine a possible chiral induction in this
process. Unfortunately, the reaction gave the desired product in
a moderate yield (28%) and with practically no enantioselective
excess (entry 12).[11] The investigation of copper source showed
that both Cu(I) and Cu(II) worked well in this catalytic system,
2
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Scheme 3. Control experiments
To further demonstrate the synthetic utility of the reaction, we
performed a coupling of benzoxazole 1f with 1-bromo-1-
fluoroalkane 2a under the standard reaction conditions on a
gram scale (Scheme 4). Product 3fa was obtained even in a
slightly higher yield (70%) compared to its synthesis on a small
scale (61%), thus offering a reliable and practical access to
otherwise
difficult-to-prepare
monofluoroalkylated
benzoxazoles.[15] We demonstrated that 3fa can be efficiently
further modified through transition metal catalyzed cross-
coupling
reactions
to
lead
to
more
complex
mono(fluoro)alkylated benzoxazole derivatives. For example,
palladium catalyzed cyanation[16] and vinylation[17] of 3fa
proceeded smoothly to give product 4 and 5 in a very good yield,
and the Suzuki coupling reaction[18] between 3fa and 1-
benzothiophene-2-boronic acid readily furnished product 6 in
95% yield.
In conclusion, we have developed a copper catalyzed direct
monofluoroalkylation of biomedically relevant benzoxazoles.
Most importantly, to the best of our knowledge, this is the first
example of an employment of simple 1-fluoro-1-haloalkanes with
no adjacent functional groups and with -hydrogens in C-H
functionalization reaction. Further studies to uncover the detailed
Scheme 2. Substrate Scope of Copper-Catalyzed Monofluoroalkylation of
Benzoxazoles. Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0
equiv), Cu2Cl2(PPh3)3 (7.5 mol%), L1 (20 mol%), NaOtBu (0.4 mmol, 2.0
equiv), toluene (2 mL), 90 °C, 24 h, isolated yields.
Subsequently, the scope of 1-bromo-1-fluoroalkanes was
explored. The reaction of several analogues of compound 2a
proceeded smoothly to yield the desired products 3ab-af, 3ee
and 3fe in good yields. Exclusive chemoselectivities were
observed in the reaction of substrate 2e bearing both aryl and
alkyl halide functionalities, with no C-H arylation product
detected (see products 3ae, 3ee, 3fe).[14] The presence of aryl-Cl
and aryl-Br moieties in the products 3ea, 3fa, 3ka, 3ee, 3fe, 3eg,
3ei, 3ek offers the synthetic potential for further elaboration via
transition metal catalyzed cross coupling reactions (vide infra).
The reaction is suitable for geminal (fluoro)bromoalkanes with
linear and branched alkyl chains, affording corresponding
products 3ag, 3eg, 3ah, 3bh, 3ai, 3ci, 3ei in moderate to good
yield. Notably, 1-bromo-1-fluoroalkanes 2j-l bearing such
functional groups as protected amine (PhthN), ether and ester
could also be applied in our monofluoroalkylation reaction (see
products 3aj, 3ak, 3ck, 3ek, 3al).
reaction
mechanism
and
to
develop
further
C-H
mono(fluoro)alkylations are in the progress in our laboratories.
Interestingly, no desired product was observed when 1.0
equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 1,1-
diphenylethylene, efficient free radical inhibitors, were added
under the standard reaction conditions. Although the reaction
mechanism is not clear yet, we can assume that an oxidative
addition of fluoro(bromo)alkane takes place via a two-step
radical pathway to result in Cu(III)(Ar)(CH(F)R) species, which,
in turn, undergo reductive elimination to furnish Ar-CH(F)R
product.
Scheme 4. Reaction on the gram-scale and further transformations of the
product. Reaction conditions: a) 2.5 mol% tBuXPhos Pd G3, 0.66 equiv
Zn(CN)2, THF/H2O, 40 °C, 18 h; b) 5 mol% Pd(PPh3)4, 1.2 equiv potassium
vinyltrifluoroborate, 2.0 equiv Cs2CO3, 1,4-dioxane/H2O, 120 °C, 5 h; c) 5
mol% Pd(PPh3)4, 1.5 equiv 1-benzothiophene-2-boronic acid, 1.75 equiv
Na2CO3, DME/H2O, 100 °C, 16 h.
Acknowledgements
Supported in part at the Technion by a Technion-Guangdong
Fellowship, and by Israeli Science Foundation, Grant 1449/19.
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Keywords: C-H activation • secondary alkyl fluorides • cross-
coupling • copper • benzoxazoles
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COMMUNICATION
Entry for the Table of Contents
Fluoroalkylation. Copper-catalyzed cross-coupling reaction allowed the first direct C-H monofluoroalkylation of benzoxazole with 1-
fluoro-1-haloalkanes, which bear β-hydrogens and no directing groups in vicinity to the reaction center.
Institute and/or researcher Twitter usernames: ((optional))
Dr. Wei Li received his Ph.D. from Nankai University (Tianjin, China) in 2014, working under the supervision of
Prof. Qilin Zhou. He did his post-doctoral studies in the Schulich Faculty of Chemistry of the Technion in 2015-
2017 in the group of Prof. Gandelman. Currently, Wei works as a process chemist at Novartis Chemical and
Analytical Development in Suzhou.
Bio: Andrii Varenikov received his BSc and MSc in chemistry from the Kharkiv National University in 2013 (under
supervision of Dr. Hab. Alexander Roshal). Then he joined the Prof. Mark Gandelman`s group as a PhD student,
and his main research interest is enantioselective construction of trifluoromethyl-substituted stereogenic centres
via cross-coupling reactions.
Mark Gandelman is a Professor of chemistry at the Technion-Israel Institute of Technology. He received a Ph.D.
degree in 2003 from the Weizmann Institute of Science under the supervision of Prof. Milstein. Following his post-
doctoral studies at Harvard University with Prof. Jacobsen, he joined the Schulich Faculty of Chemistry in the
Technion in 2005. His major research interested encompass areas of organometallic chemistry and catalysis.
5
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