Highly Site-Selective Formation of Perfluoroalkylated Anilids via a Protecting Strategy by Molybdenum Hexacarbonyl Catalyst

Article abstract of DOI:10.1021/acs.orglett.9b02362

Introducing a perfluoroalkyl group on the aromatic ring with high site selectivity remains a challenging area in organofluorine chemistry. We herein report a highly para-selective C-H perfluoroalkylation of aniline substrates using the molybdenum hexacarbonyl catalyst. Various substituted anilids derived from anilids were well-tolerated, affording the corresponding products in moderate to good yields. Preliminary mechanism studies and density functional theory calculations revealed the coordination of Mo catalyst with amides as the key factor to realize para selectivity.

Full text of DOI:10.1021/acs.orglett.9b02362

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Site-Selective Formation of Perfluoroalkylated Anilids via a
Protecting Strategy by Molybdenum Hexacarbonyl Catalyst
Chunchen Yuan, Ping Dai, Xiaoguang Bao,* and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: Introducing a perfluoroalkyl group on the aromatic ring with high site selectivity remains a challenging area in
organofluorine chemistry. We herein report a highly para-selective C−H perfluoroalkylation of aniline substrates using the
molybdenum hexacarbonyl catalyst. Various substituted anilids derived from anilids were well-tolerated, affording the
corresponding products in moderate to good yields. Preliminary mechanism studies and density functional theory calculations
revealed the coordination of Mo catalyst with amides as the key factor to realize para selectivity.
Scheme 1. C−H Perfluoroalkylation of Aromatic
erfluoroalkyl groups substituted on aromatic rings
Ptypically modify the physical and biological properties of
organic molecules significantly.1 Thus, it is highly important to
introduce perfluoroalkyl groups into bioactive organic
molecules later in the reaction.2 In the past several decades,
thermal,3 electrophilic,4 and photochemical5 reactions have
been extensively explored for C−H perfluoroalkylation.
However, high site-selective introduction of perfluoroalkyl
groups on the multsubstituted benzene ring still remains rare.6
Hence, the development of a method to address the site
selectivity issue would be a milestone in C−H aromatic
perfluoroalkylation reactions. Herein, we report the first
example of the highly para-selective perfluoroalkylation of
acetyl-protected anilids with molybdenum hexacarbonyl (Mo-
(CO)6) as the catalyst. Various meta- and ortho-substituted
acetyl-protected anilids were well-tolerated, leading to the
corresponding products in moderate to good yields. More
importantly, the perfluoroalkylated Vorinostat, Leflunomide,
Teriflunomide, and Prilocaine could be easily obtained through
this new method. A density functional theory (DFT)
calculation revealed the coordination of Mo(CO)6 with amides
as the key factor to realize the para selectivity.
Compounds
transformation into a suitable anilide (Scheme 1b). This
formation of the anilide not only reduces the reactivity of
aniline but also provides a coordination center for transition
metals. Meanwhile, this transform can activate the amide-
linked aromatic ring and provide a bulk condition at another
position, which would result in a highly para-selective product.
More importantly, the anilide is the key structure of various
bioactive compounds, which can provide a direct approach to
the functionalization of drugs.
With these conditions in mind, acetanilide was selected to
assess whether the site-selective C−H perfluoroalkylation
could be achieved with this protecting strategy. Acetanilide
(1a) was treated with perfluorobutyl iodide (2a) in the
presence of [RuCl2(p-cymene)]2 (5 mol %), AgSbF6 (10 mol
%), and Na2CO3 (2 equiv) in dimethyl sulfoxide (DMSO) at
120 °C for 24 h. The para-perfluoroalkylated product 3a was
obtained in 15% yield, along with trace amount ortho-
perfluoroalkylated product 3a′. Several other catalyst systems
The aniline backbone can usually be found in various natural
and medicinally relevant compounds, which can be used to
treat diseases such as rheumatism, lymphoma, multiple
sclerosis, and others. Since the pioneering work of Zhou and
Huang on free perfluoroalkyl radical aromatic substitution
reactions,7 various approaches to realize the C−H perfluor-
oalkylation of anilids have been regularly investigated (Scheme
1a). Recently, our group demonstrated site-selective C−H
difluoromethylation at the meta or para position by adjusting
the coordination ability of the directing group8 or the steric
effect of the catalyst.9 Here, we proposed that the site-selective
perfluoroalkylation of aniline could be realized via the
Received: July 9, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b02362
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a
including [Rh(COD)Cl]2 (COD = 1,5-Cyclooctadiene),
Ru3(CO)12, and Fe(acac)2 (acac = acetylacetone)were
screened. The Ru3(CO)12 catalyst provided the product 3a
in 19% yield, along with a trace amount of ortho-
perfluoroalkylated product (3a/3a′ > 20:1). Further screening
of the catalysts indicated Mo(CO)6 as the best catalyst for this
para-selective perfluoromethylation reaction, generating prod-
uct 3a in 26% yield (3a/3a′ > 20:1). Next, several ligands and
additives were investigated (see Supporting Information). The
results showed that, when the reaction was performed under a
carbon monoxide atmosphere, an improved yield of 3a (43%)
was obtained. It may be because carbon monoxide can stabilize
Mo(CO)6.10 Interestingly, potassium fluoride also displayed a
good promoting effect in combination with carbon monoxide
for this transformation, leading to the product 3a in 68% yield.
Although the role of potassium fluoride is unclear, excess
amounts fluorine anions may stabilize the perfluoroalkyl
radical.11 Finally, when the reaction was performed at 140
°C for 48 h, the highly para-selective product 3a could be
obtained at 80% yield, while the side product only formed in
trace amounts.
Scheme 3. Scope of Anilids
With optimal reactions known, a variety of perfluoroiodides
were subjected to the standard reaction conditions (Scheme
2). The low-boiling iodopentafluoroethane and heptafluor-
a
Scheme 2. Scope of Perfluoroalkyl Iodides
a
Reaction performed at a 0.2 mmol scale with 2 (3 equiv) in a sealed
tube; yields of isolated products.
meta-substituted anilids performed well under the standard
reaction conditions, leading to para-perfluoroalkylated prod-
ucts in moderate to good yields (4a−4d). Dihydro-2-
quinolone is another effective substrate, providing the
perfluoroalkylated product 4e in 61% yield. The 2,5-
disubstituted anilids proceeded well and provided products
in good yields (4f and 4g). All of the ortho-substituted
substrates reacted well, yielding the products in yields of 41%−
80% (4h−4s). Interestingly, the perfluoroalkylation selectively
occurred at the amide-linked aromatic ring and not the free
phenyl ring (4i and 4p). These results indicated that the Mo
coordinated with amide might provide an activated aromatic
ring, which preferentially traps the free radical of the
perfluoroalkyl group compared to the inactive phenyl rings.
The pivaloyl- and benzoyl-protected anilids were compatible in
this newly developed method, generating the corresponding
products in acceptable yields (4t and 4u). However, the
benzyloxycarbonyl (Cbz)- and tert-butyloxycarbonyl (Boc)-
protected aniline only lead to a complicated reaction, yielding
trace amount products, respectively. It might be these
carbamates are unstable under the standard reaction condition.
Since the introduction of a perfluoroalkyl group into a drug
may modify its solubility, bioavailability, and metabolic
stability, functionalization of known drugs is important. To
our great delight, a variety of perfluoroalkyl groups can be
selectively installed on the key precursor of Vorinostat
(Scheme 4, 6a−6e),12 which is used for the treatment of
cutaneous-T-cell-lymphoma. The perfluoroalkylated Vorino-
stat could be easily obtained in good yields by treating 6e with
NH2OH. The perfluoroalkylated key precursor of Prilocaine
(7b) was obtained in acceptable yields under the optimized
reaction conditions. Next, a gram-scale reaction was performed
with substrate 1a, leading to the compound 3a in good yield
(Scheme 5). The acetyl protecting group could be removed,
a
Reaction performed at a 0.2 mmol scale with 2 (3 equiv) in a sealed
tube; yields of isolated products.
opropyl iodide both performed well, leading to the highly para-
selective perfluoroalkyated products 3b and 3c in good yields,
along with recovery of the starting material. The perfluoroalkyl
iodides (C5F11I, C6F13I, C7F15I, C8F17I, and C10F21I) were all
compatible, leading to the corresponding products in
satisfactory yields (3d−3h; 56%−87%). When heptafluoroiso-
propyl iodide was employed as the coupling partner, the
corresponding perfluoroalkylated product 3i was only isolated
at 21% yield, indicating that the steric effect greatly affects this
transformation. Impressively, trifluoromethyl iodide was also
shown to be a suitable substrate, leading to the trifluor-
omethylated product 3j at acceptable yields. It may be that the
low boiling point of trifluoromethyl iodide resulted in low
conversion.
The scope of anilids was next evaluated, and the results are
listed in Scheme 3. To facilitate the separation of products, a
longer-chain perfluoroalkyl iodide 2g (C8F17I) was employed.
Various functional groups such as OMe, Me, MeS, OBn,
CF3CH2O, Et, i-Pr, t-Bu, Ph, Cl, Br, and NO2 were all well-
tolerated and provided highly para-selective perfluoroalkylated
products in moderate to good yields (4a−4s; 26%−88%). The
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mixture of para- and ortho-perfluoroalkylated products 3a and
3a′ were obtained without site selectivity (Scheme 6a).7 Third,
when the D2O was added to the reaction as the additive under
the standard reaction conditions, 3a was isolated in 61% yield
(Scheme 6b). However, there is no D/H scrambling occurred
on the aromatic ring of 3a. Finally, N-methyl-N-phenyl-
acetamide could not yield any perfluoroalkylated products, and
the starting material was completely recovered (Scheme 6c).
Furthermore, control experiments revealed that Mo(CO)6 is
essential for this transformation (Scheme 6d). Altogether,
these results indicated that the Mo complex should coordinate
with amide in the anilide, thereby activating the aromatic ring
linked to the amide group without forming a five-membered
transition metacycle. Although it is hard to clarify the valence
variation during the catalytic cycle at this stage, based on the
previous report and the experimental result, it is rationally
considered that a perfluoroalkyl radical was generated via a
single-electron transfer (SET) by the oxidation of Mo(CO)6
with perfluoroalkyl iodide.15 The Mo(I) cation complex could
act as a Lewis acid to combine with the amide to generate
complex I, which would then activate the amide-linked
aromatic ring.16 The free perfluoroalkyl radical could react
with complex I to afford the complex II, followed by
aromatization to provide 3a (Scheme 7).
Scheme 4. Functionalization of Bioactive Compounds
Scheme 5. Synthesis of Perfluoroalkylated Drugs
Scheme 7. Plausible Catalytic Cycle
providing the perfluoroalkylated 8 in excellent yield, which
could then be easily transformed into the perfluoroalkylated
Teriflunomide (10) and Leflunomide (12). These results
highlighted the synthetic importance of this new method,
which might facilitate new developments in medicinal
chemistry.
Several parallel experiments were performed to understand
the reaction pathway of this Mo-catalyzed para-selective C−H
perfluoroalkylation reaction (Scheme 6). First, the radical
Scheme 6. Preliminary Mechanism Studies
Computational studies were performed to understand the
regioselectivity of this para-selective perfluoroalkylation.17
Three possible attacking sites leading to ortho, meta, and
para adducts were considered, and the optimized transition
states were denoted as TS1-o, TS1-m, and TS1-p, respectively.
The predicted energy barriers of the radical addition step were
15.2, 16.6, and 13.9 kcal/mol for ortho, meta, and para
adducts, respectively, demonstrating that the radical attack at
the para position has the lowest energy barrier. In addition, the
formation of the para adduct was slightly thermodynamically
stable by 1.5 kcal/mol, while the formation of the ortho adduct
was thermo-neutral. Thus, for the radical attack step, the
addition of perfluoroalkyl radical to the para position was
favorable both kinetically and thermodynamically among the
three possible sites. Moreover, the ionization energy (IE) of
the formed radical adduct was calculated to qualitatively
characterize the subsequent oxidation step via SET. The
calculated IE of the para, ortho, and meta adduct was 88.4,
92.9, and 117.8 kcal/mol, respectively (Figure 1). Computa-
tional results indicate that the para adduct has the lowest IE,
which is 4.5 kcal/mol lower than that of the ortho adduct,
suggesting that the formed para adduct could be more ready to
be oxidized via SET process than the ortho adduct. Thus, the
computational studies demonstrate that not only is the para
scavengers including 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) and butylated hydroxytoluene (BHT) were added
to the reaction mixture, and the results showed that the
reaction was completely inhibited when 3 equiv of radical
scavengers was used, implying the reaction undergoes a free-
radical pathway (see Supporting Information).13 Second, the
perfluoroalkyl radical can be generated with palladium(0),
which was reported by Chen and co-workers.14 When the
substrate 1a was directly treated with perfluoroalkyl radical, a
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Letter
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selective C−H perfluoroalkylation of other aromatic com-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02362.
■
S
Experimental procedures and H and 13C NMR spectra
for new compounds (PDF)
1
(17) See Supporting Information for computational details.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xgbao@suda.edu.cn. (X.-G.B.)
*E-mail: yszhao@suda.edu.cn. (Y.-S.Z.)
ORCID
Xiaoguang Bao: 0000-0001-7190-8866
Yingsheng Zhao: 0000-0002-6142-7839
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Natural Science Foundation of
China (Nos. 21772139, 21572149, and 21642004) and by
Jiangsu Province Natural Science Found for Distinguished
Young Scholars (BK20180041).
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DOI: 10.1021/acs.orglett.9b02362
Org. Lett. XXXX, XXX, XXX−XXX