Silver-mediated trifluoromethylation-iodination of arynes

Article abstract of DOI:10.1021/ja312711c

An unprecedented silver-mediated vicinal trifluoromethylation-iodination of arynes that quickly introduces CF₃ and I groups onto aromatic rings in a single step to give o-trifluoromethyl iodoarenes has been developed. A new reactivity of AgCF₃ has been revealed, and 2,2,6,6-tetramethylpiperidine plays an important role in this difunctionalization reaction.

Full text of DOI:10.1021/ja312711c

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Communication
Silver-Mediated Trifluoromethylation-Iodination of Arynes
Yuwen Zeng, Laijun Zhang, Yanchuan Zhao, Chuanfa Ni, Jingwei Zhao, and Jinbo Hu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja312711c • Publication Date (Web): 11 Feb 2013
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Silver-Mediated TrifluoromethylationIodination of Arynes
Yuwen Zeng, Laijun Zhang, Yanchuan Zhao, Chuanfa Ni, Jingwei Zhao, and Jinbo Hu*
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Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Ling-Ling Road, Shanghai 200032, China
Supporting Information Placeholder

stability and softness (than the previously used“CF3 ”8a)
ABSTRACT: An unprecedented silver-mediated vicinal
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which enable its reaction with aryne. Therefore, in situ-
trifluoromethylationiodination of arynes has been developed,
generated aryne species could be trapped by MCF3 to form o-
which quickly introduces CF3 and I groups onto aromatic rings
(trifluoromethyl)arylmetal complex, which further reacts with
in a single step to give o-trifluoromethyl iodoarenes. A new
electrophiles to give vicinally difunctionalized arenes (eq 4).
reactivity of AgCF3 has been revealed, and 2,2,6,6-
o-CF3-containing functionalized arenes can serve as highly
tetramethylpiperidine (TMP) plays an important role in this
useful synthetic building blocks for many applications.
difunctionalization reaction.
Table 1. Reaction of Benzyne, Trifluoromethylmetals, and
Various Electrophilesa
Trifluoromethylated arenes are intriguing compounds for the
development of new pharmaceuticals, agrochemicals, and
functional materials because of their unique properties such as
increased stability, lipophilicity, and bioavailability.1 As a
result, much endeavors have been exerted to develop efficient
methods of introducing CF3 group(s) onto aromatic rings.2 The
previously known methods for this transformation can be
divided into three categories: a) methods that involve
trifluormethyl radicals3 (eq 1); b) methods that involve
transition-metal-mediated4,5
cross-couplings
with
aryl
halides4a-d or aryl boron agents4e-j using nucleophilic or
electrophilic CF3 sources (eq 2); and c) methods that involve
an arene CH activation process followed by a Pd(IV)-
mediated trifluoromethylation5d (eq 3). However, all these
trifluoromethylation methods feature monofunctionalization
(trifluoromethylation) of aromatic compounds (eqs 13). In
this communication, we wish to disclose a new protocol for
the trifluoromethylation, that is, vicinal difunctionalization of
arenes via Ag-mediated trifluoromethylationiodination of
arynes in one step (eq 4).
Our study began with mixing various MCF3 species with
benzyne to see whether trifluoromethylation takes place (Table
1). Initially, we examined the reaction of CuCF3, 2-
(trimethylsilyl)phenyl triflate (1a; as a benzyne precursor7a)
and CsF; however, no trifluoromethylation product was
observed (entry 1). Replacing CuCF3 by Zn(CF3)2 gave a
similar result (entry 2). Gratifyingly, we found that
trifluoromethylsilver (AgCF3) can smoothly react with
benzyne to form PhCF3 in 80% yield (entry 3). AgCF3 was
preprepared by mixing TMSCF3 and AgF in 1:1 ratio in
acetonitrile at rt for 30 min.9a It is noteworthy that although
AgCF3 was known as an effective nucleophilic
trifluoromethylating agent for certain activated organohalides9
and as a precursor of CF3 radical,3d,3f its reaction with benzyne
has been never reported. To take advantage of benzyne as a
vicinally difunctionalizable substrate, a series of electrophiles
were added in the reaction to trap the o-
(trifluoromethyl)arylsilver intermediate (entries 413). While
benzaldehyde was unreactive (entry 4), N-chlorosuccinimide
(NCS) gave the o-chloro-trifluoromethyl-benzene in 6% yield,
with 31% yield of PhCF3 being formed (entry 5). Other
halogenating reagents such as N-bromosuccinimide (NBS) and
Benzyne, with its low-lying LUMO, offers the strategic
advantage of rapidly constructing multifunctionalized arenes
which are otherwise difficult to synthesize.6,7 Previously,
during our investigation of the hard/soft nature of α-fluoro
carbanions,8 we found that nucleophilic trifluoromethylation
of benzyne failed presumably owing to the low stability of

“CF3 ” (generated from TMSCF3/F) and the mismatch

between the soft benzyne and the hard “CF3 ”species.8a We
envisioned that this synthetic problem might be solved by
using a proper trifluoromethyl organometallic species (MCF3),
with the hope that the MCF3 species possesses increased
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N-iodosuccinimide (NIS) failed to give the desired o-
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halogenated trifluoromethylbenzene, and only a small amount
of PhCF3 was formed in both cases (entries 6 and 7). Our
attempts to obtain transmetallation products by using
organotin reagents also failed (entries 8 and 9). Allyl chloride
and bromide were found to be unsuitable electrophiles for the
reaction (entries 10 and 11). Other mild X+ reagents such as 1-
bromophenylacetylene and 1-iodophenylacetylene were tried,
and to our delight, the latter one gave the desired iodination
product in 31% yield (with 43% of protonated product PhCF3
being also formed; see entries 12 and 13). 11
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Table 2. Optimization of the Trifluoromethylation-Iodination
of Benzyne by Screening of External Ligandsa
Encouraged by the iodination result (Table 1, entry 13), we
further optimized the reaction conditions, mainly focusing on
the suppression of the undesired protonation product PhCF3.
Our initial attempts to completely suppress the undesired
protonation process10 by carrying out all operations under
anhydrous condition were unsuccessful. Therefore, we
changed our strategy to adding an external additive/ligand to
accelerate the iodination process, thus enhancing the ratio of
iodinated/protonated products (Table 2). After
a quick
screening (entries 1-6), we concluded that alkylamines are
suitable ligands for promoting the iodination. Further studies
showed that the hindered secondary amine 2,2,6,6-
tetramethylpiperidine (TMP) could serve as a previledged
ligand for the reaction (entries 7-13), and 70% of iodinated
product was obtained with complete supression of undesired
protonation (no PhCF3 being observed; see entry 13). Finally,
after further tuning of the reaction paprameters, the best result
(82% yield of o-iodo-trifluoromethylbeneze with no formation
of PhCF3) was obtained by using 1a (0.1 mmol), CsF (0.4
mmol), fleshly prepared AgCF3 (0.3 mmol), 3 (0.3 mmol), and
TMP (0.3 mmol) in MeCN (4 mL) (see Table 2, entry 14).
Having the optimized reaction conditions in hand, we then
examined the scope of the reaction using a variety of
structurally diverse aryne precursors (Table 3). It was found
that substrates bearing electron-donating groups (entries 3 and
6)
are
amenable
to
the
present
Ag-mediated
trifluoromethylationiodination process. Other functional
groups such as acetal, bromo and allyl are also compatible
with this reaction (entry 3, 9 and 10). Noteworthy is the
perfect regioselectivity observed in the reaction with 3-
substituted benzynes, thus 4f, 4i, and 4j were formed as the
single isomers. In contrast, the reactions with 4-phenylbenzyne
and 4-methylbenzyne gave almost 1:1 ratio of regioisomeric
products 4e and 4g in 94% and 61% yield, respectively.
Table 3. Scope of Silver-Mediated Trifluoromethylation-
iodination of Arynesa
To
gain
more
insights
into
the
present
trifluoromethylationiodination reaction, we carried out
preliminary mechanistic studies. First, we examined the
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interaction between AgCF3 and TMP (Figure 1).9 Naumann et
al. reported that there is an equilibrium between the neutral
1
species AgCF3•D and the ionic species [Ag(CF3)2] and the
degree of equilibrium varies in different solvents (eq 5).9b We
found that the ratio of AgCF3•MeCN to [Ag(CF3)2] was 1:3.8
in MeCN (Figure 1a); however, after adding TMP to AgCF3
(in a 1:1 ratio), a new silver-amine complex (AgCF3•TMP)
was instantaneously formed (as monitored by 19F NMR), and
the ratio of AgCF3•TMP to Ag(CF3)2 is 18.8:1 (Figure 1b). It
is reasonable to assume that this new complex (AgCF3•TMP)
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have better reactivity than [Ag(CF3)2] towards benzyne owing
to its increased electron density on silver atom by coordination
with TMP.
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Figure 2. Monitoring the Halogen Bonding Between 1-
Iodophenylacetylene and TMP by 13C NMR at rt
Figure 1. Monitoring the Coordination Between AgCF3
and TMP by 19F NMR at rt
We also investigated the interaction between TMP and 1-
iodophenylacetylene. Although the halogen bonding between
1-iodoacetylene and various donors has been extensively
studied by Laurence et al.12 and Goroff et al.13 using infrared
and 13C NMR spectroscopies, the donor-acceptor interaction
between 1-iodophenylacetylene and TMP in MeCN has never
been reported. Indeed, our 13C NMR study showed that there
was a strong halogen bonding interaction beween TMP and 1-
Scheme 1. Proposed Mechanism of Ag-Mediated
TrifluoromethylationIodination of Arynes
iodophenylacetylene,
as
the
C-1
atom
in
1-
iodophenylacetylene was significantly deshielded (Figure 2).13
To probe whether the present trifluoromethylation–
iodination process involves
a radical process, TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy), a well-known radical
scavenger, was added into the standard reaction (as shown in
Table 2, entry 14). It was investigated that the desired product
was still formed in 80% yield (eq 7), which suggests that a
mechanism involving radical pathway is less likely.14 We also
studied the feasibility of deprotonation of TMP under the
standard reaction conditions. When AgCF3, CsF and
deuterated TMP were mixed together, CHF3 and CDF3 were
slowly generated (eq 8), indicating that deprotonation of TMP
is possible during the reaction. Furthermore, as shown in Table
2, tertiary amines are far less effective than primary amines
and secondary amines in promoting the iodination (Table 2,
entry 6-13); therefore, a hydrogen bonding may play an
important role in the reaction. In addition, the great difference
between piperidine and TMP (Table 2, entry 11 and 13)
indicates that the reaction is also sensitive to the steric
hinderance of a ligand.
With the aforementioned experimental results and
mechanistic considerations, we propose a plausible reaction
mechanism for this unprecedented Ag-mediated and TMP-
promoted trifluoromethylationiodination process (Scheme 1).
The in-situ generated aryne reacts with AgCF3•TMP via a
carboargentation step to afford intermediate a,15 which has
hydrogen bonding with another TMP to form intermediate b.16
Intermediate b undergoes deprotonation to generate anionic
intermediate c, which can be stabilized by charge
delocalization. Subsequent coordination of
c
with
iodophenylacetylene via halogen bonding gives rise to
intermediate d,12,13 which is followed by an intramolecular
nucleophilic attack to afford the ate complex e.17 The ate
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9516. (j) Novák, P.; Lishchynskyi, A.; Grushin, V. V. Angew.
complex
e
readily produces the substituted ortho-
trifluoromethyl iodobenzene f and silver phenylacetylide18 as a
by-product in the presence of silver species.19 The beneficial
effects of TMP may be summarized as follows: a) TMP may
increase the electron density on Ag and thus enhance the
nucleophilicity of AgCF3;20 b) TMP may reduce the energy
barrier of the iodination step by means of forming a six-
membered ring by hydrogen bonding and halogen bonding
(see d in Scheme 1); and c) the steric hindrance of TMP may
enhance the rigidity of transition state and therefore increase
the proximity between aryl group and iodine atom (see d in
Scheme 1; and Table 2, entry 11 and 13).
1
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3
4
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Chem., Int. Ed. 2012, 51, 7767.
Ⅱ
(5) Pd -mediated formation of Ar-CF3 bonds: (a) Grushin, V. V.;
Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644. (b) Cho, E.
J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. PdIV-mediated
formation of Ar-CF3 bonds: (c) Ball, N. D.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878. (d) Wang, X.;
Truesdale, L.;Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.
(6) For recent reviews, see: (a) A. M. Dyke, A. J. Hester, G. C.
Lloyd-Jones, Synthesis 2006, 24, 4093. (b) P. M. Tadross, B. M.
Stoltz, Chem. Rev. 2012, 112, 3550.
(7) For selected examples, see: (a) Himeshima, Y.; Sonoda, T.;
Kobayashi, H. Chem. Lett. 1983, 1211. (b) Tambar, U. K.; Stoltz,
B. M. J. Am. Chem. Soc. 2005, 127, 5340. (c) Henderson, J. L.;
Edwards, A. S.; Greaney, M. F. J. Am. Chem. Soc. 2006, 128,
7426. (d) Yoshida, H.; Asatsu, Y.; Mimura, Y.; Ito, Y.; Ohshita,
J.; Takaki, K. Angew. Chem., Int. Ed. 2011, 50, 9676. (e)
Candito, D. A.; Panteleev, J.; Lautens, M. J. Am. Chem. Soc.
2011, 133, 14200.
(8) (a) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699. (b)
Zhang, W.; Ni, C.; Hu, J. Top. Curr. Chem. 2012, 308, 25.
(9) For the preparation and reactivity of AgCF3, see: (a) Tyrra, W. E.
J. Fluorine Chem. 2001, 112, 149. (b) Naumann, D.; Wessel, W.;
Hahn, J.; Tyrra, W. J. Organomet. Chem. 1997, 547, 79. (c)
Wessel, W.; Tyrra, W.; Naumann, D. Z. Anorg. Allg. Chem.
2001, 627, 1264. (d) Tyrra, W. Heteroatom Chem. 2002, 13, 561.
(e) Nair, H. K.; Morrison, J. A. J. Organomet. Chem. 1989, 376,
149. (f) Refs 3d and 3f.
(10) Arylsilver species are known to readily undergo protolysis, see:
(a) Miller, W. T.; Sun, K. K. J. Am. Chem. Soc. 1970, 92, 6985.
(b) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009,
131, 1662. (c) Cornella, J.; Lahlali, H.; Larrosa, I. Chem.
Commun. 2010, 46, 8276.
(11) For more discussion on the reactivity of electrophiles, see
supporting information.
(12) (a) Laurence, C.; Queignec-Cabanetos, M.; Dziembowska, T.;
Queignec, R.; Wojtkowiak, B. J. Am. Chem. Soc. 1981, 103,
2567. (b) Laurence, C.; Queignec-Cabanetos, M.; Wojtkowiak,
B. J. Chem. Soc., Perkin Trans.Ⅱ 1982, 1605.
(13) (a) Rege, P. D.; Malkina, O. L.; Goroff, N. S. J. Am. Chem. Soc.
2002, 124, 370. (b) Moss, W. N.; Goroff, N. S. J. Org. Chem.
2005, 70, 802.
(14) A mechanism involving Ag(ш) intermediates has also been
discussed, see supporting information.
(15) For a discussion on the possibility of aryl anion pathway, see
supporting information.
(16) For hydrogen-bond basicity of aliphatic amines, see: Graton, J.;
Berthelot, M.; Besseau, F.; Laurence, C. J. Org. Chem. 2005, 70,
7892.
(17) (a) Tripathy, S.; Hussain, H.; Durst, T. Tetrahedron Lett. 2000,
41, 8401. (b) Wiberg, K. B.; Sklenak, S. J. Org. Chem. 2000, 65,
2014. (c) Hamura, T.; Chuda, Y.; Nakatsuji, Y.; Suzuki, K.
Angew. Chem., Int. Ed. 2012, 51, 3368.
(18) (a) Dillinger, S.; Bertus, P.; Pale, P. Org. Lett. 2001, 3, 1661. (b)
Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395.
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In conclusion, we have developed an unprecedented protocol
for trifluoromethylationiodination of arynes in one step. This
method provides a simple and efficient route for various o-
trifluoromethylated iodoarenes, which are otherwise difficult
to be synthesized by traditional methods21 but have many
potential synthetic applications in life science- and material
science-related fields. Additionally, the new reactivity of
AgCF3 reported herein promises to trigger further development
of silver-mediated fluoroalkylation reactions, which is
underway in our laboratory.
ASSOCIATED CONTENT
Supporting
characterization and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Information.
Experimental
procedures,
AUTHOR INFORMATION
Corresponding Author
jinbohu@sioc.ac.cn
ACKNOWLEDGMENT
Support of our work by the National Basic Research Program of
China (2012CB215500 and 2012CB821600), the NSF of China
(20825209, 21102163), and the Chinese Academy of Sciences is
gratefully acknowledged.
REFERENCES
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(19) It was found that an offwhite powder precipitated out during the
reaction. This insoluble powder reacted with I2 and HCl to give
1-iodophenylacetylene and phenylacetylene, respectively.
(20) Ligands may weaken and thus activate the silvercarbon bond,
see: ref 17b. Similar activations were proposed in copper
chemistry, see: (a) Ref 4c. (b) Wei, C.; Mague, J. T.; Li, C.-J.
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