Copper(I)-Catalyzed Alkylation of Polyfluoroarenes through Direct C - H Bond Functionalization

Article abstract of DOI:10.1002/anie.201412450

The copper(I)-catalyzed alkylation of electron-deficient polyfluoroarenes with N-tosylhydrazones and diazo compounds has been developed. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of C(sp²) - C(sp³) bonds with polyfluoroarenes through direct C - H bond functionalization. Mechanistically, copper(I) carbene formation and subsequent migratory insertion are proposed as the key steps in the reaction pathway.

Full text of DOI:10.1002/anie.201412450

Angewandte
Chemie
DOI: 10.1002/anie.201412450
Synthetic Methods
Copper(I)-Catalyzed Alkylation of Polyfluoroarenes through Direct
À
C H Bond Functionalization**
Shuai Xu, Guojiao Wu, Fei Ye, Xi Wang, Huan Li, Xia Zhao, Yan Zhang, and Jianbo Wang*
À
Abstract: The copper(I)-catalyzed alkylation of electron-
deficient polyfluoroarenes with N-tosylhydrazones and diazo
compounds has been developed. This reaction uses readily
limit the direct C H bond functionalization of polyfluoroar-
enes. First, compared with electron-rich arenes, polyfluoroar-
enes have poor coordination ability with the catalysts. Second,
the strong s-bonds between transition metals and polyfluoro-
aryl groups result in difficulties for subsequent transforma-
tions. In 2006, Fagnou and co-workers reported the first direct
arylation of polyfluoroarenes with a palladium catalyst.[3] In
this transformation, polyfluoroarenes are deprotonated and
then coordinate with the catalyst. Daugulis and co-workers
later developed the transformation with a copper catalyst.[4]
Moreover, the direct arylation through oxidative coupling,[5]
allylation,[6] alkynylation,[7] and Heck-type reactions[8] of
polyfluoroarenes were reported. In addition to palladium
catalysts, nickel,[9] and copper[10] have also been used to
catalyze some reactions involving polyfluoroarenes.
available starting materials and is operationally simple, thus
2
À
representing a practical method for the construction of C(sp )
3
À
C(sp ) bonds with polyfluoroarenes through direct C H bond
functionalization. Mechanistically, copper(I) carbene forma-
tion and subsequent migratory insertion are proposed as the
key steps in the reaction pathway.
C
ompounds bearing F-containing groups are useful in
materials and life sciences because of the unique effects of
F substituents.[1] Polyfluoroarenes are a representative class of
such F-containing molecules and have found wide applica-
tions. As a result, the development of efficient methods to
introduce a polyfluoroaryl group has become an important
undertaking for synthetic organic chemists and significant
progress has been made in the past years. Most of the methods
so far developed are based on polyfluoroaryl metals, halides,
or carboxylic acids (Scheme 1a,b).[2]
The studies mentioned above are focused on the con-
2
2
À
struction of a C(sp ) C(sp ) bond. It is worth mentioning that
Friedel–Crafts alkylation reactions cannot be applied to
polyfluoroarenes because of their electron-deficient nature.
As a result, the reports on alkylation of perfluoroarenes are
rare.[4a] In 2009, Nakamura and co-workers reported the
alkylation with a polyfluoroaryl zinc agent.[11] The group of
Zhang subsequently reported the palladium-catalyzed pri-
mary benzylation of polyfluoroarenes (Scheme 2a).[12] How-
À
Apparently, the methods based on direct C H function-
alization of polyfluoroarenes are favored in terms of atom and
step economy. However, there are at least two factors that
Scheme 1. General methods for introducing polyfluoroarene groups.
2
3
À
Scheme 2. C(sp ) C(sp ) bond-forming reactions of polyfluoroarenes.
[*] S. Xu, G. Wu, F. Ye, X. Wang, H. Li, X. Zhao, Dr. Y. Zhang,
Prof. Dr. J. Wang
ever, the reaction is only limited to primary benzylation.
Secondary benzyl halides are not used as the substrates,
presumably because of the competing b-hydride elimination.
In 2010, Zhao and co-workers reported rhodium-catalyzed
olefin hydroarylation with polyfluoroarenes, which can be
considered as an alternative approach toward alkylation of
polyfluoroarenes (Scheme 2b).[13] However, the secondary
benzylation and general alkylation of polyfluoroarenes are
still difficult to achieve.
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry
Peking University, Beijing 100871 (China)
E-mail: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
À
Recently, we developed copper(I)-catalyzed C H bond
[**] The project is supported by the National Basic Research Program of
China (973 Program, No. 2015CB856600) and NSFC (Grant No.
21272010 and 21332002)
functionalization of terminal alkynes,[14] 1,3-azoles[15] and
N-iminopyridinium ylides[16] with N-tosylhydrazones. In
these transformations, the reactions are proposed to involve
the following general sequence: deprotonation of the rela-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412450.
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tively acidic C H bond of the substrates followed by trans-
metalation to a copper(I) catalyst, formation of a copper(I)
carbene species with the in situ generated diazo substrate,
migratory insertion of the carbene, and finally protonation of
the copper(I) species to complete the catalytic cycle. Since the
À
polyfluoroarenes contain C H bonds of similar acidity as that
of terminal alkynes and 1,3-zaoles, it is thus expected that
polyfluoroarenes could be alkylated in the similar reaction
system. In our previous study we have noticed that 1,2,4,5-
tetrafluorobenzene could be benzylated, albeit with low
efficiency.[15] Herein we report an efficient and general
copper(I)-catalyzed alkylation of polyfluoroarenes (Sche-
me 2c).
Table 1: Optimization of reaction conditions.[a]
Entry
Solvent
Ligand
Base
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
MeCN
–
bpy
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
Cs2CO3
NaOtBu
KOtBu
LiOtBu
LiOtBu
26
60
70 (69)
50
27
24
16
5
70
phen
PPh3
dppe
phen
phen
phen
phen
phen
1,4-dioxane/MeCN (1:1)
75 (74)
[a] Reaction conditions: the solution of 2a (0.1 mmol) and 1a (2.0 equiv)
in solvent (0.5 mL) was heated at 908C for 1 h. [b] Yield determined by
1H NMR spectroscopy using CH3NO2 as the internal standard. [c] The
yield given within parentheses refers to that of the isolated product.
bpy=bipyridine, Ts=4-toluenesulfonyl.
As shown in Table 1, 1,2,4,5-tetrafluorobenzene (1a) and
the N-tosylhydrazone 2a were used for the optimization of
the reaction conditions. The reaction with 20 mol% CuI and
LiOtBu in 1,4-dioxane without a ligand gave the expected
alkylation product 3a in 26% yield (Table 1, entry 1). We
then examined the effect of ligands and found that the
addition of either bipyridine (bpy), 1,10-phenanthroline
(phen), or PPh3 could significantly improve the yields
(entries 2–4), presumably as a result of the improvement of
the solubility of the catalyst. The trans-effect of the appro-
priate ligand may also accelerate the transmetalation pro-
cess.[17] The reaction is sensitive to the base and it was
identified that LiOtBu could give best results (entries 6–8).
Also, an excess amount of 1a is necessary for obtaining the
optimal yield. Finally, the examination of the solvent used
showed that the mixed solvent of 1,4-dioxane and acetonitrile
in a 1:1 ratio could slightly improve the yield.
Scheme 3. Scope of N-tosylhydrazones. Reaction conditions: fluoroar-
ene 1a (0.60 mmol, 2.0 equiv), N-tosylhydrazone 2a–u (0.30 mmol,
1.0 equiv), CuI (20 mol%), 1, 10-phenanthroline (20 mol%), LiOtBu
(3.0 equiv), 1,4-dioxane (0.75 mL), and MeCN (0.75 mL), 908C, 2 h.
[a] The reaction was scaled up to 10.0 mmol of N-tosylhydrazone.
[b] The reaction was carried out at 1108C.
affording the corresponding products 3a–u in moderate to
good yields. In general, the substrates with electron-donating
groups on the aromatic ring gave slightly higher yields (3b–d).
The reaction proceeded well with the substrates bearing
halogen substituents, thus giving the products in moderate
yields (3e–g). For the substrate with an iodo substituent, the
addition of one equivalent of LiI could suppress the by-
product resulting from iodo substitution.[4a]
With the optimized reaction conditions in hand, we
proceeded to investigate the scope of the reaction. First,
with 1a as the substrate, we studied the scope of
N-tosylhydrazones. As shown in Scheme 3, the reaction
worked well with a series of N-tosylhydrazones (2a–u), thus
In addition to the N-tosylhydrazones derived from
acetophenones, those derived from acetonaphthone (3j)
and propiophenone (3k) are also suitable substrates
(Scheme 3). N-Tosylhydrazones derived from cyclic ketone
and 2-acetylfuran also worked well in this reaction to give 3m
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and 3n, respectively. Next, N-tosylhydrazones derived from
benzaldehydes were examined and the reaction proceeded
smoothly (3o,p). Notably, the reaction with N-tosylhydrazone
derived from alkyl aldehyde was found to give the desired
product, although it was necessary to carry out the reaction at
an elevated temperature (3q). In addition, the reaction with
N-tosylhydrazones derived from benzophenones gave the
corresponding triarylmethane derivatives 3r–t, which have
various applications in materials science[18] and biological
studies.[19]
Next, we investigated the scope of other polyfluoroarenes.
As summarized in Scheme 4, polyfluoroarenes 1b–e were
Scheme 5. Copper(I)-catalyzed reaction of diazo compounds with poly-
fluoroarenes. [a] Conditions A: fluoroarene (0.40 mmol, 2.0 equiv),
diazo compound (0.20 mmol, 1.0 equiv), CuI (20 mol%), 1, 10-phe-
nanthroline (20 mol%), LiOtBu (3.0 equiv), 1,4-dioxane (1.0 mL),
908C, 3 h. [b] Conditions B: fluoroarene (0.40 mmol, 2.0 equiv), diazo
compounds (0.20 mmol, 1.0 equiv), [Cu(MeCN)4]BF4 (20 mol%),
LiOtBu (2.0 equiv), 1,4-dioxane (1.0 mL), 908C, 3 h.
After achieving the alkylation of polyfluoroarenes with
N-tosylhydrazones, we further investigated the direct reaction
of diazo compounds under the similar reaction conditions
(Scheme 5). The reaction with diaryldiazomethanes pro-
ceeded smoothly under the same reaction conditions as
shown above, thus affording the corresponding alkylation
products 5a–c in good yields (Scheme 5, conditions A).
However, only trace amounts of the alkylation product could
be obtained when using diazoesters as the substrates under
the same reaction conditions. Upon screening the catalysts, it
was found that 20 mol% [Cu(CH3CN)4]BF4 afforded the
optimal results (Scheme 5, conditions B). Notably, the
reactions with diazoesters are sensitive to the substituents
on the aromatic ring of the diazo substrates. The diazoesters
bearing an electron-donating group or electron-withdrawing
group on the aromatic ring afforded the desired products 5h
and 5i in diminished yields.
Scheme 4. Scope of polyfluoroarenes and N-tosylhydrazones. Reaction
conditions: fluoroarene 1b–e (0.60 mmol, 2.0 equiv), N-tosylhydrazone
(0.30 mmol, 1.0 equiv), CuI (20 mol%), 1,10-phenanthroline
(20 mol%), LiOtBu (3.0 equiv), 1,4-dioxane (0.75 mL), and MeCN
(0.75 mL), 908C, 2 h. [a] The reaction time was 30 min.
submitted to this transformation and the corresponding
alkylation products could be obtained in moderate to good
yields. Pentafluorobenzene (1b) reacted with various
N-tosylhydrazones, including that derived from cinnamalde-
hyde which afforded the allylation product 4h. Other
polyfluoroarenes, such as 1,2,4,5-tetrafluoro-3-methoxyben-
zene (1c) or 1,2,3,5-tetrafluorobenzene (1d) also worked,
thus giving the corresponding products 4j and 4k. As for
2,3,5,6-tetrafluoropyridine (1e), the reaction time needed to
be shortened to 30 minutes to prevent fluoro substitution by
tBuOÀ. In this case the desired alkylation product 4l could be
obtained in 70% yield.
Based on our previous studies,[14–16] we propose the
reaction mechanism as shown in Scheme 6. The reaction is
À
initiated by the deprotonation of the relatively acidic C H
bond of the polyfluoroarene substrate. It is then followed by
transmetalation to a copper(I) catalyst to generate the
polyfluoroaryl copper species A. Subsequently, A reacts with
the in situ-generated diazo substrate to form the copper
carbene species B, from which migration insertion occurs to
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[1] For selected reviews, see: a) E. A. Meyer, R. K. Castellano, F.
Diederich, Angew. Chem. Int. Ed. 2003, 42, 1210; Angew. Chem.
2003, 115, 1244; b) K. Muller, C. Faeh, F. Diederich, Science
2007, 317, 1881; c) A. R. Murphy, J. M. J. Frꢀchet, Chem. Rev.
2007, 107, 1066; d) F. Babudri, G. M. Farinola, F. Naso, R. Ragni,
Chem. Commun. 2007, 1003; e) S. Purser, P. R. Moore, S.
Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; f) H.
Amii, K. Uneyama, Chem. Rev. 2009, 109, 2119; g) T. Ahrens, J.
Kohlmann, M. Ahrens, T. Braun, Chem. Rev. 2015, 115, 931.
[2] For selected papers, see: a) R. J. Harper, Jr., E. J. Soloski, C.
Tamborski, J. Org. Chem. 1964, 29, 2385; b) T. Korenaga, T.
Kosaki, R. Fukumura, T. Ema, T. Sakai, Org. Lett. 2005, 7, 4915;
c) A. C. Albꢀniz, P. Espinet, B. Martꢁn-Ruiz, D. Milstein, J. Am.
Chem. Soc. 2001, 123, 11504; d) A. C. Albꢀniz, P. Espinet, B.
Martꢁn-Ruiz, D. Milstein, Organometallics 2005, 24, 3679; e) R.
Shang, Y. Fu, Y. Wang, Q. Xu, H. Z. Yu, L. Liu, Angew. Chem. Int.
Ed. 2009, 48, 9350; Angew. Chem. 2009, 121, 9514; f) R. Shang, Q.
Xu, Y. Y. Jiang, Y. Wang, L. Liu, Org. Lett. 2010, 12, 1000.
[3] a) M. Lafrance, C. N. Rowley, T. K. Woo, K. Fagnou, J. Am.
Chem. Soc. 2006, 128, 8754; b) M. Lafrance, D. Shore, K. Fagnou,
Org. Lett. 2006, 8, 5097.
[4] a) H. Q. Do, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128;
b) H.-Q. Do, R. M. K. Khan, O. Daugulis, J. Am. Chem. Soc.
2008, 130, 15185.
[5] a) C. Y. He, S. Fan, X. Zhang, J. Am. Chem. Soc. 2010, 132,
12850; b) Y. Wei, W. Su, J. Am. Chem. Soc. 2010, 132, 16377.
[6] a) S. Fan, F. Chen, X. Zhang, Angew. Chem. Int. Ed. 2011, 50,
5918; Angew. Chem. 2011, 123, 6040; b) G. W. Wang, A.-X.
Zhou, S.-X. Li, S.-D. Yang, Org. Lett. 2014, 16, 3118.
[7] Y. Wei, H. Zhao, J. Kan, W. Su, M. Hong, J. Am. Chem. Soc.
2010, 132, 2522.
Scheme 6. Proposed reaction mechanism.
generate the intermediate C. Finally, protonation of C delivers
the alkylation product and completes the catalytic cycle.
An alternative mechanism to account for the reaction is
copper(I) carbene aromatic substitution. However, such
electrophilic substitution reaction normally occurs for rela-
tively electron-rich aromatic rings.[20] To gain further insights
into the reaction, we carried out the reaction in the absence of
base by using the diaryldiazomethane (6) as the substrate
[Eq. (1)]. Inspection of the crude reaction mixture by GC-MS
1
and H NMR spectroscopy indicated that alkylation product
[8] a) X. Zhang, S. Fan, C. Y. He, X. Wan, Q. Q. Min, J. Yang, Z. X.
Jiang, J. Am. Chem. Soc. 2010, 132, 4506; b) C. Z. Wu, C. Y. He,
Y. G. Huang, X. Zhang, Org. Lett. 2013, 15, 5266.
[9] Y. Nakao, N. Kashihara, K. S. Kanyiva, T. Hiyama, J. Am. Chem.
Soc. 2008, 130, 16170.
5c was not formed. The result is not supportive of an
electrophilic substitution mechanism, in which case the base is
not necessary.
[10] a) N. Matsuyama, M. Kitahara, K. Hirano, T. Satoh, M. Miura,
Org. Lett. 2010, 12, 2358; b) T. Yao, K. Hirano, T. Satoh, M.
Miura, Angew. Chem. Int. Ed. 2011, 50, 2990; Angew. Chem.
2011, 123, 3046; c) A. Nakatani, K. Hirano, T. Satoh, M. Miura,
Org. Lett. 2012, 14, 2586.
[11] T. Hatakeyama, Y. Kondo, Y. i. Fujiwara, H. Takaya, S. Ito, E.
Nakamura, M. Nakamura, Chem. Commun. 2009, 1216.
[12] S. Fan, C. Y. He, X. Zhang, Chem. Commun. 2010, 46, 4926.
[13] Z.-M. Sun, J. Zhang, R. S. Manan, P. Zhao, J. Am. Chem. Soc.
2010, 132, 6935.
[14] a) Q. Xiao, Y. Xia, H. Li, Y. Zhang, J. Wang, Angew. Chem. Int.
Ed. 2011, 50, 1114; Angew. Chem. 2011, 123, 1146; b) F. Ye, X.
Ma, Q. Xiao, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2012, 134,
5742.
[15] X. Zhao, G. Wu, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2011, 133,
3296.
[16] Q. Xiao, L. Ling, F. Ye, R. Tan, L. Tian, Y. Zhang, Y. Li, J. Wang,
J. Org. Chem. 2013, 78, 3879.
[17] A. V. Babkov, Polyhedron 1988, 7, 1203.
In conclusion, we have developed an efficient copper(I)-
catalyzed alkylation reaction of polyfluoroarenes with
À
N-tosylhydrazones through direct C H functionalization,
thus affording the diarylmethane derivatives or triarylme-
thane derivatives in moderate to good yields. Considering the
ease of synthesis for N-tosylhydrazones and the benefits of
the cheap copper(I) catalyst, this reaction represents an
efficient and practical access to introduce an alkyl group (in
particular secondary benzyl group) to polyfluoroarenes,
a reaction which is difficult to realize through other tran-
[18] D. F. Duxbury, Chem. Rev. 1993, 93, 381.
[19] a) M. Terrier, T. Boubaker, L. Xiao, P. G. Farrell, J. Org. Chem.
1992, 57, 3924; b) M. R. Detty, S. L. Gibson, S. J. Wagner, J. Med.
Chem. 2004, 47, 3897.
[20] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclo-
propanes to Ylides, Wiley, New York, 1998.
À
sition-metal-catalyzed C H bond functionalization methods.
Received: December 29, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · carbenes · copper ·
diazo compounds · synthetic methods
.
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Synthetic Methods
S. Xu, G. Wu, F. Ye, X. Wang, H. Li,
X. Zhao, Y. Zhang,
J. Wang*
&&&& — &&&&
2
3
À
Copper(I)-Catalyzed Alkylation of
Polyfluoroarenes through Direct C H
Bond Functionalization
Along came “Poly”: C(sp ) C(sp ) bond
diazo compounds. The transformation
À
À
formation through direct C H function-
represents a highly efficient practical
method for the direct alkylation of poly-
fluoroarenes. phen=1,10-phenanthro-
line, Ts=4-toluenesulfonyl.
alization proceeds through a copper(I)-
catalyzed alkylation of electron-poorpoly-
fluoroarenes with N-tosylhydrazones or
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