Highly para-Selective C?H Alkylation of Benzene Derivatives with 2,2,2-Trifluoroethyl α-Aryl-α-Diazoesters

Article abstract of DOI:10.1002/anie.201611809

Compared to the most popular directing-group-assisted strategy, the “undirected” strategy for C?H bond functionalization represents a more flexible but more challenging approach. Reported herein is a gold-catalyzed highly site-selective C(sp²)?H alkylation of unactivated arenes with 2,2,2-trifluoroethyl α-aryl-α-diazoesters. This protocol demonstrates that high site-selective C?H bond functionalization can be achieved without the assistance of a directing group. In this transformation, both the gold catalyst and trifluoroethyl group on the ester of the diazo compound play vital roles for achieving the chemo- and regioselectivity.

Full text of DOI:10.1002/anie.201611809

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International Edition: DOI: 10.1002/anie.201611809
German Edition: DOI: 10.1002/ange.201611809
Diazo Compounds
À
Highly para-Selective C H Alkylation of Benzene Derivatives with
2,2,2-Trifluoroethyl a-Aryl-a-Diazoesters
Ben Ma, Zhaowei Chu, Ben Huang, Zhenli Liu, Lu Liu,* and Junliang Zhang*
À
Abstract: Compared to the most popular directing-group-
benzenes). “Undirected” functionalization of C H bonds,
a strategy which involves the use of either a catalyst or
reagent to control the site selectivity, is potentially more
flexible but more challenging.[8] In most cases, the site
selectivity is still a big issue, especially for monosubstituted
À
assisted strategy, the “undirected” strategy for C H bond
functionalization represents a more flexible but more challeng-
ing approach. Reported herein is a gold-catalyzed highly site-
2
À
selective C(sp ) H alkylation of unactivated arenes with 2,2,2-
trifluoroethyl a-aryl-a-diazoesters. This protocol demonstrates
unactivated arenes.[9,10] Therefore, the development of a gen-
eral strategy for highly para-selective C(sp ) H functionali-
zation of arenes, especially for monosubstituted arenes with-
out a coordinating atom, would be highly desirable, and also
requires conveniently operational steps, mild reaction con-
ditions, high efficiency, broad substrate scope, low catalyst
loading, and scalability.
2
À
À
that high site-selective C H bond functionalization can be
achieved without the assistance of a directing group. In this
transformation, both the gold catalyst and trifluoroethyl group
on the ester of the diazo compound play vital roles for
achieving the chemo- and regioselectivity.
À
I
n the past century, the direct transformation of an unac-
The insertion of carbenes into C H bonds has become an
[11,12]
À
À
tivated carbon–hydrogen bond (C H) to either a carbon–
important aspect of undirected C H functionalization.
2
À
À
À
carbon or carbon–heteroatom (C X) bond, termed C H
bond functionalization, has been a fundamentally important
subject in organic and sustainable chemistry.[1] To make this
strategy generally useful in organic synthesis, controlling site
However, the highly site-selective C(sp ) H functionalization
of aryl rings of monoalkyl-substituted arenes remains elu-
sive[13] because of the several competing reactions which
occur when mixing an alkyl benzene with diazo esters in the
presence of transition metals (Scheme 1a). For example, the
groups of Pꢀrez, Woo, and Dias reported that the Buchner
reaction occurred under the catalysis of iron, silver, and
copper complexes, respectively.[13a–c] Alternatively, the groups
À
selectivity of inert C H bonds has remained a key challenge.
Substituted benzenes are ubiquitous motifs in nature, the
synthetic world, and materials-related fields.[2] For example,
they constitute the most frequently used skeleton in the small-
molecule drugs listed in the FDA orange book.[3] Thus, the
of Che and Davies demonstrated the rhodium-catalyzed
3
benzylic C(sp ) H functionalization of toluene.[13d–e]
À
À
direct site-selective aromatic C H functionalization of a ben-
2
À
zene ring is highly important, especially for post-modification
of bioactive compounds. The classic electrophilic aromatic
substitution of monosubstituted unactivated arenes, such as
toluene, introduced in textbooks for organic chemistry, may
be the most common method used for aromatic C(sp ) H
Recently, the C(sp ) H functionalization of alkyl arenes
was realized, but they produced a mixture of ortho-, meta-,
and para-alkylation products.[13f–g] Herein, we wish to present
our progress on the gold-catalyzed,[14] highly para-selective
2
À
À
C H functionalization of monoalkyl-substituted (aryl/halo)
functionalization, but typically delivers mixtures of ortho- and
para-substituted products.[4] Transition-metal-catalyzed,
directing-group-assisted approaches have emerged as one of
the most efficient and popular solutions to the site-selectivity
unactivated arenes (Scheme 1b).
À
Recently, a few examples of gold-catalyzed C H func-
tionalizations of activated arenes,[15] such as phenol,
N-acylaniline, and anisole with a-diazoesters,[16] were devel-
oped. However, during the course of expanding the substrate
problem.[5–7] A variety of directing groups (DGs) have been
2
À
À
developed and widely utilized for ortho C(sp ) H function-
scope to toluene, the desired para-C H functionalization
2
À
alization, and in some cases for meta C(sp ) H functionaliza-
product 3aa was obtained in very low yield (25%), even with
slow addition of the methyl a-aryl-a-diazoacetate 2a to
toluene (1a), thus delivering the dimer of 2a as the major
product (Table 1, entry 1). Further attempts to screen other
gold catalysts and metal catalysts did not address the low yield
and bad selectivity, and the best result was obtained when the
reaction was catalyzed by (2,4-tBu2C6H3O)3PAuPhCNSbF6
(entry 3). We assumed that the low nucleophilicity of toluene
tion[6] of arenes. Nonetheless, this approach is hardly applied
to the para C(sp ) H bond functionalization,[7] especially for
2
À
molecules lacking functional groups (e.g., alkyl-substituted
[*] B. Ma, Z. Chu, B. Huang, Z. Liu, Prof. Dr. L. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical Pro-
cesses, School of Chemistry and Molecular Engineering
East China Normal University
À
might account for the low yield of C H functionalization and
3663 North Zhongshan Road, Shanghai 200062 (China)
E-mail: lliu@chem.ecnu.edu.cn
jlzhang@chem.ecnu.edu.cn
Homepage: http://faculty.ecnu.edu.cn/s/1811/t/20975/main.jspy
thus the dimerization reaction occurs. Given the fact that we
could not change this inherent low reactivity of toluene and
inspired by gold-stabilized carbocation species[6b,17,18] as the
key intermediate, we envisaged that the enhancement of the
electrophilicity of the gold carbocation species, by installing
an electron-withdrawing group on the ester group of
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611809.
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Table 1: Optimization of reaction conditions.[a]
Entry
R (2)
Catalyst (5 mol%)
Yield [%][b]
3/4/5/6/7
1
2
3
4
5
Me (2a)
Me (2a)
Me (2a)
CH2CCl3 (2b)
CH2CBr3 (2c)
CH2CF3 (2d)
CH2CF3 (2d)
CH2CF3 (2d)
CH2CF3 (2d)
CH2CF3 (2d)
LAuSbF6
(25):0:0:0:(57)
trace:0:0:0:85
45:0:0:0:46
(72):(3):0:0:10
(70):(0):0:0:12
(87):0:0:0:(5)
0:0:(57):0:(18)
15:4:9:43:0
Ph3PAuSbF6
LAuPhCNSbF6
LAuPhCNSbF6
LAuPhCNSbF6
LAuPhCNSbF6
Rh(OAc)2
Fe(OTf)2
AgSbF6
LAuPhCNSbF6
Scheme 1. The reaction of monosubstituted arenes and diazo esters.
6
7
8[c]
9
a-diazoesters, may provide an opportunity to address the low
efficiency. Given this hypothesis, diazo esters with electron-
withdrawing groups, instead of a methyl group, were prepared
63:9:0:0:0
(76):0:0:0:(10)
10[d]
À
and tested (entries 4–6). To our delight, the C H functional-
[a] Unless otherwise noted, the solution of 2 (0.4 mmol) in 0.2 mL of
toluene was introduced into catalyst (5 mol%) in toluene (0.4 mL) at
room temperature by a syringe in 1 min and then being stirred for
another 2 min. [b] Determined by NMR spectroscopy. The number within
parentheses is the yield of the isolated product. [c] 1108C. [d] Toluene
(2 equiv) was used in CH2Cl2 (1 mL). L=(2,4-tBu2C6H3O)3P, Tf=tri-
fluoromethanesulfonyl.
ization product 3ad was isolated in 82% yield when the
trifluoroethyl a-aryl-a-diazoester 2d was used as the sub-
strate (entry 6; standard reaction conditions). A series of
other metal catalysts, such as Rh, Ru, Cu, Fe, and others,
which are commonly used in carbene transfer, were
employed, and diverse products arising from either benzylic
À
C H insertion, cyclopropanation, Buchner reaction, ortho-
À
C H functionalization, or diazo coupling, were detected
attached to the alkyl substituent. To our delight, ester and
2
À
(entries 7–9 and Table S1 in the Supporting Information).
These results clearly indicated that the gold catalyst displayed
a unique selectivity compared to other metal catalysts.
Gratifyingly, this transformation proceeds smoothly, even
with the use of only 2 equivalents of toluene, in CH2Cl2
(entry 10).
OTIPS groups are compatible with this para C(sp ) H
alkylation reaction (3kj and le). When p-xylene was used,
À
the reaction with a diazoester also delivered the ortho C H
bond functionalization product 3mi in 75% yield. This result
also demonstrates that this gold-catalyzed reaction of donor/
acceptor carbenes has a strong preference for functionaliza-
2
3
À
À
To explore the substrate scope, a variety of trifluoroethyl
tion of aromatic C(sp ) H bonds instead of C(sp ) H bonds,
a-aryl diazoesters (2a–n) were prepared and examined
(Table 2).The exclusive para C(sp ) H functionalization
products 3ae–an were isolated in good to excellent yields. It
is noteworthy that none of the products derived from benzylic
C(sp ) H insertion or ortho-, meta-C(sp ) H functionaliza-
tion, or Buchner reaction were detected. Furthermore,
a gram-scale reaction using 1.1 grams of 2e and 1a also
works well, even with a much lower catalyst loading
(0.5 mol%), thus furnishing 1.12 grams of the corresponding
product 3ae in 83% yield.
even though the para-position is occupied. Gratifyingly,
2
À
Table 2: Scope with respect to diazo compounds.[a]
3
2
À
À
We then examined a variety of substituted benzenes
(Table 3). The reactions of either monoalkyl- or monoaryl-
substituted arenes (1b–e) with 2a proceeded smoothly, thus
affording moderate to excellent yield of the corresponding
À
para-selective C H functionalization products 3bi–ei. Nota-
bly, the reaction of the arene equipped with an allyl
À
substituent could give the para C H bond alkylation product
3 fj without detection any product by either cyclopropanation
3
À
or secondary C(sp ) H insertion of the doubly activated
benzyl position, thus indicating that this approach is highly
chemo- and regioselectivity. Of course, bialkyl- and trialkyl-
substituted benzene are also compatible in this transforma-
tion, and deliver the corresponding site-selective alkylation
products 3gi–ji. Next, we wondered if the reaction could be
conducted in the presence of arenes with heteroatoms
[a] Unless otherwise noted, a solution of 2 (0.4 mmol) in 0.2 mL of
toluene was introduced to (2,4-tBu2C6H3O)3PAuPhCNSbF6 (5 mol%) in
toluene (0.4 mL) at room temperature by a syringe over a period of 1 min
and the reaction mixture stirred for another 2 min (standard conditions).
[b] Used 0.5% catalyst.
2
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Table 3: Scope with respect to various arenes.[a]
Scheme 2. Preliminary mechanism studies.
shuttle, and is consistent with our previous mechanistic study
(Scheme 2b–d).[18]
Most importantly, this method may be useful for the facile
synthesis of useful building blocks and bioactive compounds
from readily available starting materials (Scheme 3). The
[a] Used arenes (2 equiv) in CH2Cl2 (1 mL). [b] Used 7.5% catalyst.
À
[c] Yield of the isolated alcohols resulting from C H alkylation and
reduction. TIPS=triisopropylsilyl.
simple benzene is also applicable to this process and the
desired product 3nj was obtained in 83% yield. To our
surprise, halobenzenes (F, Cl, Br, I) could also selectively
Scheme 3. Synthetic application. a) NaOH, MeOH, reflux, 2 h; b) 3-
phenylpropylamine, HUAT, Et3N, DMF, RT, 10 h; c) NH2OH·HCl, KOH,
MeOH, RT, 3 h; d) AuCl3, NBS, DCE, RT,30 h. DCE=1,2-dichloro-
ethane, DMF=N,N-dimethylformamide, HUAT=o-(7-azabenzotriazol-
1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, NBS=N-
bromosuccinimide.
À
undergo the para C H functionalization (3oj–rj). The
electron-withdrawing nature of halogens may account for
the slightly lower yield. It is not surprising to find that the
reaction of an arene with an electron-donating group (OMe)
could afford the para-selective product 3sj in 99% yield.
Furthermore, this strategy is applicable to late-stage modifi-
cation of natural products or pharmaceutical compounds
because of its operational convenience and mild reaction
conditions. To our delight, a cholesterol derivative and
analogue of ibuprofen, 8w, the most widely used nonsteroidal
anti-inflammatory drugs (NSAIDs), was prepared in 83%
À
À
a menthol derivative gave the para-selective C H function-
yield by the direct C H functionalization and hydrolysis from
alization in 84 and 82% yield, respectively (3tj and 3uj), and
highlights the potential usage of this transformation for the
screening of benzene-containing lead compounds. It should
be emphasized that only 2 equivalents of the arene 1 were
readily available starting materials.[19a] The antiproliferative
9a and the inhibitors (10e and 10v) of histone deacetylase
were efficiently accessed by amidation in good yields.[19b–c]
Interestingly, the unexpected gold-catalyzed benzylic bromi-
nation of 3ai was observed to deliver the product 11a in 52%
yield. The structure of 9a was confirmed by single-crystal
X-ray analysis.[20]
À
used and high yields of the corresponding para-selective C H
functionalization products 3 (e.g., 3kj, 3rj, 3tj, 3uj) were
obtained.
To gain mechanistic insight to the present transformation,
several control experiments were carried out. The result of
Scheme 2a shows that this transformation does not exhibit
In summary, we have developed a novel gold-catalyzed
À
highly para-selective C H functionalization of unactivated
arenes with 2,2,2-trifluoroethyl a-aryl-a-diazoesters, thereby
directly generating synthetically useful diarylacetates with
convertible functional groups in good yields under mild
reaction conditions. A wide range of benzene derivatives are
compatible with this new process. The salient features of this
À
a kinetic isotope effect, thus indicating that the C H bond
cleavage for toluene is not involved in the rate-determining
step. Additional control experiments demonstrate that water
in the solvent participates in the reaction process as a proton
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À
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Acknowledgements
We are grateful to the Shanghai Pujiang Program
(14PJ1403100), 973 Program (2015CB856600), the National
Natural Science Foundation of China (21372084, 21425205,
21572065), and Changjiang Scholars and Innovative Research
Team in University (PCSIRT) for financial supports.
À
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Conflict of interest
The authors declare no conflict of interest.
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À
Keywords: arenes · C H activation · diazo compounds · gold ·
homogeneous catalysis
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[20] CCDC 1508516 (9a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
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Manuscript received: December 5, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Diazo Compounds
B. Ma, Z. Chu, B. Huang, Z. Liu, L. Liu,*
J. Zhang*
&&& — &&&
À
Highly para-Selective C H Alkylation of
Benzene Derivatives with 2,2,2-
Convertible: A highly para-selective, gold-
resulting products are produced in good
yields under mild reaction conditions,
and are synthetically useful diarylacetates
containing convertible functional groups.
À
Trifluoroethyl a-Aryl-a-Diazoesters
catalyzed C H functionalization of unac-
tivated arenes with 2,2,2-trifluoroethyl a-
aryl-a-diazoesters is reported. The
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!