Selective alkylation and arylation of C-F bond with grignard reagents

Article abstract of DOI:10.1021/ol403479r

Selective alkylation and arylation of the C-F bonds of polyfluoroaryl imines with Grignard reagents were discovered in the absence of metal catalysts. The aldazine-N atom as an anchoring group has a special effect on the regioselectivity of the reaction. The Ci - N bond addition reaction with Grignard reagents was also explored. A possible mechanism was proposed on the competition between the nucleophilic substitution and addition reaction.

Full text of DOI:10.1021/ol403479r

Letter
pubs.acs.org/OrgLett
Selective Alkylation and Arylation of C−F Bond with Grignard
Reagents
Faguan Lu, Hongjian Sun, Aiqin Du, Lei Feng, and Xiaoyan Li*
School of Chemistry and Chemical Engineering, Key Laboratory of Special Functional Aggregated Materials, Ministry of Education,
Shandong University, Shanda Nanlu 27, 250100 Jinan, People’s Republic of China
S
* Supporting Information
ABSTRACT: Selective alkylation and arylation of the C−F
bonds of polyfluoroaryl imines with Grignard reagents were
discovered in the absence of metal catalysts. The aldazine-N
atom as an anchoring group has a special effect on the
regioselectivity of the reaction. The CN bond addition
reaction with Grignard reagents was also explored. A possible mechanism was proposed on the competition between the
nucleophilic substitution and addition reaction.
luorinated compounds are of considerable current interest
in diverse fields of science and technology. More than 150
kinds of fluorinated drugs, nearly up to 20% of all
pharmaceuticals, have come to market, and even 30% of
agrochemicals contain fluorine atoms.1
anchoring group, C−F functionalization could also occurred.12c
Morter summarized some examples in this field.12d
F
Scheme 1. Reaction with MnCl2 as Catalyst
Aromatic fluorides are the most widely used fluorinated
compounds. Selective functionalization of C(sp2)−F bonds has
occupied an important position in the synthesis of aromatic
fluorides. Transition-metal-catalyzed C−C bond-forming re-
actions are of great significance including Heck, Kumada,
Sonogashira, Negishi, Stille, Suzuki, and Hiyama reactions. One
approach to new aromatic fluorides is direct nucleophilic
substitution of fluoroaromatics as a result of C−F bond
activation and functionalization. However, the yields and
selectivity are often low.2,3
In 1973, Kumada reported the first example of catalytic C−C
cross-coupling of fluorobenzene with Grignard reagents by
nickel catalysts.4 In 2001, Herrmann reported that aryl fluorides
reacted with aryl Grignard reagents affording a variety of biaryls
using a nickel carbene complex.5 In 2006, Radius disclosed the
first examples of Ni-catalyzed C−C bond coupling between
fluoroarenes and organoboron compounds.6 Love reported
another Ni-catalyzed Suzuki coupling in 2011. Organoboronic
acids could react with the ortho-fluorine close to an aldazine-N
atom in nearly quantitative conversion.7 In 2012, Lu reported
an example of ortho-(C−F) activation on palladium-catalyzed
Suzuki−Miyaura reaction of polyfluorophenyl oxazoline.8 Love
reported a Pt-catalyzed C−F activation and functionalization
with ortho-imine as directing group.9 The similar catalysis could
also be realized with nickel or cobalt complexes.10 Weng
published the synthesis of polyfluorinated aryl ethers via ligand-
free palladium-catalyzed C−F activation of pentafluorobenzene
with phenols.11
While weak Lewis acidic magnesium reagents such as
Grignard reagents are not believed to be able to activate strong
C−F bonds, Koga explored the reaction without metal catalysts
and proposed a possible mechanism involving a four-membered
ring (Scheme 2).13 Recently, Cao described nucleophilic
substitution reaction of polyfluoroarenes with Grignard
reagents via pyridine-directed cleavage of C−F bond.14
The transition-metal-free C−C bond formation was of great
significance in practical applications. Particularly in the
pharmaceutical industry, the demand for the absence of any
transition metal impurity in final product was very strict. On the
Scheme 2. Possible Mechanism of a Four-Membered Ring
In addition, the early work with a directing group was done
by Meyers.12a Cahiez described that MnCl2 could significantly
improve the yield of the nucleophilic substitution reaction of
Grignard reagents with an aryl fluoride bearing an imino group
in the ortho-position (Scheme 1).12b With heterocyclic group as
Received: December 2, 2013
© XXXX American Chemical Society
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Letter
Table 1. ortho-Alkylation or Arylation of Perfluoroaryl Imines
a
Yield of compound 3 was based on in-situ 19F NMR spectra with (trifluoromethyl)benzene as an internal standard and was the average of 2 times
Isolated yields of 4.
b
basis of the principle of green chemistry, we launched the
research on synthesis approaches to aromatic fluorides without
transition metal catalyst.
also studied the reactions of perfluoroaryl imines (1b and 1c)
with different Grignard reagents (2b−2j) (Table 1).
Nearly all of the studied aliphatic Grignard reagents have a
desired yield in 50 °C except 2d (entry 4). The aromatic
Grignard reagents could not have an ideal result until the
temperature rose to 80 °C. Comparing the results of entry 9 to
15, it was concluded that 1c is the most active imine and 1b is
more active than 1a. A heterocyclic Grignard reagent had
similar activity with those of aliphatic and aromatic Grignard
reagents (entry 15).
In this paper, we explored the functionalization of
polyfluoroaryl imines with an aldazine-N atom as an anchoring
group. We discovered that Grignard reagents could achieve
nucleophilic substitution via C−F bond cleavage in high yield
without metal catalysts with the excellent selectivity at the
ortho-position close to the CN bond. As far as we know,
there has been no report on the imine-N atom-directed
regioselectivity of this kind nucleophilic substitution in the
range of C−F bond functionalization in the absence of metal
catalysts.
The first investigation is the reaction of N-((perfluoro-
phenyl)methylene)aniline (1a) with n-butyl MgBr (2a). Both
of the two ortho-fluorine atoms were substituted by n-butyl
within 4 h in 95% yield. After hydrolysis of 3, 2,6-dibutyl-3,4,5-
trifluorobenzaldehyde (4a) was obtained via column chroma-
tography in 85% yield. To explore the reaction universality, we
In addition to perfluoroaryl imines, we also explored the
polyfluoroaryl imines with two or three C−F bonds. While we
chose 2,4-difluoroaryl imines and 2,6-difluoroaryl imines as the
substrates, it was very difficult for us to control the selectivity
between the substitution of the ortho-F atom(s) and the
addition of CN bond. The selectivity could be improved by
changing the steric hindrance. Compounds 5 and 8 were
selected because both of them have isopropyl groups close to
the CN bond. The introduction of two ortho-isopropyl
B
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Letter
groups protected the imine group from the nucleophilic attack
of Grignard reagents.
Scheme 5. ortho-Alkylation of 2,4,5-Trifluoroaryl Imine
With the decreasing of number of F atoms on the aryl ring,
the C−F bond activation became more difficult and the
nucleophilic substitution needed longer time and higher
temperature (Schemes 3 and 4).
Scheme 3. ortho-Alkylation or Arylation of 2,4-Difluoroaryl
Imines
The nucleophilic addition product 14a was isloated from the
reaction of 1c with 2k in the yield of 73%. It is obvious that the
addition of CN bond competed with the substitution
reaction. More experimental results supported this opinion
(Scheme 6). All the imines have a common feature. An
Scheme 6. Addition Reaction of CN Bond
a
Yields of 6 was based on in-situ 19F NMR spectra with
(trifluoromethyl)benzene as an internal standard and was the average
b
of 2 times. Isolated yields of 7.
Scheme 4. ortho-Alkylation or Arylation of 2,6-Difluoroaryl
Imines
electron-withdrawing Cl atom is at the para-position in the
phenyl ring, which links to the imine-N atom. This makes the
imine-C atom more positively charged. In addition, no
substituents at 2/6-position(s) are beneficial to the nucleophilic
attack. However, the phenylated Grignard reagents could hardly
react with the CN bonds of the substrates under these
conditions. This could be explained by their weak nucleophil-
icity and relatively larger steric hindrance.
On the basis of the experimental results and literature, a
plausible mechanism was put forward on the regioselectivity of
the nucleophilic substitution reaction in Scheme 7. The first
step for the C−F bond functionalization should be the
coordination of the N atom of the CN bond to the
magnesium center in the Grignard reagent. The interaction
between the ortho-fluorine atom and the magnesium atom is
beneficial to the attack of negatively charged alkyl group of the
Grignard reagent on the ortho-carbon atom. Therefore, this six-
membered chelate ring is formed by three C atoms, one N, one
F, and one Mg atom. A new C−C bond is formed through the
nucleophilic interaction between the R group and the
electropositive carbon atom of the ortho-(C−F) bond. After
hydrolysis, the imine transforms into the aldehyde (Path
SUBSTITUTION).
It was noteworthy that the products of 8 with Grignard
reagents could be monoalkylated or diphenylated (Scheme 4).
It might be explained that the disubstitution product was
formed from the monosubstitution product. The mono-
phenylated intermediate to this nucleophilic substitution is
more active than the monoalkylated products.
With trifluorinated imine 11 the monoalkylated products,
aldehydes 12, as ortho-(C−F) bond activation products were
also isoalted in good yields (Scheme 5). This result is
consistent with the imine-N atom-directed regioselectivity of
C−F bond cleavage and C−C formation.
C
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Scheme 7. Proposed Mechanism
REFERENCES
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The nucleophilic addition of CN bond with Grignard
reagents proceeds via also the coordination of the imine-N
atom to the Mg center (Path ADDITION). This mechanism is
similar to that of the reaction between Grignard reagent and
carbonyl compound. Electron-withdrawing groups on the
imine-N-phenyl ring and the small steric hindrance are in
favor of nucleophilic addition. The yields depend on the activity
of both Grignard reagents and electrophiles.
The functionalization of the ortho-(C−F) bond of poly-
fluoroaryl imines with Grignard reagents competed with the
addition of imine group. We consider that several factors, such
as the number and the position of the F atoms, the property
(aromatic or aliphatic of Grignard reagents, the steric effect of
both substrates), play important role in this competition. In
most of the cases we mainly obtained the substitution products
in good to excellent yields, but we can not make use of the
results of this paper to sum up the reaction rule. In some cases
higher temperature is beneficial to the nucleophilic addition.
For the excellent ortho-selectivity, the imine group must play a
decisive role in the substitution.
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In summary, we report an ortho-selective nucleophilic
substitution of polyfluoroarenes with Grignard reagents via
C−F bond activation to generate fluorinated benzaldehyde
under mild conditions without transition metal catalyst. A
possible mechanism is proposed. In general, the reactions have
high yields, and the process is simply operated. This work is of
great significance for C−F bond activation and functionaliza-
tion of organic fluorides.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and full spectroscopic data
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xli63@sdu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this work by NSFC (No.21172132) is gratefully
acknowledged.
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