N-heterocyclic carbene-catalysed pentafluorophenylation of aldehydes

Article abstract of DOI:10.1039/c5ra05487g

N-heterocyclic carbenes have been utilized as highly efficient organocatalysts to catalyse multifluorophenylation of aldehydes with pentafluorophenyltrimethylsilane or bis(trimethylsilyl)tetrafluorobenzene to afford the corresponding fluorinated adducts in 49-99% yields.

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N-Heterocyclic Carbene-Catalysed
Pentafluorophenylation of Aldehydes
Cite this: DOI: 10.1039/x0xx00000x
GuangꢀFen Du,a,b Fen Xing,b ChengꢀZhi Gu,*b Bin Dai*b and Lin Heb
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-Heterocyclic carbenes have been utilized as highly efficient properties of a known molecule significantly, which has
organocatalysts to catalyse multifluorophenylation of become a routine strategy in new drug discovery.
aldehydes
bis(trimethylsilyl)tetrafluorobenzene
corresponding fluorinated adducts in 49-99% yields.
with
pentafluorophenyltrimethylsilane
to afford
or Therefore, the development of efficient methods for the
the introduction of fluorinated groups into organic molecules
has attracted considerable research interest.
Among
different
fluorinated
moieties,
The last decade has witnessed an explosive growth in Nꢀ
heterocyclic carbenes (NHCs) catalysis.1 As an important
type of organocatalyst, NHCs have been utilized widely in
organic synthesis. Aside from the classical benzoin
reaction2 and Stetter reaction,3 a large number of NHCs
catalysed transformations, such as homoenolate reaction
of enals,4 redox reaction of functional aldehydes,5
cycloaddition of ketenes,6 transesterification,7 Michael
addition8 and other reactions9 have been studied. To
date, three different activation modes based on the
corresponding ambiphilicity, nucleophilicity and basicity of
NHCs have been established.1d More interestingly, NHCs
exhibit extremely high reactivity toward the activation of
siliconꢀbased nucleophiles.10 For example, Song and coꢀ
workers reported that only 0.01 mol% of NHC was
enough to efficiently catalyse the cyanosilylation reaction
of TMSCN and aldehydes.11 Based on this nucleophilic
activation strategy, several NHC catalysed reactions such
as trifluoromethylation reaction,12a Mukaiyama aldol
pentafluorophenyl group is an important subset, and
compounds containing this moiety are widely utilized in
pharmaceuticals, functional material and other fields.16
The nucleophilic addition of pentafluorophenyllithium or
the Grignard reagent to carbonyl compounds is the most
straightforward approach17 for the construction of these
vital fluorinated molecules. However, many sensitive
functional groups can’t be well tolerated and the reaction
suffers from harsh reaction conditions. Therefore, the
development
pentafluorophenylation reaction is highly desirable.
The commercially available
pentafluorophenyltrimethylsilane 1a can serve as
precursor of pentafluorophenyl carbanion to react with
carbonyl compounds. TASF and the toxic KCN can
catalyse the addition reactions,18 but with very limited
substrate scope. Recently, Lam and coꢀworkers
reported19 that transition metal catalyst Cu(OAc)2—dppe
can catalyse pentafluorophenylation of aldehydes and
of
mild
and
highly
efficient
reaction,12bꢀd ring opening reaction,12e silylꢀReformasky
active
ketones.
However,
some
heteroaromatic
13
reaction,12f, 12g groupꢀtransfer polymerization
and ringꢀ
aldehydes are not suitable for the reaction. We have
developed NHCsꢀcatalysed vinylogous Mukaiyama aldol
reaction, phosphaꢀaldol reaction and silylꢀReformasky
reaction via nucleophilic activation of silylated
nucleophiles.12 We envisioned that NHCs can activate Arꢀ
Si bonds to catalyse pentafluorophenylation reaction of
aldehydes. Herein, we would like to disclose this result.
Our studies commenced with the reaction of
opening polymerization14 have been developed recently.
Despite remarkable progress made in this research field,
NHC catalysed activation of ArꢀSi bonds remains elusive.
Organofluorine compounds are widely applied in
pharmaceutical and agricultural chemistry as well as
material science.15 Owing to the special electronic
properties of fluorine, the incorporation of fluorinated
moieties can modify the biological and physiological
pentafluorophenyltrimethylsilane
1a
and
4ꢀ
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DOI: 10.1039/C5RA05487G
chlorobenzaldehyde 2a
.
To our delight, under the positions of the substituents showed no obvious impact
(1,3ꢀbis (2,6ꢀ on the reaction yields (entries 11ꢀ17). Interestingly,
catalysis of
5
mol% NHC
4
diisopropylphenyl)imidazolꢀ2ꢀylidene, IPr),20 the reaction heteroaromatic aldehydes and cinnamaldehyde were
proceeded smoothly in THF to produce the desired proved to be good candidates for the addition, releasing
product 3a in 66% yield (Table 1, entry 1). Encouraged by the desired adducts in excellent yields (entries 18ꢀ20).
this result, other common NHCs were next examined. The experiment results indicate that aliphatic aldehydes
NHCs generated in situ from imidazolium, imidazolinium underwent smooth reaction to produce the corresponding
and different bases can catalyse the reaction efficiently products in moderate to high yields (entries 21ꢀ23). It is
(Table 1, entries 2ꢀ5). Whereas NHCs derived from noteworthy that these pentafluorophenylation reactions of
thiazolium and triazolium showed very low efficiency aldehydes can be conveniently conducted on gramꢀscale
(Table 1, entries 6ꢀ8). A brief screening of reaction media without sacrificing reaction yield (entry 24).
indicated that the polar solvents of acetonitrile and
Table 2 Evaluation of aldehydes a
formdimethylamide (DMF) can give high yields (Table 1,
entries 9ꢀ12). Reduction of catalyst loading to 1 mol% led
to decrease of reaction rate, but with high yield
maintained (Table 1, entry 13).
1) 4 (5 mol%)
CH3CN, rt
2) H3O+
OH
TMSC6F5
+
RCHO
R
C6F5
1a
2
3
Entry
1
R
Time (h) Product Yieldb (%)
Table 1 Screening of reaction conditions a
2
1
2
1
1
2
2
3a
3b
3c
3d
3e
3f
88
96
93
92
94
99
94
Cl
F
F
OH
2
3
4
5
6
7
CHO
F
F
1) 5 mol% NHC
solvent
TMSC6F5
+
2) H3O+
Cl
Cl
N
F
1a
2a
Br
F
3a
Cl
Ar
NC
O2N
Cl
Ar
N
N
N
N
N
Ar
Ar
Ar
Ar
4
5
6
Ar = 2, 6ꢀ(iꢀPr)2C6H3
Ar = 2, 4, 6ꢀMe3C6H2
Ar = 2, 6ꢀ(iꢀPr)2C6H3
N
HO
3g
X
R
N
Ph
N
S
N
Cl
8
7a: R = Bn, X = Cl
7b: R = Me, X = I
8
2
3h
91
Entry
1
2
3
4
5
6
7
8
9
Conditions
4, THF
Time (h)
Yieldb (%)
66%
64%
47%
63%
55%
18%
14%
< 10%
67%
2
2
3
2
2
6
6
6
2
5, tBuOK, THF
6, tBuOK, THF
5, DBU, THF
5, Cs2CO3, THF
7a, DBU, THF
7b, DBU, THF
8, DBU, THF
4, PhCH3
9
2
4
3
3i
3j
88
95
81
H3C
10
11
H3CO
3k
OCH3
10
11
12
13c
4, CH2Cl2
4, CH3CN
4, DMF
4, CH3CN
2
2
2
12
45%
88%
84%
85%
12
13
14
1
2
1
3l
3m
3n
91
93
92
H3CO
a 1a (1.5 eq.), 2a (1.0 eq.). b Isolated yield. c Using 1 mol% NHC 4.
CH3
Cl
With the optimal reaction conditions in hand, the
generality of the reaction was next investigated and the
results are summarized in Table 2. Both aromatic and
aliphatic aldehydes can undergo the addition smoothly to
produce the corresponding products. Aromatic aldehydes
with electronꢀwithdrawing (entries 1ꢀ5), ꢀneutral (entries 6ꢀ
9), and donating groups (entries 9 and 10) can participate
in the reaction smoothly to afford the corresponding
products in excellent yields. Meanwhile, different
2 | J. Name., 2012, 00, 1-3
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15
16
17
1
1
3
3o
3p
3p
98
Br
Table 3 NHCs-catalysed dual tetrafluorophenylation of
aldehydes a
F
F
F
F
1) 4 (5 mol%)
CH3CN, rt
2) H3O+
99
93
Cl
HO
R
OH
R
+ RCHO
TMS
TMS
Cl
F
F
F
F
O
O
1b
2
9
Entry
1
R
Time (h)
2
Product
9a
Yieldb (%)
74
18
19
20
2
2
2
3q
3r
3s
92
90
92
O
S
2c
3
12
2
9a
9b
9c
9d
72
71
51
68
Cl
4
3
21
2
3t
49
H3CO
5
2
22
23
2
2
3u
3v
69
86
O
[a] Reaction conditions: 5 mol% of NHC 4, 2.0 equiv of 2, 0.3 mol L-1 of 1b,
room temperature for 2-3 h. [b] Isolated yield. [c] Using 1 mol% of NHC 4.
24c
12
3a
92
Cl
Based on the pioneering work of NHCsꢀcatalysed
nucleophilic addition of silylated reagents with carbonyl
compounds,11ꢀ12 a plausible mechanism is speculated and
[a] Reaction conditions: 5 mol% of NHC 4, 1.5 equiv of 1a, 0.3 mol L-1 of 2,
room temperature for 1-3 h. [b] Isolated yield. [c] 1a (18 mmol), 2a (15
mmol), using 1 mol% of NHC 4, anhydrous acetonitrile 10.0 mL, room
temperature for 12 h.
illustrated in Scheme
group of 1a to form a reactive hexavalent silicon species21
), which might initiate the following addition to aldehyde
and produce the desired product after acidic work up.
1. NHC attacks the trimethylsilyl
(I
We also found that
NHCs
can facilitate
tetrafluorophenylation of aldehydes efficiently (Table 3).
Under the optimized reaction conditions, 1,4ꢀ
N
N
Ar
Ar
bis(trimethylsilyl)tetrafluorobenzene 1b served as
synthon of tetrafluorobenzene dianion to undergo dual
addition with two equiv. of aldehydes to produce
a
Me
Me
Me
RCHO
Si
Me3SiC6F5 (1a)
NCMe
MeCN
C6F5
(I)
tetrafluorophenylation adducts
yields.
9 in moderated to good
C6F5
O
R
N
N
Ar
Ar
SiMe3
OH
OSiMe3
C6F5
HCl
Ar
Ar
N
N
R
C6F5
R
Scheme 1 Proposed Reaction Mechanism
Conclusions
In summary, NHCꢀcatalysed pentafluorophenylation
and dual tetrafluorophenylation of aldehydes have been
developed. The extremely mild reaction conditions,
simple procedure and high yields provide a novel and
efficient organocatalytic protocol for the incorporation of
multifluorophenyl groups into aldehydes. Further
exploration of NHCsꢀcatalysed introduction of other
fluorinated moieties are onꢀgoing in our laboratory.
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DOI: 10.1039/C5RA05487G
Notes and references
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Tianjin 300072, P. R. of China
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School of Chemistry and Chemical Engineering, Shihezi University,
Xinjiang Uygur Autonomous Region, 832000, China. Fax: (+86) 993-
2057270
E-mail: gcz_tea@shzu.edu.cn; db_tea@shzu.edu.cn
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China (No. 21262027) and the Natural Science Foundation of Shihezi
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J. Name., 2012, 00, 1-3 | 5

RSC Advances
Page 6 of 6
View Article Online
DOI: 10.1039/C5RA05487G
Graphical Abstract
N-heterocyclic carbene-catalysed pentafluorophenylation of aldehydes.
F
F
F
F
OH
F
F
F
TMS
F
F
TMS
F
TMS
HO
R
OH
R
R
F
F
F
F
F
RCHO
NHC 4 (1-5 mol%)
F
F
NHC 4 (1-5 mol%)
CH3CN, rt, 1-4 h
F
CH3CN, rt, 2-3 h
23 examples
49-99% yield
4 examples
51-74% yield
iPr
iPr
N
N
iPr
iPr
NHC 4: IPr