Pentafluorophenyltrifluorosilane in the silicon Mannich reaction

Article abstract of DOI:10.1016/j.tetlet.2006.06.164

The synthesis of α-C₆F₅-substituted amines by a three-component coupling reaction of C₆F₅SiF₃, aromatic aldehydes, and N-trimethylsilylamines has been elaborated. The optimized conditions include perf

Full text of DOI:10.1016/j.tetlet.2006.06.164

Tetrahedron Letters 47 (2006) 6217–6219
Pentafluorophenyltrifluorosilane in the silicon Mannich reaction
Alexander D. Dilman,* Vladimir V. Gorokhov, Pavel A. Belyakov,
Marina I. Struchkova and Vladimir A. Tartakovsky
ND Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
Received 10 April 2006; revised 20 June 2006; accepted 29 June 2006
Abstract—The synthesis of a-C6F5-substituted amines by a three-component coupling reaction of C6F5SiF3, aromatic aldehydes,
and N-trimethylsilylamines has been elaborated. The optimized conditions include performing the reaction in dimethylformamide
in the presence of stoichiometric amounts of lithium acetate.
Ó 2006 Elsevier Ltd. All rights reserved.
Amines bearing, at the a-position, fluorinated substitu-
ents may serve as potential pharmaceutical and agro-
chemical agents.1 Recently, we proposed a method
for the synthesis of a-C6F5-substituted amines via
Mannich-type coupling of aldehydes, amines and
(C6F5)3SiOMe (Scheme 1).2 The major disadvantage of
this method is that from the rather expensive reagent
(C6F5)3SiOMe, only one C6F5-group can be used, since
the resulting bis(pentafluorophenyl)silyl derivative is not
reactive.2a Herein we report a solution to this problem.
Initial experiments employing benzaldehyde and pyrrol-
idine as model substrates and performing the reaction in
acetonitrile for 2 h at room temperature were rather dis-
appointing, affording the desired product 1a in very low
yield (Table 1, entry 1). The utilization of N-trimethyl-
silylated amine led to an increase in the yield of 1a to
27% (entry 2). Since conducting the reaction for longer
times had virtually no effect, it was surmised that the
poor conversion was associated with the presence of
F3SiOSiMe3, produced as a by-product of the reaction,
which binds to benzaldehyde to form an inert acetal,
PhCH(OSiMe3)(OSiF3).
The key feature of the pentafluorophenylation reaction
is the generation of a five-coordinate siliconate inter-
mediate, which serves as a nucleophile towards the iminium
cation. Based on the ability of fluorine to exert signifi-
cant stabilization of hypercoordinate silicon species3,4
we decided to study the applicability of pentafluorophen-
yltrifluorosilane3 for the synthesis of C6F5-substituted
amines.
Table 1. Variation of conditionsa
O
2 h, r.t.
N
+
+
C6F5SiF3
Ph
N
Y
Ph
C6F5
1a
O
R
R
R
Entry
Y
H
Solv.
Additive
Yield of 1a,b
%
R
R
N
R
R2NH
N
HO
OMe
Si C6F5
R
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
—
—
py
8
27
46
55
65
46
78
20
C6F5
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
H
C6F5 C6F5
MeOSi(C6F5)3
MeO C6F5
Si
HO C6F5
2,20-bipy
py-N-oxide
—
AcOLi
AcOLi
Scheme 1.
DMF
DMF
a The ratio of reagents PhCHO/amine/C6F5SiF3/additive =
Keywords: Fluorinated silanes; Hypervalent silicon; Mannich reaction.
*
Corresponding author. Fax: +7 495 135 53 28; e-mail: adil25@
mail.ru
1:1.2:1.2:1.1.
b Isolated yield.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.164

6218
A. D. Dilman et al. / Tetrahedron Letters 47 (2006) 6217–6219
Rewardingly, a notable improvement was achieved by
addition of stoichiometric amounts of a Lewis base such
as pyridine, 2,20-bipyridine, or pyridine-N-oxide which
are capable of complexing F3SiOSiMe3 (entries 3–5).
Further experimentation revealed that lithium acetate
in dimethylformamide proved to be the best condition
for the three-component coupling, furnishing amine 1a
in 78% isolated yield (entry 7).
amine worked well. However, when the less nucleophilic
N-silylmorpholine was used in combination with benzal-
dehyde, considerable amounts of pentafluorobenz-
hydrol were observed, resulting from addition of
C6F5SiF3 to benzaldehyde promoted by lithium acetate.
Nevertheless, the target amine 1k could be obtained in
71% yield by employing pyridine-N-oxide in acetonitrile
(entry 10).
Under the optimized conditions, a series of aldehydes
and N-silylamines were reacted with C6F5SiF3 to give
a-C6F5-substituted amines5 (Table 2). Aromatic and
heteroaromatic aldehydes gave good yields of products,
whereas enolizable aliphatic aldehydes proved to be
unsuitable substrates for this reaction. Silylated amines
such as pyrrolidine, piperidine, diethylamine and diallyl-
The product 1l, derived from a-furaldehyde and N-silyl-
diallylamine, was isolated in 88% yield, but it turned out
to be unstable. Although compound 1l can be stored for
at least five days at ꢀ25 °C, it undergoes isomerization
into tricycle 2 at room temperature (15% conversion in
20 h in CDCl3) (Scheme 2). On a preparative scale this
intramolecular cycloaddition was effected by refluxing
Table 2. Three-component couplinga
NR2
2
AcOLi, DMF
Me3SiNR2
R1CHO
C6F5SiF3
+
+
R1
C6F5
2
2 h, r.t.
1
Entry
1
Aldehyde
Amine
1
Yield of 1,b
%
O
Me3Si
N
1b
1c
78
Cl
O
2
Me3SiNEt2
70
MeO
3
4
PhCHO
Me3SiNEt2
Me3SiNEt2
1d
1e
70
79
O
S
N
5
6
1f
1g
1h
1i
81
89
67
62
80
71
Me3Si
N
O
O
NSiMe3
(
)
2
MeO
Ph
O
7
Me3Si
N
N
N
N
O
8
Me3Si
Me3Si
Me3Si
O
O
9
1j
t
-Bu
10c
PhCHO
1k
O
a The ratio of reagents PhCHO/amine/C6F5SiF3/AcOLi = 1:1.2:1.2:1.1, 0.5 M in DMF, 2 h unless otherwise stated.
b Isolated yield.
c Reaction was performed in MeCN in the presence of pyridine-N-oxide for 28 h.

A. D. Dilman et al. / Tetrahedron Letters 47 (2006) 6217–6219
6219
Acknowledgements
O
AcOLi, DMF
2 h, r.t.
NSiMe3
+
+
C6F5SiF3
(
)
2
O
This work was supported by the Ministry of Science
(project MK-2235.2005.3).
O
N
PhMe, Δ, 30 min
H
N
C6F5
88%
O
Supplementary data
C6F5
2
1l
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.164.
89%
Scheme 2.
References and notes
Ha
Ha
Hb
He
O
Hb
He
O
HCl (gas.), CDCl3
1. (a) Kim, C.-Y.; Chang, J. S.; Doyon, J. B.; Baird, T. T., Jr.;
Fierke, C. A.; Jain, A.; Christianson, D. W. J. Am. Chem.
Soc. 2000, 122, 12125; (b) Faraci, W. S.; Walsh, C. T.
Biochemistry 1989, 28, 431; (c) Welch, C. T.; Eswarakrish-
nan, S. Fluorine in Bioorganic Chemistry; John Wiley &
Sons: New York, 1991.
Hg
C6F5
Hg
Hf
Hf
Hc
Hc
Hd
Hd
N
N
C6F5
Cl
H
2
2·HCl
2. (a) Dilman, A. D.; Belyakov, P. A.; Korlyukov, A. A.;
Struchkova, M. I.; Tartakovsky, V. A. Org. Lett. 2005, 7,
2913; For the use of other tris(pentafluorophenyl)silyl
derivatives as a source of nucleophilic C6F5-group towards
the iminium cation, see: (b) Dilman, A. D.; Levin, V. V.;
Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Synthesis 2006, 447; (c) Levin, V. V.; Dilman, A. D.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.;
Antipin, M. Y.; Tartakovsky, V. A. Synthesis 2006, 489.
3. Dilman, A. D.; Levin, V. V.; Karni, M.; Apeloig, Y. J. Org.
Chem., in press.
4. (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem.
Rev. 1993, 93, 1371; (b) Kost, D.; Kalikhman, I. In The
Chemistry of Organic Silicon Compounds; Apeloig, Y.,
Rappoport, Z., Eds.; Wiley: Chichester, UK, 1998; Vol. 2,
p 1339.
5. General procedure: Under an argon atmosphere, to solid
AcOLi (73 mg, 1.1 mmol) were successively added DMF
(2 mL), aldehyde (1 mmol), and N-silylamine (1.2 mmol).
The mixture was cooled to 0 °C and C6F5SiF3 (302 mg,
1.2 mmol) was added via a syringe. After stirring for 2 h at
room temperature the mixture was quenched with satd aq
Na2CO3 (0.4 mL), and diluted with excess ether. The
organic phase was decanted, washed with water (10 mL),
and the aqueous phase was washed with ether (10 mL). The
combined organic phase was dried (MgSO4), concentrated
under vacuum and purified by flash chromatography on
silica gel using hexane/ethyl acetate (see Supplementary
data for compound characterization data).
Figure 1. Summary of the NOE data based on NOE-difference and
2D-NOESY experiments.
in toluene for 30 min. Importantly, only one isomer of
2 corresponding to the exo-cycloaddition mode was
produced.
The relative stereochemistry was established on the basis
of extensive NMR measurements on compound 2 and
1
its hydrochloride salt 2ÆHCl in which the H NMR sig-
nals were better resolved (Fig. 1). In particular, the
observation of an NOE between Ha–Hb and Hc–Hd sug-
gested that the proton Hd was located trans to the oxy-
gen. The position of the C6F5-group was determined
from the NOE between protons He and Hg.
An intramolecular cycloaddition for a similar substrate
with an NO2CH2-group instead of pentafluorophenyl
has recently been described6 and required heating in
THF for seven days. Probably, the accelerating effect
of the C6F5-group is associated with its influence on
the conformational population of the substrate.
In summary, we have demonstrated that pentafluoro-
phenyltrifluorosilane can be conveniently employed in
the Mannich-type coupling of aromatic aldehydes and
N-silylamine, providing an efficient approach to a-
C6F5-substituted amines.
6. Namboothiri, I. N. N.; Ganesh, M.; Mobin, S. M.;
Gojocaru, M. J. Org. Chem. 2005, 70, 2235.