Synthesis of pentafluorophenylmethylamines via silicon mannich reaction

Article abstract of DOI:10.1021/ol050845l

(Chemical Equation Presented) The three-component coupling of aldehydes, secondary amines, and methoxytris(pentafluorophenyl)silane, MeOSi(C ₆F₅)₃, affording pentafluorophenylmethylamines has been described. The generation

Full text of DOI:10.1021/ol050845l

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2913-2915
Synthesis of
Pentafluorophenylmethylamines via
Silicon Mannich Reaction
Alexander D. Dilman,*,† Pavel A. Belyakov,† Alexander A. Korlyukov,‡
Marina I. Struchkova,† and Vladimir A. Tartakovsky†
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47,
Russian Federation, and A. N. NesmeyanoV Institute of Organoelement Compounds,
119991 Moscow, VaViloV str. 28, Russian Federation
adil25@mail.ru
Received April 18, 2005
ABSTRACT
The three-component coupling of aldehydes, secondary amines, and methoxytris(pentafluorophenyl)silane, MeOSi(C6F5)3, affording pentafluo-
rophenylmethylamines has been described. The generation of the five-coordinate silicate intermediate is believed to be the key feature responsible
for the efficiency of the reaction.
Amines containing, at the R-position, a perfluoroalkyl or
perfluoroaryl substituent have garnered considerable attention
Scheme 1. Synthesis of Fluorinated Amines
from the synthetic community due to their ability to serve
as potential pharmaceutical and agrochemical agents.1-3
These compounds are usually produced from imines, with
the fluorinated moiety coming either from the addition of
an appropriate nucleophile2 (path a) or from the imine itself3
(path b) (Scheme 1). However, problems associated with the
generation and reactivity of fluorinated nucleophiles, harsh
reaction conditions, and the high cost of the starting material
often limit the scope of this methodology. A more general
and straightforward approach to amines such as 1 would be
only one such reaction has been described previously; it
through three-component Mannich-type coupling of alde-
employed in situ generated titanium reagents RfTi(NEt2)3 for
hydes, amines, and a nucleophile (path c). In the literature,
the transfer of fluorinated and diethylamino groups on
aromatic aldehydes.4
† N. D. Zelinsky Institute of Organic Chemistry.
‡ A. N. Nesmeyanov Institute of Organoelement Compounds.
We became interested in performing the Mannich reaction
(1) (a) Kim, C.-Y.; Chang, J. S.; Doyon, J. B.; Baird, T. T., Jr.; Fierke,
using silicon fluorinated nucleophiles R3SiRf since (a) these
C. A.; Jain, A.; Christianson, D. W. J. Am. Chem. Soc. 2000, 122, 12125.
reagents are stable and easy-to-handle compounds, (b)
nontoxic waste is produced on workup, and (c) their
reactivity can be finely modulated by variation of the
substituents.5
(c) Faraci, W. S.; Walsh, C. T. Biochemistry 1989, 28, 431. (d) Fluorine in
Bioorganic Chemistry; Welch, C. T., Eswarakrishnan, S., Eds.; John Wiley
& Sons: New York, 1991.
(2) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77. (b)
Petrov, V. A. Tetrahedron Lett. 2000, 41, 6959.
(3) (a) Magueur, G.; Crousse, B.; Bonnet-Delpon, D. Tetrahedron Lett.
2005, 46, 2219. (b) Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M.
Chem. Commun. 2004, 1928.
(4) Chen, Q.-Y.; Wu, J.-P. J. Chem. Res., Synop. 1990, 268.
10.1021/ol050845l CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

The three-component Mannich reaction involving mod-
erately nucleophilic allylic silanes has recently been reported
and prescribed utilization of a Lewis acid for generation of
iminium cation electrophiles.6 However, fluorinated silanes,
R3SiRf, cannot be used in this process owing to their very
low nucleophilicity. According to Mayr’s reactivity scale,
the iminium ions (e.g., R2N+dCH2) have electrophilicity
parameters E from -5 to -8.7 At the same time, based on
the data of Eaborn that protodesilylation of C6F5SiMe3 occurs
ca. 105 times slower than that of C6H5SiMe3,8 the nucleo-
philicity parameter N of C6F5SiMe3 can be expected to be
well below -4. Therefore, the rate constant for direct
coupling between the iminium cation and C6F5SiMe3 will
be less than 10-9 L mol-1 s-1. To render the silicon species
more reactive an additional nucleophilic activator is required5a,9
that must be compatible with iminium carbocations. The
general mechanistic scenario for base-assisted silicon Man-
nich reaction is presented in Scheme 2.
Table 1. Variation of Silane Reagenta
entry
R3SiC6F5
yield of 4a,b %
1
2
3
4
5
6
7
Me3SiC6F5
-
-
trace
12
-
Me2Si(C6F5)2
MeSi(C6F5)3
Si(C6F5)4
(EtO)3SiC6F5
(EtO)2Si(C6F5)2
MeOSi(C6F5)3
trace
86
a The ratio of reagents PhCHO/pyrrolidine/R3SiC6F5 ) 1:1.1:1. b Isolated
yield.
the first transfer step (cf. Table 1, entry 6). The structure of
5, established by X-ray diffraction analysis (Figure 1),
features a short Si-O bond distance of 1.60 Å that may
reflect enhanced electron deficiency of the silicon atom.
Scheme 2. Silicon Mannich Reaction
The combination of aldehyde and amine first affords a
hemiaminal, which interacts with silane generating iminium
ion 2 and pentacoordinate silicon intermediate 3. Subsequent
transfer of a fluorinated group from 3 to 2 effects C,C-bond
formation providing amine 4.
We began our investigations with variation of pentafluo-
rophenylsilane nucleophile using benzaldehyde and pyrro-
lidine as model substrates, performing the reaction in
dichloromethane (Table 1). Among the different reagents
tested,10 methoxytris(pentafluorophenyl)silane (5) turned out
to be the most reactive, presumably owing to the presence
of several electron-withdrawing substituents stabilizing the
five-coordindate intermediate 3.11,12 Silane 5 can transfer only
one C6F5 group, which may be rationalized by the low
activity of the dioxy species (C6F5)2Si(OMe)OH formed after
Figure 1. X-ray structure of MeOSi(C6F5)3 (5).
The less nucleophilic morpholine reacted much slower
giving only traces of product. Variation of solvent (Table 2)
showed that polar aprotic solvents significantly accelerated
the reaction, and in addition induced the formation of
pentafluorobenzhydrol 6. The latter byproduct arises from
the transfer of C6F5 group on benzaldehyde, and contribution
of this process is most pronounced in strongly donating
DMSO and DMF. Acetonitrile, which serves as a polar and
weakly coordinating medium, was found to be the solvent
of choice for the three component coupling allowing for high
4b/6 ratio (entry 5).
(5) (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757. (b)
Weber, W. P. Silicon Reagents for Organic Synthesis; Springer: New York,
1983.
(6) (a) Ella-Menye, J.-R.; Dobbs, W.; Billet, M.; Klotz, P.; Mann A.
Tetrahedron Lett. 2005, 46, 1897. (b) Veenstra, S. J.; Schmid, P.
Tetrahedron Lett. 1997, 38, 997. (c) Billet, M.; Schoenfelder, A.; Klotz,
P.; Mann, A. Tetrahedron Lett. 2002, 43, 1453.
(7) (a) Mayr, H.; Ofial, A. R. Tetrahedron Lett. 1997, 38, 3503. (b) For
general description of Mayr’s scale, see: Mayr, H.; Kempf, B.; Ofial, A.
R. Acc. Chem. Res. 2003, 36, 66.
(8) Eaborn, C.; Treverton, J. A.; Walton, D. R. M. J. Organomet. Chem.
1967, 9, 259.
(9) (a) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.; Vyazankin,
N. S. Tetrahedron 1988, 44, 2675. (b) Prakash, G. K. S.; Mandal, M. J.
Fluorine Chem. 2001, 112, 123.
(10) Silanes from entries 1-6 can easily be obtained starting from C6F5-
MgBr and chloro- or ethoxysilanes, see: (a) Whittingham, A.; Jarvie, A.
W. P. J. Organomet. Chem. 1968, 13, 125. (b) Wall, L. A.; Donadio, R.
E.; Pummer, W. J. J. Am. Chem. Soc. 1960, 82, 4846. (c) For the synthesis
of silane 5 see Supporting Information.
(11) (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,
U.K., 1998; Vol. 2, p 1339.
(12) Formation of 2 and 3 can be considered as abstraction of hydroxide
group from the hemiaminal by the Lewis acidic silane; see: Dilman, A.
D.; Ioffe, S. L Chem. ReV. 2003, 103, 733.
2914
Org. Lett., Vol. 7, No. 14, 2005

Table 2. Optimization of Solventa
Table 3. Three-Component Couplinga
entry
solvent
4b/6b
yield of 4b,c %
1
2
3
4
5
CH2Cl2
MeOH
DMSO
DMF
trace
-
d
36
58
1:6
6.5:1
20:1
MeCN
a The ratio of reagents PhCHO/morpholine/5 ) 1:1.1:1. b Determined
by 1H NMR analysis of crude product. c Isolated yield. d Alcohol 6 was
isolated in 12% yield.
Under the optimized conditions, a variety of aldehydes
and amines entered into the silicon Mannich reaction with
MeOSi(C6F5)3 affording pentafluorophenylmethylamines 4
(Table 3). Aromatic, heteroaromatic, and aliphatic R-branched
aldehydes gave good yields of products, whereas linear
aliphatic aldehydes were not suitable partners for this
reaction, presumably due to competing aldolization. Ketones
were unreactive even in the presence of strongly nucleophilic
amines. For example, when acetophenone was used in
combination with pyrrolidine no coupling product was
detected; instead, the nucleophilic attack by the amine on
the pentafluorophenyl ring of 5 occurred yielding compound
7 after desilylative workup (Scheme 3).
Scheme 3. Interaction of 5 with Amine
a The ratio of reagents RCHO/amine/5 ) 1:1.1:1, 0.4 M, in acetonitrile
unless stated otherwise. b Isolated yield. c Performed in CH2Cl2 with RCHO/
amine/5 ) 1:1.15:1.15. d AcOH was used as additive, RCHO/amine/5/AcOH
) 1:1.1:1:1.
In summary, a new approach to fluorinated amines based
on three component coupling of aldehydes, amines, and a
fluorinated silane nucleophile has been described. The
generation of pentacoordinate silicate species is believed to
be responsible for the efficiency of the reaction. Our future
efforts will be directed toward expanding the scope of the
discovered process.
The coupling reaction is sensitive to the nature of the
amine. Thus, while pyrrolidine, piperidine, and dialkylamines
are suitable substrates, weakly nucleophilic amines such as
N-Boc-protected piperazine and N-methylethanolamine led
to moderate yields of the products. Primary amines are not
effective at all, furnishing imines as the only observable
compounds.13 Nevertheless, successful involvement of diallyl
and dibenzylamines opens up opportunities for the synthesis
of primary and secondary fluorinated amines via a selective
deprotection technique.14
Acknowledgment. This work was supported by INTAS
(Project No. 2003-55-1185). We also thank Prof. S. L. Ioffe
for start-up funding.
Supporting Information Available: Experimental pro-
cedures; spectroscopic, analytical, and X-ray data (CIF) for
the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL050845L
(13) At the same time, no reaction was observed between preformed
imines and 5. We thank the reviewer for suggesting this experiment.
(14) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
41, 2535.
Org. Lett., Vol. 7, No. 14, 2005
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