Mg-Promoted Double Silylation of Trifluoroacetimidoyl Chlorides. A New Entry to the Fluorinated Dianion Equivalents

Article abstract of DOI:10.1021/ol035528y

(Equation presented) A Mg(0)/Me₃SiCl system was found to be effective for the preparation of a novel fluorinated dianion equivalent. A one-pot reaction sequence involving reductive C-F and C-Cl bond cleavage reactions of trifluoroacetimidoyl ch

Full text of DOI:10.1021/ol035528y

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4297-4300
Mg-Promoted Double Silylation of
Trifluoroacetimidoyl Chlorides. A New
Entry to the Fluorinated Dianion
Equivalents
Takeshi Kobayashi, Takashi Nakagawa, Hideki Amii,* and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama UniVersity,
3-1-1 Tsushimanaka, Okayama 700-8530, Japan
uneyamak@cc.okayama-u.ac.jp
Received August 13, 2003
ABSTRACT
A Mg(0)/Me3SiCl system was found to be effective for the preparation of a novel fluorinated dianion equivalent. A one-pot reaction sequence
involving reductive C−F and C−Cl bond cleavage reactions of trifluoroacetimidoyl chlorides afforded bis-silylated difluoroenamines. Subsequent
carbon−carbon bond-forming reactions of the bis(silyl)enamines with two kinds of electrophiles gave a variety of difluorinated imines.
An acyl anion equivalent is of great interest as an intermedi-
ate for nucleophilic introduction of the acyl group into
organic molecules.1 A highly functionalized acyl anion is
especially attractive because it provides direct access to the
multifunctionalized ketones. (1-Siloxyvinyl)silane 1a2 and
(1-siloxyvinyl)stannane 1b3 are synthetically useful dianion
equivalents which function not only as acyl anions but also
as enolate anions. However, in general, multistep procedures
have been used for the introduction of silicon and tin atoms
into the dianion equivalents 1a and 1b.
useful synthons in accessing the fluorinated ketones and their
derivatives. And in recent years, gem-difluorinated organic
compounds have received considerable attention because
many of these compounds exhibit interesting biological
activities and high performance in medicinal chemistry such
as anticancer agent gemcitabine,11 HIV-1 protease inhibi-
tors,12 phosphotyrosine (pTyr) mimetics,13 and fluorinated
sugars.14 Accordingly, there has been a growing interest in
developing new difluorinated building blocks for the syn-
thesis of the gem-difluorinated compounds. Percy demon-
strated the preparations of 2a and 2b and their utilization
for a variety of difluorinated compounds.8
(4) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds. Biochemical
Frontiers of Fluorine Chemistry; American Chemical Society: Washington,
DC, 1996. (b) Filler, R.; Kobayashi, Y., Eds. Biomedicinal Aspects of
Fluorine Chemistry; Kodansha Ltd. and Elsevier Biomedical Press: Tokyo
and Amsterdam, 1982. (c) Welch, J. T. Tetrahedron 1987, 43, 3123. (d)
Walsh, C. Tetrahedron 1982, 38, 871. (e) Stremler, K. E.; Poulter, C. D. J.
Am. Chem. Soc. 1987, 109, 5542. (f) Resnati, G. Tetrahedron 1993, 49,
9385. (g) Iseki, K.; Kobayashi, Y. J. Synth. Org. Chem. Jpn. 1994, 52, 40.
(h) Iseki, K.; Kobayashi, Y. ReV. Heteroat. Chem. 1995, 15, 211.
(5) (a) Jin, F.; Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 33, 1221. (b)
Jin, F.; Xu, Y. J. Fluorine Chem. 1993, 62, 207. (c) Jin, F.; Xu, Y.; Huang,
W. J. Chem. Soc., Chem. Commun. 1993, 814. (d) Jin, F.; Xu, Y.; Huang,
W. J. Chem. Soc., Perkin Trans. 1 1993, 795.
In synthetic organofluorine chemistry, the fluorinated acyl
anions and their equivalents5-10 have been regarded as highly
(1) Ager, D. J. In Umpoled Synthons: A SurVey of Sources and Uses in
Synthesis; Hase, T. A., Ed.; Wiley: New York, 1987; p 19.
(2) (a) Bassindale, A. R.; Brook, A. G.; Harris, J. J. Organomet. Chem.
1975, 90, C6. (b) Murai, S.; Ryu, I.; Iriguchi, J.; Sonoda, N. J. Am. Chem.
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50, 5410. (d) Yamamoto, Y.; Ohno, M.; Eguchi, S. Tetrahedron 1994, 50,
7783.
(3) (a) Verlhac, J. B.; Pereyre, M.; Shin, H. A. Organometallics 1991,
10, 3007. (b) Verlhac, J. B.; Kwon, H.; Pereyre, M. J. Organomet. Chem.
1992, 437, C13. (c) Barbero, A.; Pulido, F. J. Synlett 2001, 827.
(6) Bordeau, M.; Clavel, P.; Barba, A.; Berlande, M.; Biran, C.; Roques,
N. Tetrahedron Lett. 2003, 44, 3741.
(7) Dubuffet, T.; Sauvetre, R.; Normant, J.-F. Bull. Soc. Chim. Fr. 1989,
677.
10.1021/ol035528y CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/18/2003

Scheme 1
Herein, we report a one-pot preparation of new gem-
difluorinated dianion equivalents 3 involving reductive C-F
and C-Cl bond cleavage reactions of trifluoroacetimidoyl
chlorides 4.15 Mg(0)-promoted double silylation of 4 in a
one-pot procedure provided bis-silylated difluoroenamines
3 serving as both an acyl anion synthon and an enolate
synthon.
quently under mild conditions; each reaction was completed
within 30 min. As shown in Scheme 1, the presence of
electron-withdrawing and electron-donating substituents on
the N-aryl groups in 4 had little effect on the yields of 3.
Notably, Cl-arene functionalities in 3d and 3e were compat-
ible under the present reaction conditions.
The formation of 3 can be explained by assuming the
pathway pictured in Scheme 2. Initially, the reductive
The preparation of the requisite dianion equivalents 3 is
very simple. When imidoyl chlorides 4 were treated with
Mg metal (8 moleequiv to 4) and chlorotrimethylsilane (4
equiv) in distilled THF at 0 °C for 30 min, the dehalogenative
double silylation reactions proceeded smoothly to afford bis-
silylated difluoroenamines 3 in high yields (Scheme 1). Both
C-F and imidoyl C-Cl bonds in 4 were cleaved subse-
Scheme 2
(8) (a) Patel, S. T.; Percy, J. M.; Wilkes, R. D. Tetrahedron 1995, 51,
9201. (b) Howarth, J. A.; Owton, W. M.; Percy, J. M. J. Chem. Soc., Chem.
Commun. 1995, 757. (c) Howarth, J. A.; Owton, W. M.; Percy, J. M.; Rock,
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H. Chem. Lett. 1991, 961. (e) Ichikawa, J.; Hamada, S.; Sonoda, T.;
Kobayashi, H. Tetrahedron Lett. 1992, 33, 337. (f) Okada, Y.; Minami, T.;
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T.; Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1992, 33, 3779. (h)
Ichikawa, J.; Ikeura, C.; Minami, T. Synlett 1992, 739. (i) Ichikawa, J.;
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1993, 34, 1941. (b) Tamura, K.; Yan, F.-Y.; Sakai, T.; Uneyama, K. Bull.
Chem. Soc., Jpn. 1994, 67, 300. (c) Watanabe, H.; Yan, F.-Y.; Sakai, T.;
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Sadamune, K. J. Org. Chem. 1996, 61, 6055.
(11) Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.; Laikin,
R. E.; Hunt, A. H. Synthesis 1992, 565.
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burger, J. M.; Neises, B.; Flynn, G.; Remy, J. M.; Tarnus, C. Bioorg. Med.
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references therein.
cleavage of C-Cl bonds of the imidoyl chlorides 4 took
place to generate imidoylmagnesium species 5, which reacted
with chlorotrimethylsilane to provide the imidoylsilanes 6.16,17
Subsequent two-electron reduction of the imidoylsilanes 6
afforded the â-fluorinated organomagnesium species 7, which
readily underwent â-elimination to form 3.
An interesting feature of the present “one-pot” reactions
is the double functionalization of imidoyl C-Cl bonds and
C-F bonds of 4 which possess their different nature.
Generally, C-Cl bonds of acyl chlorides and imidoyl
chlorides are highly reactive toward nucleophiles. Due to
the aggressive nature of their C-Cl bonds, these compounds
have been widely used for the electrophilic introduction of
acyl and imidoyl groups into organic molecules. On the
contrary, a C-F bond is known to be strong; the cleavage
of a C-F bond is not easy due to the large bond energy (ca.
552 kJ mol-1).18 However, the bond breaking does rather
easily occur when a CF3 group is attached to the π-electron
system because electron acceptance into the π-system and
subsequent extrusion of a fluoride ion may make large
(14) (a) Barnett, J. E. D. Carbon-Fluorine Compounds; Elsevier:
Amsterdam, The Netherlands, 1972. (b) Taylor, N. F., Ed. Fluorinated
Carbohydrates; American Chemical Society: Washington, DC, 1996.
(15) (a) Uneyama, K. J. Fluorine Chem. 1999, 97, 11. (b) Tamura, K.;
Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama, K. J. Org. Chem. 1993,
58, 32.
(16) Bourgeois, P.; Dunogues, J.; Duffaut, N.; Lapouyade, P. J. Orga-
nomet. Chem. 1974, 80, C25.
(17) The formation of the imidoylsilane 6b (Ar ) PMP) was observed
by conducting the reaction with a reduced amount of Mg (3 equiv) at much
lower temperature (-75 °C).
4298
Org. Lett., Vol. 5, No. 23, 2003

contributions to the driving force of the reaction.19 Both
electrochemical reduction20 and chemical reduction by the
use of Mg metal21 were found to be effective for the selective
defluorination of trifluoromethyl ketones, imines, and tri-
fluoroacetates. These reductive C-F bond cleavage reactions
were applied successfully to the preparation of difluoro-
methylene building blocks.
Table 1. Lewis Acid-Catalyzed C-C Bond Formation of 3b
with Carbonyl Compoundsa
R1R2CdO
entry
R1
R2
8
yield (%)b
1
2
3
4
5
6
7
8c
Ph
H
H
H
H
H
H
H
Me
8a
8b
8c
8d
8e
8f
88
84
86
87
85
59
87
40
4-MeOC6H4
4-ClC6H4
2-furyl
2-thienyl
(E)-PhCHdCH
i-Pr
By means of the successive double dehalogenation reac-
tions as shown above, the resultant bis-silylated difluoro-
enamines 3 are very promising bifunctional synthetic blocks,
which have not only N-silylenamine skeletons but also
R-aminovinylsilane skeletons. An interesting application of
3 is represented by chemoselective sequential transformations
with different electrophiles (3 f 8 f 9 in eq 1). First, the
reactions of 3 with electrophiles (E1) by utilizing the
properties of difluoroenamine would provide the difluorinated
imidoyl silanes 8. Second, the resulting imidoyl silanes 8
would undergo in turn the reactions with other electrophiles
(E2) by utilizing the properties of imidoylsilane, giving a
wide variety of difluorinated iminoacyl compounds 9.
The first stage of the reaction sequence involved the Lewis
acid-catalyzed aldol-type reaction of bis(silyl)enamines 3.
In each case, C-C bond formation with high chemoselec-
tivity at the â-carbon atom of 3b has been accomplished
(Table 1). Treatment of enamine 3b with various aldehydes
in the presence of BF3 etherate in CH2Cl2 at 0 °C provided
â-hydroxy-R,R-difluoro imidoylsilanes 8a-g in moderate to
high yields (entries 1-7). With R,â-unsaturated aldehyde,
enamine 3b selectively underwent 1,2-addition (entry 6). In
contrast, the reaction of 3b with acetone gave the corre-
sponding adduct 8h in 40% yield (entry 8).
8g
8h
Me
a Unless noted, each reaction was carried out at 0 °C for 1.5 h by the
use of aldehyde (1.2 equiv) and BF3‚OEt2 (1.2 equiv). b Isolated yields.
c The reaction was carried out at 0 °C for 30 min by the use of acetone (4
equiv) and BF3‚OEt2 (4 equiv).
The aldol-type reactions of 3b with aldehydes and ketones
afforded â-hydroxy imidoylsilanes 8a-h, new fluorinated
acyl anion equivalents possessing both difluoromethylene and
hydroxy groups. Instead of aldehydes, aldimines were used
as an electrophile in these reactions providing the amino
group-containing acyl anion equivalents. In the presence of
BF3‚OEt2, the aldol reaction of 3b worked well with
N-benzylideneaniline to give the corresponding â-amino-R,R-
difluoro imidoylsilane 8i in 79% yield (Scheme 3). Further-
Scheme 3
(18) (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem. ReV.
1994, 94, 373. (b) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem. Ber.
Recl. 1997, 130, 145. (c) Richmond, T. G. In ActiVation of UnreactiVe Bonds
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S.; Troupel, M. Synthesis 1990, 369. (b) Saboureau, C.; Troupel, M.; Sibille,
S.; Pe´richon, J. J. Chem. Soc., Chem. Commun. 1989, 1138. (c) Andrieux,
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C.; Serein-Spirau, C. F.; Bordeau, M.; Roques, N.; Marzouk, H. Synthesis
1999, 829. (e) Stepanov, A. A.; Minyaeva, T. V.; Martynov, B. I.
Tetrahedron Lett. 1999, 40, 2203. (f) Clavel, P.; Biran, C.; Bordeau, M.;
Roques, N.; Tre´vin, S. Tetrahedron Lett. 2000, 41, 8763. (g) Clavel, P.;
Lessene, G.; Biran, C.; Bordeau, M.; Roques N.; Tre´vin, S.; de Montauzon,
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Lett. 1998, 39, 3741. (b) Uneyama, K.; Kato, T. Tetrahedron Lett. 1998,
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Commun. 1999, 1323. (b) Amii, H.; Kobayashi, T.; Uneyama, K. Synthesis
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more, the reaction of 3b with the Schiff base of ethyl
glyoxylate22 gave a fascinating acyl anion equivalent 8j
endowed with an R-amino acid moiety.
These successful results of selective functionalizations of
bis(silyl)enamines 3 at the â-carbon atoms with various
electrophiles encouraged us in our own pursuit of further
synthetic applications. In general, an imidoylsilane per se is
a stable compound, but it is amenable to a reaction as an
acyl anion equivalent in the presence of fluoride ion.10d
(22) Tietze, L. F.; Bratz, M. Synthesis 1989, 439.
Org. Lett., Vol. 5, No. 23, 2003
4299

We have explored iodination of O-protected imidoylsilane
8a′ as a synthetically useful transformation. Upon treatment
with 1.1 equiv of KF, the reaction of 8a′ with I2 (1.2 equiv)
proceeded cleanly at 0 °C to afford the corresponding imidoyl
iodide 9 in 96% yield (Scheme 4). A particularly good use
at room temperature for 20 h in the presence of a catalytic
amount of Pd2(dba)3‚CHCl3 to provide imino esters 10a (R
) Et) and 10b (R ) Bn) in almost quantitative yields.
In conclusion, the novel fluorinated synthetic blocks 3
were obtained from trifluoroacetimidoyl chlorides 4, which
were readily prepared by refluxing a mixture of commercially
available trifluoroacetic acid, arylamines, PPh3, and Et3N in
CCl4.15b The double silylation of 4 with use of only a Mg/
Me3SiCl system allowed selective formation of the dianion
equivalents 3. The chemoselective homologation sequences
of 3 acting as enolate and acyl anion equivalents were
accomplished. Thus, the protocols involving one-pot cleavage
of both C-F and C-Cl bonds, introduction of two silyl
groups, and their individual transformations greatly expanded
the scope of the fluorinated building blocks in synthetic
organic chemistry.
Scheme 4
Acknowledgment. This work has been supported by the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan (Grant-in-Aid for Scientific Research (B), No.
13555254, Grant-in-Aid for Young Scientists (B), No.
14750684, and Grant-in-Aid for Scientific Research on
Priority Areas (“Reaction Control of Dynamic Complexes”),
No. 15036249). We also thank the SC-NMR laboratory of
Okayama University for 19F NMR analysis.
of the iodination product 9 is made for transition metal
catalyzed C-C bond formation.23 Pd-catalyzed carboalkoxy-
lation reactions of imidoyl iodide 9 would provide the
iminoesters 10, promising precursors of the highly function-
alized R-amino acids.24 Under a CO atmosphere, the imidoyl
iodide 9 smoothly underwent the carboalkoxylation reactions
Supporting Information Available: Experimental pro-
cedures and details of compound characterization for com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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