Trifluoromethylation of N-benzoylhydrazones

Article abstract of DOI:10.1021/jo800782w

(Chemical Equation Presented) A method for the nucleophilic trifluoromethylation of N-benzoylhydrazones using Me₃SiCF ₃/AcONa has been described. The C=N bond of the hydrazones is activated by difluoroboron group, which is introduced by means of boron trifluoride and allylsilane.

Full text of DOI:10.1021/jo800782w

applicable to a wide variety of compounds such as aldehydes,
ketones, esters, and lactones.2,5 At the same time, analogous
addition to the CdN bond is quite limited in scope, owing to
low electrophilicity of the azomethine fragment, and only certain
imines,5b,6 nitrones,7 and iminium salts8 can be successfully
trifluoromethylated. Reactions of fluorinated silanes with hy-
drazones have not been documented.
Trifluoromethylation of N-Benzoylhydrazones
Alexander D. Dilman,*,† Dmitry E. Arkhipov,†
Vitalij V. Levin,† 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
Our group has focused on the reactions of fluorinated silanes
with various imines and iminium ions.8a,b,9 Recently we
described an approach for the activation of the CdN bond
through the intramolecular complexation with Lewis acidic
difluoroboryl group, which enables the interaction of poorly
reactive N-alkylimines with Me3SiCF3 in the presence of Lewis
base.10 Herein we report the application of this methodology
toward the trifluoromethylation of N-acylhydrazones.
adil25@mail.ru
ReceiVed April 8, 2008
N-Acylhydrazones are known to serve as useful templates in
a number of allylation,11 cycloaddition,12 and radical addition13
processes proceeding through the five-membered chelate struc-
tures. In this respect, we proposed that the difluoroboron
complex bearing activated CdN bond would be amenable to
coupling with the Me3SiCF3/Lewis base system.
(5) For recent studies, see: (a) Prakash, G. K. S.; Panja, C.; Vaghoo, H.;
Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A.
J. Org. Chem. 2006, 71, 6806. (b) Kawano, Y.; Kaneko, N.; Mukaiyama, T.
Bull. Chem. Soc. Jpn. 2006, 79, 1133. (c) Mizuta, S.; Shibata, N.; Akiti, S.;
Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett. 2007, 9, 3707. (d) Fustero, S.;
Albert, L.; Acena, J. L.; Sanz-Cervera, J. F.; Asensio, A. Org. Lett. 2008, 10,
605.
A method for the nucleophilic trifluoromethylation of N-
benzoylhydrazones using Me3SiCF3/AcONa has been de-
scribed. The CdN bond of the hydrazones is activated by
difluoroboron group, which is introduced by means of boron
trifluoride and allylsilane.
(6) (a) Felix, C. P.; Khatimi, N.; Laurent, A. Tetrahedron Lett. 1994, 35,
3303. (b) Petrov, V. A. Tetrahedron Lett. 2000, 41, 6959. (c) Prakash, G. K. S.;
Mandal, M.; Olah, G. A. Synlett 2001, 77. (d) Prakash, G. K. S.; Mogi, R.;
Olah, G. A. Org. Lett. 2006, 8, 3589. (e) Kirij, N. V.; Babadzhanova, L. A.;
Movchun, V. N.; Yagupolskii, Y. L.; Tyrra, W.; Naumann, D.; Fischer, H. T. M.;
Scherer, H. J. Fluorine Chem. 2008, 129, 14. (f) Blazejewski, J.-C.; Anselmi,
E.; Wilmshurst, M. Tetrahedron Lett. 1999, 40, 5475. For trifluoromethylation
of imines with other reagents, see refs 3a-d
(7) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001, 66, 2572.
(8) (a) Levin, V. V.; Kozlov, M. A.; Song, Y.-H.; Dilman, A. D.; Belyakov,
P. A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2008, 49, 3108.
(b) Dilman, A. D.; Gorokhov, V. V.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Russ. Chem. Bull. 2007, 56, 1522. For reactions of pyridinium
and quinolinium salts, see: (c) Loska, R.; Majcher, M.; Makosza, M. J. Org.
Chem. 2007, 72, 5574.
Methods for the introduction of trifluoromethyl group into
organic molecules using the Ruppert-Prakash reagent
(Me3SiCF3)1 have gained considerable attention in recent years2,3
due to the importance of CF3-containing products for the
pharmaceutical and agrochemical industries.4
The most elaborated reaction of Me3SiCF3 is the Lewis base-
mediated nucleophilic addition to carbonyl group, which is
(9) For reactions of C6F5-group transfer, see: (a) Dilman, A. D.; Belyakov,
P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. Org. Lett. 2005,
7, 2913. (b) Dilman, A. D.; Levin, V. V.; Karni, M.; Apeloig, Y. J. Org. Chem.
2006, 71, 7214. (c) Dilman, A. D.; Levin, V. V.; Belyakov, P. A.; Struchkova,
M. I.; Tartakovsky, V. A. Synthesis 2006, 447. (d) Levin, V. V.; Dilman, A. D.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Antipin, M. Y.;
Tartakovsky, V. A. Synthesis 2006, 489. (e) Levin, V. V.; Dilman, A. D.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A.
MendeleeV Commun. 2007, 105. (f) Dilman, A. D.; Gorokhov, V. V.; Belyakov,
P. A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2006, 47, 6217.
(g) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky,
V. A. Tetrahedron Lett. 2006, 47, 8959.
† N.D. Zelinsky Institute of Organic Chemistry.
‡ A.N. Nesmeyanov Institute of Organoelement Compounds.
(1) (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 24,
2195. (b) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
1989, 111, 393.
(2) For reviews on the chemistry of Me3SiCF3, see: (a) Prakash, G. K. S.;
Yudin, A. K. Chem. ReV. 1997, 97, 757. (b) Prakash, G. K. S.; Mandal, M. J.
Fluorine Chem. 2001, 112, 123. (c) Singh, R. P.; Shreeve, J. M. Tetrahedron
2000, 56, 7613.
(3) For reactions of nucleophilic trifluoromethylation using other reagents,
see: (a) Xu, W.; Dolbier, W. R., Jr J. Org. Chem. 2005, 70, 4741. (b) Pooput,
C.; Dolbier, W. R., Jr.; Medebielle, M. J. Org. Chem. 2006, 71, 3564. (c)
Motherwell, W. B.; Storey, L. J. J. Fluorine Chem. 2005, 126, 489. (d)
Yokoyama, Y.; Mochida, K. Tetrahedron Lett. 1997, 38, 3443. (e) Langlois,
B. R.; Billard, T.; Roussel, S. J. Fluorine Chem. 2005, 126, 173. (f) Langlois,
B. R.; Billard, T. Synthesis 2003, 185. (g) Nowak, I.; Robins, M. J. J. Org.
Chem. 2007, 72, 2678. (h) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128,
975.
(10) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.; Belyakov, P. A.;
Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. J. Org. Chem. 2007,
72, 8604.
(11) (a) Kobayashi, S.; Sugiura, M.; Ogawa, C. AdV. Synth. Catal. 2004,
346, 1023. (b) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc.
2003, 125, 9596. (c) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc.
2004, 126, 5686.
(4) (a) Dolbier, W. R. J. Fluorine Chem. 2005, 126, 157. (b) Fluorine in
Bioorganic Chemistry; Welch, C. T., Eswarakrishnan, S., Eds; John Wiley &
Sons: New York, 1991. (c) Hiyama, T. Organofluorine Compounds. In Chemistry
and Applications; Springer: Berlin, 2000. (d) Uneyama, K. Organofluorine
Chemistry; Blackwell Publishing: Oxford, UK, 2006. (e) Mu¨ller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (f) Thayer, A. M. Chem. Eng. News
2006, 84, 15. (g) Thayer, A. M. Chem. Eng. News 2006, 84, 27.
(12) (a) Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi,
J. J. Am. Chem. Soc. 2002, 124, 13678. (b) Kobayashi, S.; Hirabayashi, R.;
Shimizu, H.; Ishitani, H.; Yamashita, Y. Tetrahedron Lett. 2003, 44, 3351. (c)
Shirakawa, S.; Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127,
9974.
(13) Friestad, G. K.; Marie, J.-C.; Suh, Y. S.; Qin, J. J. Org. Chem. 2006,
71, 7016.
10.1021/jo800782w CCC: $40.75
Published on Web 06/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5643–5646 5643

These experiments prompted us to surmise that the decreased
yields are associated with the presence of ammonium salts.15
To circumvent this problem we proposed a different approach
for the difluoroborylation. Thus, treatment of hydrazone 1a with
BF3 ·OEt2 and allyltrimethylsilane cleanly proceeded in chlo-
rinated solvents affording the complex 2a, with propene and
Me3SiF being the sole byproducts (eq 3).
FIGURE 1. X-ray structure of complex 2a presented in thermal
ellipsoids at 50% probability.
For initial evaluation, N-benzoylhydrazone of benzaldehyde
(1a) was selected as a model substrate. The silylation of 1a
followed by treatment of crude silylhydrazone with boron
trifluoride etherate afforded difluoroboron complex 2a in 72%
yield after recrystallization (eq 1). The complex 2a was
characterized by NMR spectroscopy and X-ray diffraction
analysis (Figure 1). It should be noted, that compound 2a is
the first well-defined boron-hydrazone complex.14
Although in the case of 1a the difluoroborylation occurred
within 30 min at room temperature, for some other substrates
brief heating was required. Consequently, the reflux in dichlo-
roethane for 5 min was selected as a general procedure for the
formation of boron complexes. Evaporation of solvent followed
by addition of DMF, Me3SiCF3, and sodium acetate furnished
compound 3a in 94% yield.16
To probe the influence of the acyl group on the efficiency of
the reaction, hydrazones 4a-c bearing at nitrogen different
substituents were evaluated under similar conditions (eq 4).
Although in the case of acetyl group a reasonable yield of 75%
was obtained, substrates with formyl and methoxycarbonyl
groups gave products in notably decreased yields.
It was rewarding to find that treatment of 2a with Me3SiCF3
and sodium acetate in DMF at room temperature afforded
desired product 3a in excellent yield after aqueous workup (eq
2). In this process, acetate anion behaves as a Lewis basic
activator of the silicon reagent.
A variety of N-benzoylhydrazones were involved in the
trifluoromethylation reaction using the BF3 ·OEt2/allylsilane
system for the generation of difluoroboron complexes (Table
1, method A). Hydrazones derived from aromatic, R,ꢀ-unsatur-
ated, heteroaromatic, and R-branched aldehydes furnished very
good yields of products (entries 1-8). However, reactions of
R-unbranched substrates were accompanied by unidentified
impurities, removal of which by conventional column chroma-
tography was problematic.17 In this case, employment of
silylation and silicon-boron exchange for the generation of
borane complexes (method B) cleanly provided the desired
trifluoromethylated products (entries 10, 12).
N-Benzoylhydrazones obtained from typical ketones were also
tested in the trifluoromethylation process (Table 2). Although
the formation of boron complexes proceeded cleanly, they
proved to be significantly less reactive compared to aldehyde-
derived counterparts, and elevated temperatures (50-55 °C)
were required for their reactions with Me3SiCF3. Hydrazones
of cyclohexanone, cyclopentanone, and acetone worked quite
well, whereas lower yields were noted for acetophenone and
cyclopropylmethyl ketone hydrazones.18
The three-step synthesis of 3a can be performed without
purification of intermediate silylhydrazone and complex 2a with
the overall yield of 88%. However, this procedure is inconve-
nient, since it requires handling of moisture-sensitive silylhy-
drazone, the isolation of which even in crude form involves
filtration under argon.
To find a more practical protocol obviating complicated steps
we attempted to perform silylation and silicon-boron exchange
in one reaction flask followed by reaction with Me3SiCF3/
AcONa. Disappointingly, after extensive variation of stoichi-
ometry, order of mixing, solvent, and temperature, the yields
of 3a not exceeding 75% were achieved. Application of the
borylation procedure using EtN(i-Pr)2 and BF3 ·OEt2 that we
reported earlier for salicyl aldimines10 also gave only 40% yield
of the product.
(16) Difluoroborylation with BF3 · OEt2 and allyltrimethylsilane cannot be
performed in DMF, presumably due to high Lewis basicity of this solvent.
(17) We may propose that the side products originate from cycloaddition of
boron complex with allylsilane, see ref 12b. However, when hydrazone 1j,
BF3 · OEt2, and allylsilane were refluxed in dichlorethane for 6.5 h, a complex
mixture was formed.
(18) The reactions of these substrates provided complex mixtures, which may
be associated with enolization of the methyl group followed by interaction of
enamine fragment with the difluoroboryl group.
(14) Silicon and tin hydrazone complexes are known; see refs 11c and (a)
Kalikhman, I.; Gostevskii, B.; Girshberg, O.; Sivaramakrishna, A.; Kocher, N.;
Stalke, D.; Kost, D. J. Organomet. Chem. 2003, 686, 202. (b) Dey, D. K.; Lycka,
A.; Mitra, S.; Rosair, G. M. J. Organomet. Chem. 2004, 689, 88.
(15) Ammonium salt may inhibit either formation or reaction of difluoroboron
complex. For example, mixing of 2a with Et3NHCl, Me3SiCF3, and AcONa gave
product in only 82% yield.
5644 J. Org. Chem. Vol. 73, No. 14, 2008

TABLE 1. Trifluoromethylation of N-benzoylhydrazones 1a
TABLE 2. Trifluoromethylation of N-benzoylhydrazones 6
a Isolated yield.
TABLE 3. Variation of fluorinated silanes
a Conditions for the reaction of boron complexes with silanes.
b Isolated yield.
from aldehydes are the best substrates for the reaction, leading
to the fluorine-containing products inaccessible by other means.
The intermediacy of the difluoroboron complexes constitutes
the key feature of the reaction.
a Method A: 1: BF3 ·OEt2: allylsilane ) 1: 1.5: 1.5. Method B: 1:
NEt3: Me3SiCl: BF3 ·OEt2 ) 1: 1.2: 1.2: 1.2. For the second step, 2
equiv Me3SiCF3, 4 equiv AcONa. b Isolated yield. c Determined by
NMR spectroscopy.
Experimental Section
Besides the trifluoromethyl group, various other fluorinated
substituents can be transferred from corresponding silanes,
as demonstrated for the hydrazone 1a (Table 3, entries 1-3).
Even poorly reactive trifluorovinylsilane19 was used as a
source of trifluorovinyl fragment when reaction was carried
out at harsher conditions (entry 4). At the same time, the
reaction with the ketone hydrazone 6c turned out to be
notably less efficient (entry 5).20
General Procedures for the Trifluoromethylation of
N-Benzoylaldohydrazones. Method A. Allyltrimethylsilane
(166 µL, 1.05 mmol) and BF3 ·OEt2 (133 µL, 1.05 mmol) were
successively added to a suspension of N-bezoylhydrazone (0.7
mmol) in 1,2-dichloroethane (1.4 mL), and the mixture was
heated at gentle reflux for 5 min. The solvent was evaporated
in vacuum, the residue was dissolved in DMF (1.4 mL) followed
by addition of Me3SiCF3 (207 µL, 1.4 mmol) and NaOAc (230
mg, 2.8 mmol). The mixture was stirred for 2 h at room
temperature, quenched with 1 mL of saturated aqueous Na2CO3,
and stirred for additional 5 min. The mixture was diluted with
water (∼10 mL) and extracted with ether (for 3a-c,e,g-k) or
ethyl acetate (for 3d,f) (4 × 4 mL). The combined organic phase
was dried with Na2SO4, concentrated, and the residue was flash
chromatographed on silica gel.
In summary, a convenient method for the addition of a
trifluoromethyl group, as well other fluorinated fragments, to
N-benzoylhydrazones has been described. Hydrazones derived
(19) Ritter, S. K.; Kirchmeier, R. L.; Shreeve, J. M.; Oberhammer, H. Inorg.
Chem. 1996, 35, 4067.
(20) The low yield is due to incomplete conversion. This is likely owing to
increased steric interactions upon the C-C bond-forming event between
ketohydrazone electrophile and pentafluorophenyl nucleophile.
J. Org. Chem. Vol. 73, No. 14, 2008 5645

Method B. Chlorotrimethylsilane (306 µL, 2.4 mmol) was
added in one portion to a vigorously stirred mixture of hydrazone
(2 mmol) and NEt3 (334 µL, 2.4 mmol) in CH2Cl2 (4 mL). The
resulting suspension was stirred for 10 min and then evaporated
in vacuum. The residue was extracted with hexane (3 × 5 mL),
filtering the hexane phases under argon, and the combined
hexane extracts were concentrated, affording silylhydrazone as
an oil. The crude silylhydrazone was dissolved in 1,2-dichlo-
roethane (2 mL), and BF3 ·OEt2 (304 µL, 2.4 mmol) was added.
This mixture was refluxed for 5 min and then concentrated in
vacuum. The residue was dissolved in DMF (4 mL) followed
by successive addition of Me3SiCF3 (443 µL, 3.0 mmol) and
NaOAc (492 mg, 6.0 mmol). The mixture was stirred for 2 h at
room temperature, quenched with 2 mL of saturated aqueous
Na2CO3, and worked up as described in Method A.
7.70 (dd, 2H, J ) 7.6, 1.5), 8.01 (d, 1H, J ) 5.8). 13C NMR
(75 MHz, CDCl3), δ: 66.7 (q, J ) 27.8), 125.0 (q, J ) 281.4),
127.0, 128.6, 128.7, 128.9, 129.6, 131.9 (q, J ) 1.7), 132.1,
132.2, 167.8. 19F NMR (282 MHz, CDCl3) δ: -73.8 (d, J )
6.9). Calcd for C15H13F3N2O (294.27): C 61.22, H 4.45, N 9.52.
Found: C 61.24, H 4.50, N 9.24.
Acknowledgment. This work was supported by the Ministry
of Science (Project MK-4483.2007.3), Russian Academy of
Sciences (Program #8), Russian Science Support Foundation,
and the Russian Foundation for Basic Research (Project 08-
03-00428).
Supporting Information Available: Experimental proce-
dures; spectroscopic, analytical, and X-ray data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
N′-(2,2,2-Trifluoro-1-phenylethyl)benzohydrazide (3a). Chro-
matography: hexanes/EtOAc, 3:1, Rf ) 0.32 (hexane/EtOAc,
1
3:1). Mp ) 97-98 °C. H NMR (300 MHz, CDCl3), δ: 4.61
(q, 1H, J ) 6.9), 5.15 (d, 1H, J ) 5.8), 7.31-7.57 (m, 8H),
JO800782W
5646 J. Org. Chem. Vol. 73, No. 14, 2008