A facile new method for the two-step substitution of hydroxy groups in primary alcohols for trifluoromethyl and pentafluoroethyl moieties

Article abstract of DOI:10.1055/s-2001-11390

In an efficient procedure the nucleophilic trifluoromethylation and pentafluoroethylation of alkyl triflates using (trifluoromethyl)- and (pentafluoroethyl)trimethylsilane in the presence of anhydrous tetramethylammonium fluoride is achieved giving 71-80% isolated yields.

Full text of DOI:10.1055/s-2001-11390

LETTER
379
A Facile New Method for the Two-step Substitution of Hydroxy Groups in
Primary Alcohols for Trifluoromethyl and Pentafluoroethyl Moieties
Dmitri V. Sevenard,a Peer Kirsch,b Gerd-Volker Röschenthaler,a Valery N. Movchun,c Alexander A. Kolomeitsevc*
a Institut für Anorganische und Physikalische Chemie, Universität Bremen, Leobener Strasse, 28334 Bremen, Germany
Fax ++49-421-218-42-67; E-mail: alex@chemie.uni-bremen.de
b MERCK KGaA, Liquid Crystals Division, Frankfurter Strasse 250, 64293 Darmstadt, Germany
c Institute of Organic Chemistry, Ukrainian National Academy of Sciences, Murmanskaya 5, 02094 Kiev, Ukraine
Received 17 November 2000
carbon derivatives. To the best of our knowledge, there
Abstract: In an efficient procedure the nucleophilic trifluorometh-
are no methods so far for substituting hydroxy groups in
alcohols directly or via their corresponding tosylates and
ylation and pentafluoroethylation of alkyl triflates using (trifluo-
romethyl)- and (pentafluoroethyl)trimethylsilane in the presence of
triflates for primary perfluoroalkyl groups. It was previ-
ously reported, that phosphitylation of alcohols with
(Et2N)2PCl followed by low temperature reaction of
CFCl3, CFBr3, CF3CCl3 or (CF3)3CBr with the intermedi-
ate diamido-O-alkylphosphites, is an effective route to in-
troduce halofluoroalkyl or perfluoro-tert.-butyl moieties
at a sp3-hybridized carbon.13 Nevertheless, it proved to be
impossible for the most synthetically useful perfluorinat-
ed primary alkyl groups, namely trifluoromethyl or pen-
tafluoroethyl, since diamido-O-alkyl phosphites do not
interact with trifluoromethyl- or pentafluoroethyl halides.
Here, we report a new facile method for the preparation of
trifluoromethylated and pentafluoroethylated alkanes
starting from easily accessible alkyl triflates, (perfluoro-
alkyl)trimethylsilane and tetramethylammonium fluoride
under very mild reaction conditions.
The treatment of primary alkyl triflates14 with an approx-
imately three-fold excess of RFSiMe3 (RF = CF3, C2F5)
and an almost stoichiometrical amount of tetramethylam-
monium fluoride15 in monoglyme at -30 °C for 2 h gave
the corresponding perfluoroalkylated AlkRF derivatives
in 71-80% isolated yields.16 The nature of the fluoride ion
source used significantly influenced this reaction. Initial-
ly, the trifluoromethylation reaction of octyl triflate 1 was
attempted in a 2:1 ratio of CF3SiMe3 and TASF in THF at
-10 °C for 1 h giving the targeted 1,1,1-trifluorononane 2,
1-fluorooctane, oct-1-ene and octan-1-ol in a 81:7:5:7 ra-
tio (GC and 19F NMR) (Scheme 1).
anhydrous tetramethylammonium fluoride is achieved giving 71-
80% isolated yields.
Key words: perfluoroalkylation, (perfluoroalkyl)trimethylsilane,
anhydrous tetramethylammonium fluoride, nucleophilic substitu-
tion
Regioselective perfluoroalkylation and, especially, triflu-
oromethylation of organic compounds is a well estab-
lished method for synthesizing compounds applicable in
agrochemistry, pharmaceutical industry and material sci-
ences.1,2 Numerous trifluoromethylating reactions of acti-
vated organic halides (aryl, vinyl, allyl and benzyl
halides) have been reported previously.1,3 However, the
only example of trifluoromethylating non-activated alkyl
halides is the reaction of aliphatic halides using a mixture
of methyl chloro- or bromodifluoroacetate, an excess of
potassium fluoride, copper iodide and cadmium iodide at
120 °C in HMPA,4 where [CF3CuI]- is supposedly the tri-
fluoromethylating reagent. This method has several disad-
vantages, such as the use of a carcinogenic solvent, toxic
cadmium salts, or high reaction temperature. In addition,
there were difficulties in isolating the trifluoromethylated
products due to moderate yields and low conversion rates
of the starting alkyl halides. The unique properties of (per-
fluoroalkyl)trimethylsilanes as reagents for perfluoro-
alkylation of different organic and heteroatom
electrophiles are well documented.5 The formation of new
C-C bonds during the perfluoroalkylation proceeding un-
der fluoride anion catalysis, was achieved in the case of
carbonyl compounds,6 imines,7 perfluoroarenes8 and
polytrifluoromethylated aromatics,9 acyl halides10 and
carboxylic esters.11 (Trifluoromethyl)triethylsilane was
also used for in situ generation of CF3Cu in the presence
of copper halides and potassium fluoride. However, the
trifluoromethyl copper species was able to trifluorometh-
ylate only benzyl and allyl halides in 73% and 23% yield,
respectively. Moreover, this procedure cannot be extend-
ed to non-activated alkyl halides.12 Considering the good
leaving group properties of the triflate group in nucleo-
philic substitution reactions, the availability and the costs
of carbinols, alkyl triflates were chosen as the most suit-
able candidates for trifluoromethylation of sp3 hybridized
Surprisingly, no trifluoromethylation was observed in the
case of CF3SiMe3/KF and alkyl triflate 3 either at 0 °C or
at room temperature. The only fluorinated products ob-
served were fluoroform, trimethylfluorosilane and potas-
sium triflate. In contrast to TASF and spray-dried KF, the
application of tetramethylammonium fluoride as a fluo-
ride anion source and performing the reaction under mild-
er reaction conditions (-30 °C, monoglyme, 2 h) afforded
the liquid crystal compound, 4-(2,2,2-trifluoroethyl)-4´-
propylbicyclohexyl 4 in 71% isolated yield. The only flu-
orinated impurity (1% mol) observed by trifluoromethyl-
ation of the triflate 3 was 4-(2,2,3,3,3-pentafluoropropyl)-
4´-propylbicyclohexyl 5 (Scheme 2).
Synlett 2001 No. 3, 379–381 ISSN 0936-5214 © Thieme Stuttgart · New York

380
D. V. Sevenard et al.
LETTER
Scheme 1
Scheme 2 Synthesis and mesophase sequences of the liquid crystals 4 and 5. (The phase transition temperatures are cited in °C;
C = crystalline, SB = smectic B, SG = smectic G, I = isotropic)
The side reaction can be rationalized by considering an in- The usefulness of this approach was demonstrated on a
sertion of difluorocarbene into the Si-C bonds, formed preparative scale by synthesizing the liquid crystal mole-
-
from the "CF3 " containing siliconate intermediates17,18 cules 4 and 5. Further studies of the reactive species na-
and generated at low temperature as it has been previously ture, scope and applicability of this method to secondary
observed for CF3Cu species.1b
and tertiary alcohols are presently under investigation in
our laboratories.
Surprisingly, the reaction of triflate 2 with C2F5SiMe3
gave less side-products than with CF3SiMe3. No fluorinat-
ed impurity was detected in the reaction mixture and the
isolated yield was 80% for 5. The difference in reactivity
of these (perfluoroalkyl)trimethylsilanes reagents could
be explained in terms of different thermal stability of the
hypervalent pentacoordinated silicon species generated
from RFSiMe3 and F- at low temperature. As we have re-
cently observed, the hypervalent bis(pentafluoroethyl)tri-
methyl-siliconate derived from C2F5SiMe3 and
tetramethylammonium fluoride is stable in monoglyme
until 20 °C. The corresponding CF3 containing intermedi-
ates, however, slowly decompose in monoglyme solution
already at 0 °C.17,19 The newly developed perfluoroalkyl-
ation protocol allows the exclusion of carcinogenic sol-
vents or toxic cadmium salts. The trifluoromethylated
products can be prepared under mild reaction conditions.
References and Notes
(1) For a review of general trifluoromethylation methods see: (a)
McClinton, M. A.; McClinton, D. A., Tetrahedron 1992, 48,
6555; (b) Burton, D. J.; Yang, Z.Y., Tetrahedron 1992, 48,
189.
(2) Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Organofluorine
Chemistry Principles and Commercial Applications,
Plenum Press: New York, 1994.
(3) Su, D.- B.; Duan, J.-X.; Chen, Q.-Y., Tetrahedron Lett. 1991,
32, 6555.
(4) Chen, Q.-Y.; Duan, J.-X., Tetrahedron Lett. 1993, 34, 4241.
(5) Prakash, G. K. S.; Yudin, A. K., Chem. Rev. 1997, 97, 757;
Singh R. P.; Shreeve J. M., Tetrahedron 2000, 56, 7613.
(6) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A., J. Am. Chem.
Soc. 1989, 111, 393; Portella, C.; Brigaud, T.; Lefebvre, O.;
Plantier-Royon, R., J. Fluorine Chem. 2000, 101, 193.
(7) Blazejewski, J.-C.; Anselmi, E; Wilmshurst, M. P.,
Tetrahedron Lett. 1999, 40, 5475; Petrov, V. A., Tetrahedron
Lett. 2000, 41, 6959.
In summary, we have developed an efficient and general
synthetic route to primary trifluoro- and pentafluoroal-
kanes by treating alkyl triflates with an excess of (perflu-
oroalkyl)trimethylsilane and almost stoichiometric
amounts of anhydrous tetramethylammonium fluoride.
(8) Bardin, V. V.; Kolomeitsev, A. A.; Furin, G. G.; Yagupolskii,
Yu. L., Izv. Akad. Nauk SSSR 1990, 1693; Chem. Abstr. 1991,
115, 279503c.
Synlett 2001, No. 3, 379–381 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Facile New Method for the Two-step Substitution of Hydroxy Groups
381
(9) Kolomeitsev, A. A.; Movchun, V. N.; Yagupolskii, Yu. L.;
Powisdiak, J.; Dmowski, W., Tetrahedron Lett. 1992, 33, 619.
(10) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S., J. Org.
Chem. 1991, 56, 984.
(11) Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash G. K. S.;
Olah, G. A., Angew. Chem., Int. Ed. 1998, 37, 820; Singh, R.
P.; Cao, G.; Krishnamurti, R.; Kirchmeier, R. L.; Shreeve, J.
M., J. Org. Chem. 1999, 64, 2873.
(12) Urata, H.; Fuchikami, T., Tetrahedron Lett. 1991, 32, 91.
(13) Kolomeitsev, A. A.; Shtarev, A.; Chabanenko, K.; Savina, T.;
Yagupolskii, Yu.; Przyborowski, J.; Lork, E.; Röschenthaler,
G.-V., J. Chem. Soc., Chem. Commun. 1998, 705.
(14) Octyltrifluoromethylsulfonate 1 was prepared according to
Porella, F. W.; Chen, S.-F.; Behrens, D. L.; Kaltenbach, R. F.;
Seitz, S. P., J. Med. Chem. 1994, 37, 2232.
temperature and then during 1.5 h allowed to reach 0 °C. The
resulting dark mixture was quenched with 150 mL water, the
aqueous layer was extracted with 3 15 mL CH2Cl2, dried
over anhydrous MgSO4 and was concentrated in vacuo. The
residue was dissolved in 10 mL pentane and filtrated through
a silica gel layer (10 cm, eluent pentane). After removal of the
solvent in vacuo followed by the crystallization (from
MeOH:EtOH, 10:1) yielded compound 4 (0.85 g, 71%) as
colorless crystals; for the mesophase sequence see Scheme 2.
1H NMR (200.13 MHz, CDCl3): = 0.82-1.34 (m, 17H);
1.53-1.89 (m, 10H); 1.97 (q.d, 2H, CH2, 3JH-F = 11.6, 3JH-H
= 6.8). 19F NMR (188.31 MHz, CDCl3): = -64.48 (t, 3JF-H
= 11.2). 13C NMR (50.32 MHz, CDCl3): 14.4 (CH3); 20.1,
29.6, 30.1, 33.4, 33.6, 39.9 and 40.8 (q, CH2, 2JC-F = 27.0);
32.9 (q, CH, 3JC-F = 2.3), 37.7, 42.8 and 43.3; 127.2 (q, CF3,
1JC-F = 277.3). MS: 290 (M+, 50); 247 ([M-C3H7]+, 5); 220
4-Trifluoro-methylsulfonylmethyl-4’-propylbicyclohexyl 3:
To a solution of 3.30 g (12 mmol) triflic anhydride in 10 mL
CH2Cl2 at 0 °C was added a mixture of 2.62 g (11 mmol) 4-
hydroxymethyl-4´-propylbicyclohexyl during 20 min and
dried 0.87 g (11 mmol) pyridine in 5 mL CH2Cl2. After stirring
for 15 min at 0 °C the reaction mixture was quenched with 100
mL cold water. After extraction with 3 10 mL CH2Cl2 the
combined organic layers were dried over Na2SO4. After
removal of the solvent in vacuo the residue was dissolved in 5
mL CHCl3 and filtrated through silica gel (10 cm layer, eluent
CHCl3). Removal of the solvent in vacuo followed by
crystallization from hexane afforded 3 (3.0 g, 74%) as a
colorless solid. Mp 41-43 °C, 1H NMR (200.13 MHz, C6D6):
= 0.47-1.79 (m, 24H); 0.91 (t, 3H, CH3, 3JH-H = 7.1); 3.78
(d, 2H, = CH2, 3JH-H = 6.4). 19F NMR (188.31 MHz, C6D6):
= -76.47 (s). 13C NMR (50.32 MHz, C6D6): = 14.7 (CH3);
20.5, 28.8, 29.0, 30.3, 33.9, 40.2 and 82.1 (CH2); 37.6, 38.0,
42.9 and 43.4 (CH); 119.4 (q, 1JC-F = 319.5). MS (Varian
([M-CF3H]+, 13); 125 (C3H7-C6H10+, 73); 69 (CF3 , 100).
+
HRMS: calcd. for C17H29F3 290.2221, found 290.2220.
4-(2,2,3,3,3-Pentafluoropropyl)-4´-propylbicyclohexyl 5,
80%, colorless crystals from methanol; for the mesophase
sequence see Scheme 2. 1H NMR (200.13 MHz, CDCl3):
= 0.69-1.38 (m, 18H); 1.59-1.99 (m, 11H). 19F NMR
(188.31 MHz, CDCl3): -117.60 (t, 2F, CF2, 3JF-H = 19.8);
-87.26 (s, 3F, CF3). 13C NMR (50.32 MHz, CDCl3): 14.4
2
(CH3), 20.06, 29.7, 30.0, 33.6, 34.0, 39.8, 37.7 (t, CH2 JC-F
= 20.9); 31.3, 37.6, 42.8, 43.3 (CH); 116.7 (t.q, CF2, 1JC-F
= 252.1, 2JC-F = 37.0); 119.6 (q.t, CF3, 1JC-F = 285.6, 2JC-F
+
= 36.3). MS: 340 (M+, 28); 125 (C3H7-C6H10+, 66); 69 (CF3 ,
+
100); 29 (C2H5 , 8). HRMS: calcd. for C18H29F5 340.2189,
found 340.2189.
The assignment of all signals in 3, 4, 5 was based on DEPT135
NMR spectra.
(17) Kolomeitsev, A. A.; Bissky, G.; Lork, E.; Movchun, V.;
Rusanov, E.; Kirsch, P.; Röschenthaler, G.-V., Chem. Comm.
1999, 1107.
(18) Maggiarosa, N.; Tyrra, W.; Naumann, D.; Kirij, N. V.;
Yagupolskii, Yu. L., Angew. Chem. 1999, 111, 2392.
(19) Bissky, G.; Lork, E.; Röschenthaler, G.-V.; Kolomeitsev, A.
A., 16th International Symposium on Fluorine Chemistry,
Durham, July 16-21 2000, Abstract 1P-81.
+
MAT 8200): 370 (M+, 10); 125 (C3H7-C6H10+, 100); 69 (CF3 ,
90). HRMS: calcd. for C17H29F3SO3 370.1790, found
370.1804.
(15) Kolomeitsev, A. A.; Seifert, F. U.; Röschenthaler, G.-V.
J. Fluorine Chem. 1995, 71, 47.
(16) Typical procedure for the trifluoromethylation of alkyl
triflates: 4-(2,2,2-Trifluoroethyl)-4´-propylbicyclohexyl 4:
To a 30 °C solution of 1.50 g (4.1 mmol) 4-trifluorometh-
ylsulfonylmethyl-4´-propylbicyclohexyl 3 and 1.73 g (12
mmol) (trifluoromethyl)trimethylsilane in 20 mL monoglyme
was added during 1 h 0.46 g (5 mmol) tetramethylammonium
fluoride. The mixture was stirred for additional 2 h at this
Article Identifier:
1437-2096,E;2001,0,03,0379,0381,ftx,en;G24000ST.pdf
Synlett 2001, No. 3, 379–381 ISSN 0936-5214 © Thieme Stuttgart · New York