Nucleophilic trifluoromethylation of cyclic imides using (trifluoromethyl)trimethylsilane CF3SiMe3

Article abstract of DOI:10.1039/b407555b

A variety of cyclic five-membered imides was trifluoromethylated in good to excellent chemical yields using (trifluoromethyl)trimethylsilane CF ₃SiMe₃ under fluoride ion catalysis. The method was successfully applied to the stereoselective synthesis of trifluoromethylated bi- and tricyclic lactams which could serve as precursors for designed thrombin inhibitors.

Full text of DOI:10.1039/b407555b

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C O M M U N I C A T I O N
Nucleophilic trifluoromethylation of cyclic imides using (trifluoro-
methyl)trimethylsilane CF3SiMe3†
Anja Hoffmann-Röder, Paul Seiler and François Diederich*
Laboratorium für Organische Chemie, ETH-Hönggerberg, CH-8093, Zürich, Switzerland.
E-mail:diederich@org.chem.ethz.ch
Received 19th May 2004, Accepted 8th July 2004
First published as an Advance Article on the web 27th July 2004
A variety of cyclic five-membered imides was trifluoro-
methylated in good to excellent chemical yields using (trifluoro-
methyl)trimethylsilane CF3SiMe3 under fluoride ion catalysis.
The method was successfully applied to the stereoselective
synthesis of trifluoromethylated bi- and tricyclic lactams which
could serve as precursors for designed thrombin inhibitors.
The incorporation of fluorinated residues into organic molecules
often leads to remarkable changes in their physical, chemical and
biological properties and consequently has become a well-es-
tablished synthetic strategy for the development of new pharma-
ceuticals, agrochemicals and materials.1 Among fluorinated
bioactive compounds, trifluoromethylated ones have attracted
much attention due to the enhanced lipophilicity (e. g., indicated by
Fig. 1 Trifluoromethylated cyclic imides reported in the literature.
the Hansch–Leo substituent parameter2 CF = 0.88 vs. CH = 0.56)
3
3
and metabolic stability associated with the trifluoromethyl substitu-
ent.3 Therefore, a wide variety of trifluoromethylation protocols
have been developed,4 among which the use of (trifluoromethyl)-
trimethylsilane5 (Ruppert’s reagent, CF3SiMe3) as a nucleophilic
trifluoromethylating agent has rapidly emerged as the method of
choice.6 Consequently, a quite impressive number of electrophiles,
e.g., aldehydes, ketones, esters, imines, enones and alkyl triflates,
have been successfully transformed into the desired trifluorometh-
ylated products utilising CF3SiMe3 under fluoride ion initiation.6,7
However, nucleophilic trifluoromethylation reactions of cyclic
imides have only been scarcely reported in the literature, despite
the fact, that the latter represent important structural elements for
natural products and pharmacologically active compounds.8 Thus,
due to deactivation resulting from electron donation from the nitro-
gen atom to the carbonyl group, nucleophilic trifluoromethylation
procedures using CF3SiMe3 have so far been mainly described for
activated imides such as -keto amides9 and imidazolidinetriones.10
Moreover, it was already shown that protected succinimide,6a
maleimide,11 as well as phthalimide,11 can undergo such trifluoro-
methylation reactions (Fig. 1), although experimental details for
these transformations are not broadly available. Thus, given the
relevance of imide-type structural elements for medicinal chemistry
together with an increasing interest in fluorinated compounds, a re-
liable protocol towards the synthesis of trifluoromethylated amides
and lactams would be highly desirable.
THF. Thus, under these conditions the desired trifluoromethylated
lactam 2 was obtained with an excellent chemical yield of 95% after
removal of the excess of CF3SiMe3 and cleavage of the initially
formed silyl ether by equivalent amounts of TBAF (Scheme 1).
Interestingly, desilylation was best achieved with 1–2 equivalents
of TBAF whereas hydrolysis of the rather stable silyl ether under
acidic conditions using aqueous HCl (4 M) did not proceed smoothly
but led to mixtures of silylated and non-silylated adducts.
Scheme 1 Nucleophilic trifluoromethylation of cyclic imide 1 with
CF3SiMe3.
The yield of 2 was found to be substantially higher when solid
TBAF·3H2O was used as fluoride source instead of its conven-
tionally employed solution in THF, which in our hands led to
considerable amounts of ring-opened by-products. Moreover, clean
conversions were obtained when CF3SiMe3 was added to a THF
solution of the imide prior to the addition of solid TBAF.‡ In this
context, it is also noteworthy, that a reduced amount of CF3SiMe3
(1.2–1.5 equivalents) resulted only in sluggish reactions furnishing
the desired product 2 in substantially lower chemical yields.
In the course of our research program directed towards the
de novo design and synthesis of novel fluorinated non-peptidic
thrombin inhibitors,12 we recently became interested in the
selective incorporation of a trifluoromethyl group into the cyclic
imide core of some of our designed bi- and tricyclic inhibitor
precursors.13 We therefore decided at first to re-examine the
nucleophilic trifluoromethylation reaction of five-membered cyclic
imides as model substrates utilising CF3SiMe3 under fluoride ion
initiation as the trifluoromethide equivalent. After screening of
various reaction conditions we were pleased to find that smooth
trifluoromethylation of benzylated phthalimide 1 took place upon
treatment with two equivalents of CF3SiMe3 in the presence of
10 mol% of tetra-n-butylammonium fluoride (TBAF·3H2O) in dry
Next, we applied this protocol to a variety of benzylated mono- and
bicyclic imides, prepared either by condensation of the corresponding
anhydrides with benzylamine or via alkylation reactions,14 and found,
that for some substrates the use of CsF or tetramethylammonium
fluoride (TMAF) proved to be advantageous over TBAF, leading to
cleaner conversions and higher yields of the CF3-adducts (Table 1).
Furthermore, while most of the tested substrates provided the desired
trifluoromethylated lactams in good to excellent chemical yields, the
corresponding six-membered homophthalimide 13 and glutarimide
15 failed almost completely to undergo the trifluoromethylation reac-
tion (entry 6 and 7). However, in case of hydantoin derivative 20 the
low chemical yield should be a consequence of the reduced reactivity
resulting from electron donation of the second amide N atom as is fur-
ther reflected in the longer reaction time and a regioselective attack of
the CF3SiMe3 at the more reactive upper carbonyl group (entry 9).
Generally, attack of the rather bulky CF3-nucleophile occurred
selectively at the less hindered face of the bicyclic imides provid-
† Electronic supplementary information (ESI) available: synthetic
protocols and spectroscopic data for compounds 2, 12, 20, 22 and 24. See
http://www.rsc.org/suppdata/ob/b4/b407555b/
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 6 7 – 2 2 6 9
2 2 6 7

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Table 1 Trifluoromethylated cyclic amides prepared according to Scheme 1 (after desilylation with TBAF)
Entry
Imide
Reaction conditions
Product
Yield (%)
1
CF3SiMe3 (2 eq.), CsF (10 mol%), THF, 0 °C → rt, 4 h
99
91
86
94
79
2
3
4
5
CF3SiMe3 (2 eq.), CsF (10 mol%), THF, 0 °C → rt, 5 h
CF3SiMe3 (2 eq.), TBAF (10 mol%), THF, 0 °C → rt, 4 h
CF3SiMe3 (2 eq.), CsF (10 mol%), THF, rt, 5 h
CF3SiMe3 (4 eq.), CsF (20 mol%), THF, rt, 16 h
6
7
8
9
CF3SiMe3 (2 eq.), CsF (20 mol%), THF, rt, 4 h
CF3SiMe3 (3 eq.), TBAF (20 mol%), THF, rt, 6 h
CF3SiMe3 (2 eq.), CsF (10 mol%), THF, 0 °C → rt, 5 h
CF3SiMe3 (2 eq.), TMAF (20 mol%), THF, rt, 12 h
tracesa
noneb
88
28c
a 79% recovery of starting material (s. m.). b 50% recov. of s. m. c 54% recov. of s. m.
ing single diastereoisomeric trifluoromethylated products, as can
be seen from NMR spectra and from the crystal structure of lactam
12 (Fig. 2), which reveals the expected trans-configuration between
the CF3-group and the annelated four-membered ring.§
novel fluorinated thrombin inhibitors.12 Thus, treatment of the endo-
configurated bicyclic imide scaffold 2113c,15 under CsF catalysis
with four equivalents of CF3SiMe3 at 0 °C in THF and subsequent
acid hydrolysis furnished trifluoromethylated lactam 22 with a
good chemical yield of 59% (Scheme 2).
Having established
a valuable access to CF3-substituted
bicyclic amides, we then applied this method to the conversion of
unsymmetrically functionalised bi- and tricyclic imides to trifluoro-
methylated lactams which could possibly serve as precursors for
Fig. 2 ORTEP representation of the structure of trifluoromethylated
amide 12 (arbitrary atom numbering) with vibrational ellipsoids obtained at
193 K and shown at the 30% probability level.
Scheme 2 Nucleophilic trifluoromethylation of functionalised cyclic
imides 21 and 23 with CF3SiMe3.
2 2 6 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 6 7 – 2 2 6 9

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Chemistry and Applications, Springer, Berlin, 2000; (e) For a recent
special issue on “Fluorine in the Life Sciences”, see: ChemBioChem,
2004, 5, 557–728.
2 A. Leo, C. Hansch and D. Elkins, Chem. Rev., 1971, 71, 525–616.
3 (a) M. Schlosser and D. Michel, Tetrahedron, 1996, 52, 99–108;
(b) D. O’Hagan and H. S. Rzepa, Chem. Commun., 1997, 645–652;
(c) B. E. Smart, J. Fluorine Chem., 2001, 109, 3–11; (d) B. K. Park,
N. R. Kitteringham and P. M. O’Neill, Annu. Rev. Pharmacol. Toxicol.,
2001, 41, 443–470.
4 (a) M. A. McClinton and D. A. McClinton, Tetrahedron, 1992, 48,
6555–6666; (b) P. Lin and J. Jiang, Tetrahedron, 2000, 56, 3635–3671;
(c) B. R. Langlois and T. Billard, Synthesis, 2003, 185–194.
5 I. Ruppert, K. Schlich and W. Volbach, Tetrahedron Lett., 1984, 25,
2195–2198.
6 (a) G. K. S. Prakash and A. K. Yudin, Chem. Rev., 1997, 97, 757–786;
(b) R. P. Singh and J. M. Shreeve, Tetrahedron, 2000, 56, 7613–7632;
(c) G. K. S. Prakash and M. Mandal, J. Fluorine Chem., 2001, 112,
123–131.
7 Some selected examples: (a) T. Brigaud, O. Lefebvre, R. Plantier-Royon
and C. Portella, Tetrahedron Lett., 1996, 37, 6115–6116; (b) R. P. Singh,
G. Cao, R. L. Kirchmeier and J. M. Shreeve, J. Org. Chem., 1999, 64,
2873–2876; (c) J.-C. Blazejewski, E. Anselmi and M. P. Wilmshurst,
Tetrahedron Lett., 1999, 40, 5475–5478; (d) G. K. S. Prakash,
M. Mandal and G. A. Olah, Angew. Chem., Int. Ed., 2001, 40, 589–590;
(e) D. V. Sevenard, P. Kirsch, G.-V. Röschenthaler, V. N. Movchun
and A. A. Kolomeitsev, Synlett, 2001, 379–381; (f) D. V. Sevenard,
V. Ya. Sosnovskikh, A. A. Kolomeitsev, M. H. Königsmann and G. V.
Röschenthaler, Tetrahedron Lett, 2003, 44, 7623–7627.
8 Recent examples: (a) Z. Mincheva, M. Courtois, J. Crèche, M. Rideau
and M.-C. Viaud-Massuard, Bioorg. Med. Chem., 2004, 12, 191–197;
(b) S. M. Capitosti, T. P. Hansen and M. L. Brown, Bioorg. Med.
Chem., 2004, 12, 327–336; (c) A. Leonardi, D. Barlocco, F. Montesano,
G. Cignarella, G. Motta, R. Testa, E. Poggesi, M. Seeber, P. G.
De Benedetti and F. Fanelli, J. Med. Chem., 2004, 47, 1900–1918;
(d) M. L. López-Rodríguez, D. Ayala, A. Viso, B. Benhamú,
R. Fernández de la Pradilla, F. Zarza and J. A. Ramos, Bioorg. Med.
Chem., 2004, 12, 1551–1557; (e) K. Kuramochi, Y. Mizushina,
S. Nagata, F. Sugawara, K. Sakaguchi and S. Kobayashi, Bioorg. Med.
Chem., 2004, 12, 1983–1989.
Interestingly, also in this case, a smaller excess of CF3SiMe3
such as two equivalents did not lead to complete conversion of
the starting amide. Moreover, desilylation of the intermediate silyl
ether took place smoothly under acidic conditions with aqueous
HCl (1 M), while the use of TBAF led to the formation of additional
by-products, presumably again due to ring-opening of the lactam
under basic conditions. As it was the case before, nucleophilic
attack of the trifluoromethylating agent took place regio- and
diastereoselectively at the less hindered position resulting in the
incorporation of the CF3-substituent from the convex exo-face of
the bicycle and at its lower carbonyl group.
The corresponding trifluoromethylation reaction of the
endo,trans-configurated tricyclic scaffold 2313,15 was also accom-
plished in a regio- and diastereoselective fashion from the exo-face,
albeit in this case at the upper carbonyl group, furnishing lactam 24
in 57% chemical yield after hydrolysis.
In conclusion, we have developed a reliable protocol for the
nucleophilic trifluoromethylation of cyclic five-membered imides
using CF3SiMe3 in the presence of TBAF·3H2O, TMAF or CsF
in THF. Application of this method to functionalised bi- and
tricyclic imides resulted in the regio- and diastereoselective forma-
tion of lactams 22 and 24 in good chemical yields, which could
serve as precursors for the synthesis of novel trifluoromethylated
thrombin inhibitors. Work towards the extension of this method to
the synthesis of other perfluoroalkylated lactams is currently under
progress in our laboratories.
This work was supported by the ETH research council. A. H.-R.
thanks the Deutsche Forschungsgemeinschaft DFG, for a post-
doctoral fellowship (Emmy Noether-Programm).
Notes and references
‡ Typical experimental protocol for the nucleophilic trifluoromethylation
using CF3SiMe3: To a solution of the imide (1.00 mmol) in dry THF
(10 cm3) under N2 at 0 °C, CF3SiMe3 (2.00 mmol) and an appropriate
F− source (TBAF·3H2O, CsF or TMAF, 10–20 mol%) were sequentially
added. The resulting suspension was stirred for 2–4 h at 0 °C and was
slowly warmed to room temperature. A solution of TBAF (1 M in THF,
2.0 cm3, 2.00 mmol) was added and after 30 min of additional stirring, the
mixture was hydrolysed with 2 M HCl (15 cm3) and extracted with EtOAc
(3 × 10 cm3). The organic layers were washed with 1 M HCl (10 cm3) and
saturated aqueous NaCl solution (10 cm3), dried (MgSO4) and concentrated
in vacuo. Purification of the resulting residue by flash column chromato-
graphy (SiO2; hexanes/EtOAc 3:1) afforded the desired trifluoromethylated
compounds.
§ Crystal data. Compound 12, C14H14F3NO2 (Mr = 285.26), triclinic,
space group P1, Dc = 1.466 g cm−3, Z = 2, a = 6.4271(3), b = 7.7669(4),
c = 14.1095(8) Å,  = 95.290(2)°,  = 94.206(2)°,  = 111.866(2)°,
V = 646.44(6) Å3, T = 193 K,  = 0.126 mm−1. Approximate crystal size
0.22 × 0.03 × 0.02 mm, 2530 unique reflections collected, R1 = 0.0467
based on 1820 reflections with I > 2(I), wR(F2) = 0.1270. CCDC reference
number 239185. See http://www.rsc.org/suppdata/ob/b4/b407555b/ for
crystallographic data in .cif or other electronic format.
9 R. P. Singh, R. L. Kirchmeier and J. M. Shreeve, J. Org. Chem., 1999,
64, 2579–2581.
10 V. Broicher and D. Geffken, Arch. Pharm. (Weinheim), 1990, 323,
929–931.
11 S. Kantamneni, PhD Thesis, University of South Carolina, 1993.
12 (a) J. A. Olsen, D. W. Banner, P. Seiler, U. Obst-Sander, A. D’Arcy,
M. Stihle, K. Müller and F. Diederich, Angew. Chem., Int. Ed., 2003,
42, 2507–2511; (b) J. A. Olsen, D. W. Banner, P. Seiler, B. Wagner,
T. Tschopp, U. Obst-Sander, M. Kansy, K. Müller and F. Diederich,
ChemBioChem, 2004, 5, 666–675; (c) J. Olsen, P. Seiler, B. Wagner,
H. Fischer, T. Tschopp, U. Obst-Sander, D. W. Banner, M. Kansy,
K. Müller and F. Diederich, Org. Biomol. Chem., 2004, 2, 1339–1352.
13 (a) U. Obst, V. Gramlich, F. Diederich, L. Weber and D. W. Banner,
Angew. Chem., Int. Ed., 1995, 34, 1739–1742; (b) U. Obst, D. W. Banner,
L. Weber and F. Diederich, Chem. Biol., 1997, 4, 287–295; (c) U. Obst,
P. Betschmann, C. Lerner, P. Seiler, F. Diederich, V. Gramlich, L. Weber,
D. W. Banner and P. Schönholzer, Helv. Chim. Acta, 2000, 83, 855–909;
(d) P. Betschmann, S. Sahli, F. Diederich, U. Obst and V. Gramlich,
Helv. Chim. Acta, 2002, 85, 1210–1245.
14 M. Ostendorf, R. Romagnoli, I. Cabeza Pereiro, E. C. Roos, M. J.
Moolenaar, W. N. Speckamp and H. Hiemstra, Tetrahedron: Asymmetry,
1997, 8, 1773–1789 and cited refs.
15 Endo, exo refer to the orientation of the 4-bromophenyl ring at C(4)
with respect to the bicyclic perhydropyrrolo[3,4-c]pyrrole scaffold, and
cis, trans to the position of this ring with respect to the configuration of
C(8a) at the fusion of the two pentagons in the perhydropyrrolizidine
bicycle; for the synthesis of this scaffold, see ref. 13.
1 (a) Fluorine in Bioorganic Chemistry, eds. J. T. Welch and
S. Eshwarakrishnan, Wiley, New York, 1991; (b) Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications, eds.
R. Filler, Y. Kobayashi and L. M. Yagupolskii, Elsevier, Amsterdam,
1993; (c) Organofluorine Chemistry—Principles and Commercial
Applications, eds. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum
Press, New York, 1994; (d) T. Hiyama, Organofluorine Compounds,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 6 7 – 2 2 6 9
2 2 6 9