22Chemistry Letters Vol.36, No.1 (2007)

A Facile Synthesis of N-[2-(Triﬂuoromethyl)allyl]amides and Their Transformation
into Angularly Triﬂuoromethylated Bicyclic Cyclopentenones
Ryo Nadano and Junji Ichikawa
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033(Received September 21, 2006; CL-061101; E-mail: Junji@chem.s.u-tokyo.ac.jp)
On treatment with sec-BuLi at 105  C, 2-bromo-3,3,3triﬂuoropropene undergoes rapid lithium–halogen exchange togenerate thermally unstable 1-(triﬂuoromethyl)vinyllithium,which reacts with N-tosylimines to aﬀord N-[2-(triﬂuoromethyl)allyl]amides in high yield. Propargylation of the amides,
followed by the Pauson–Khand reaction, readily provides
pyrrolidine ring-fused cyclopentenones with an angular triﬂuoromethyl group.

2-Triﬂuoromethyl-1-alkenes [1-(triﬂuoromethyl)vinyl compounds] constitute a versatile class of building blocks1 for the selective introduction of ﬂuorine-containing carbon substituents
into bioactive molecules and molecular devices.2,3 This is dueto their electron-withdrawing CF3 groups, reactive double bonds
toward nucleophiles, and allylic ﬂuorine atoms as potential leaving groups. Along this line, we have recently developed ﬂexible
synthetic routes to: (i) 1,1-diﬂuoro-1-alkenes via an SN20 -type
reaction;4 (ii) ﬂuorocarbon-substituted heterocycles via intramolecular nucleophilic reactions;5 and (iii) 5-triﬂuoromethyl-2-cyclopentenones via a regioselective Nazarov cyclization.6 Despite
the synthetic potential of the 1-(triﬂuoromethyl)vinyl moiety, its
introduction as a C3 unit remains a diﬃcult task, because of thethermal instability of the corresponding reactive metal species,
such as a vinyllithium reagent.7–9
In our previous paper, we reported the eﬃcient synthesis of[1-(triﬂuoromethyl)vinyl]-substituted alcohols by the ring opening of cyclic ethers with 3,3,3-triﬂuoroprop-1-en-2-yllithium(1).8 On treatment of 2-bromo-3,3,3-triﬂuoroprop-1-ene (2) withan equimolar amount of n-BuLi at 100  C, slow lithium–halogen exchange gave rise to a mixture of vinyllithium 1 andn-BuLi. We succeeded, however, in the selective trapping of 1
with appropriate electrophiles, such as oxiranes and oxetanes,in the presence of BF3 OEt2 by taking advantage of the subtle
diﬀerence between reactivities of the two lithium species.10
On the other hand, 1-(triﬂuoromethyl)vinylation of highly
reactive electrophiles has remained problematic. The vinylationof aldehydes suﬀers from nonselective addition of both 1 and nBuLi to give a poor yield of the desired allyl alcohols.7,11 Herein,
we report an eﬃcient generation of (triﬂuoromethyl)vinyllithium 1 to trap with reactive electrophiles, aldehydes and imines,
and its application to the construction of angularly triﬂuoromethylated bicyclic systems, which has been a desirable goal.
We ﬁrst reexamined the generation of vinyllithium 1 frombromotriﬂuoropropene 2 by treatment with several alkyllithiums
for 15 min. After quenching with methanol, the product distributions were observed by 19 F NMR, as shown in Table 1. When thereaction was carried out with n-BuLi at 78  C, the decomposition of vinyllithium 1 occurred to give 1,1-diﬂuoroallene (4) in
54% yield, via elimination of lithium ﬂuoride (Entry 1). When
carrying out the reaction at 105  C, we observed only a 14%.

Table 1. Preparation of 1-(triﬂuoromethyl)vinyllithium 1
CF3RLi (1.0 ma)

Br

15 min / Et2O

CF3

MeOH

+2

3ma: molar amount


•

CF2

4

EntryRtemp./ C

34

recovery of 2

12
3
4
5n-Bu

78
96
105
105
105

20%
31%
14%
60%
50%

54%
11%
1%
26%
35%

17%
58%
76%
10%
5%

sec-Butert-Buyield of 3,3,3-triﬂuoroprop-1-ene (3), along with a 76% recoveryof 2 (Entry 3). These results indicate that incomplete conversion
is inevitable in the reaction with n-BuLi, due to the slow exchange rate and the thermal instability of 1. In contrast, the lithium–halogen exchange reaction with sec-BuLi proceeded rapidly
even at 105  C to consume 90% of 2, which generated 1 in atleast 60% yield along with 26% of diﬂuoroallene 4 (Entry 4).
We then attempted the reaction of aromatic and aliphatic
aldehydes with vinyllithium 1, generated in situ from 2.0 molar
amounts of vinyl bromide 2 and sec-BuLi, in considerationof the partial decomposition of 1. The desired 2-(triﬂuoromethyl)allyl alcohols 5a and 5b were obtained in 73 and 76%
yield, respectively (eq 1). Thus, the more rapid lithium–halogen
exchange allowed the reaction with reactive electrophiles.
CF3Br
2 (2.0 ma)

sec-BuLi(2.0 ma)−105 °C
10 min / Et2O

CF3Li1RCHO

CF3R
(1)
−105 toOH−50 °C, 2 h5a 73%
R = PhR = (CH2)2Ph 5b 76%

Allylamines have been used as useful components for thesynthesis of N-heterocycles. For the construction of potential triﬂuoromethylated heterocycles, we pursued the reaction of vinyllithium 1 with imines to prepare 2-(triﬂuoromethyl)allylamines.3
Although N-benzylimine 6a was not reactive towards 1,BF3 OEt2 promoted the reaction to aﬀord the desired amine
7a in 81% yield (Table 2, Entry 1). When N-benzoyl- and N-tosylimine 6b and 6c were employed as the reactive electrophiles,
the corresponding N-allylamides 7b and 7c were obtained in excellent yield (Entries 2 and 3).12
We further examined (triﬂuoromethyl)vinylation of severalother N-tosylimines 6d–6g in view of their availability, ease ofhandling, and the synthetic applicability of the products. AllN-tosylimines 6c–6g examined provided the corresponding N[2-(triﬂuoromethyl)allyl]sulfonamides 7c–7g in good to excellent yield, as summarized in Table 2. Butanimine 6e gave 7ein good yield, even though it had acidic protons to the iminogroup (Entry 5). Whereas 1,1-diphenylmethanimine 6g showed.

Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)

23Table 2. Synthesis of [(triﬂuoromethyl)allyl]sulfonamides 7sec-BuLi(2.0 ma)

CF3Br2 (2.2 ma)

CF3

CF3−105 °C
10 min / Et 2O

R1R2NHR 3

R1R2C=NR 3 6−105 to−50 °C, 2 h

Li
17Entry

R

1R

2R

3

7Yield/%1a23b4b567H
H
H
H
H
H
PhPhPhPh
PhCH=CHn-Pr
t-Bu
Ph

CH2 C6 H5
COC6 H5TsTsTsTs
Ts

7a7b7c7d7e
7f7g

81
97
90
89
77
9676 (91)c.

a

BF3 OEt2 (1.5 ma) was added. b Solution of 6 was added
dropwise over 20 min. c Vinyl bromide 2 (3.5 ma) and secBuLi (3.2 ma) were used.
modest reactivity, employing an excess amount of 1, generated
from 2 (3.5 ma) and sec-BuLi (3.2 ma), improved the yield to91% (Entry 7).
Having accomplished the synthesis of 2-(triﬂuoromethyl)allylamides 7, we turned our attention to the constructionof fused-ring systems involving an angular triﬂuoromethylgroup,2,13 whose framework might be constructed by an intramolecular Pauson–Khand reaction.14,15 Introduction of an angulartriﬂuoromethyl group can be an attractive tool for the analog
synthesis of steroids and alkaloids, and remains a challenging
task. Furthermore, very few examples of 1,6-enynes bearing aelectron-withdrawing group at the C-2 vinylic carbon have beenreported in the Pauson–Khand reaction.16 These facts prompted
us to investigate the Pauson–Khand reaction of N-propargyl-N[2-(triﬂuoromethyl)allyl]amides 8, readily prepared by propargylation (with a propargyl bromide and NaH in DMF at rt) of
the above-obtained amides 7 in 84–92% yield.
Enyne 8a was treated with dicobalt octacarbonyl to generate
the cobalt–yne complex. Heating the complex at 60  C in acetonitrile promoted the desired Pauson–Khand reaction of a CF3 substituted terminal alkene, to aﬀord the pyrrolidine ring-fused
cyclopentenone 9a bearing an angular triﬂuoromethyl group in
81% yield with high diastereoselectivity (anti:syn = 94:6)(Table 3, Entry 1).17,18 Substrates 8b and 8c with an internalalkyne moiety or an alkyl group at the allylic position also readily underwent the cyclization to give triﬂuoromethylated pyrrolidines 9b and 9c in 85 and 71% yield, respectively (Entries 2and 3).
Table 3. Synthesis of 3a-CF3 -cyclopenta[c]pyrroles 9
R1Co2(CO)8 (1.2 ma)
TsN

CF3R28rt, 0.5 h / CH2Cl2then, 60 °C / CH 3CN

R1 CF
3TsNO
9R2

Entry

R1R2Time/h9Yield/%anti:syna

123PhPhn-PrH
EtH

3239a9b9c

8185
71

94:6b83:17c
86:14ca
Determined by 19 F NMR. b See Ref. 17. c Conﬁguration wasdetermined in analogy with 9a by comparing 1 H and19F NMR data of each isomer.

The sequence of (i) (triﬂuoromethyl)vinylation of imines,
followed by (ii) propargylation and (iii) the cobalt-mediatedintramolecular Pauson–Khand reaction, successfully provides afacile entry to the fused N-heterocycles bearing an angular triﬂuoromethyl group.
We thank Dr. N. Kanoh (the University of Tokyo) for theX-ray crystal structure analysis.
The present work is dedicated to Professor Teruaki
Mukaiyama on the occasion of his 80th birthday.
References and Notes
1 M. Shimizu, T. Hiyama, Angew. Chem., Int. Ed. 2005, 44, 214, andreferences therein.
2 For a review on the synthesis of triﬂuoromethylated cycliccompounds, see: P. Lin, J. Jiang, Tetrahedron 2000, 3635.
3 a) H. Lebel, V. Paquet, Org. Lett. 2002, 4, 1671, and references
therein. b) V. De Matteis, F. L. van Delft, H. Jakobi, S. Lindell,J. Tiebes, F. P. J. T. Rutjes, J. Org. Chem. 2006, 71, 7527.
4 J. Ichikawa, H. Fukui, Y. Ishibashi, J. Org. Chem. 2003, 68, 7800.
5 a) J. Ichikawa, T. Mori, Y. Iwai, Chem. Lett. 2004, 33, 1354, andreferences therein. b) T. Mori, Y. Iwai, J. Ichikawa, Chem. Lett.
2005, 34, 778.
6 J. Ichikawa, M. Fujiwara, T. Okauchi, T. Minami, Synlett 1998,927.
7 a) F. G. Drakesmith, O. J. Stewart, P. Tarrant, J. Org. Chem. 1968,33, 280. b) K. Iseki, Y. Kuroki, T. Nagai, Y. Kobayashi, J. Fluorine
Chem. 1994, 69, 5.
8 R. Nadano, J. Ichikawa, Synthesis 2006, 128.
9 For 1-(triﬂuoromethyl)vinylmetal species, see references in Ref. 8.
10 n-BuLi seemed less reactive than vinyllithium 1 under the reaction
conditions, presumably due to aggregation. See, Organolithiums:
Selectivity for Synthesis, ed. by J. Clayden, Elsevier, Oxford, 2002.
11 When a 1:1 mixture of 2 and n-BuLi was kept at 100  C for
15 min and then treated with benzaldehyde, two alcohols, derived
from vinyllithium 1 and n-BuLi, were obtained in 25 and 64%
yield, respectively.
12 To a solution of 2 (0.13 mL, 1.24 mmol) in Et2 O (10 mL) was added
sec-butyllithium (1.07 M in cyclohexane, 1.05 mL, 1.13 mmol) in
Et2 O (5 mL) at 105  C under Ar. After stirring for 10 min, 6c(146 mg, 0.56 mmol) in Et2 O (10 mL) was added over 20 min.
The reaction mixture was allowed to warm to 50  C over 2 h,and the reaction was quenched with phosphate buﬀer (pH 7,10 mL). Organic materials were extracted with EtOAc three times,
and the combined extracts were washed with brine, and driedover MgSO4 . After removal of the solvent under reduced pressure,
the residue was puriﬁed by silica-gel column chromatography (hexane–EtOAc, 10:1) to give 7c (180 mg, 90%) as colorless crystals.
13 For a recent example, see: T. Barhoumi-Slimi, B. Crousse, M.
Ourevitch, M. El Gaied, J.-P. Bégué, D. Bonnet-Delpon, J.
Fluorine Chem. 2002, 117, 137.
14 For reviews on the Pauson–Khand reaction, see: S. E. Gibson, N.
Mainolﬁ, Angew. Chem., Int. Ed. 2005, 44, 3022, and references
therein.
15 For the Pauson–Khand reaction in ()-dendrobin synthesis, see:J. Cassayre, S. Z. Zard, J. Organomet. Chem. 2001, 624, 316.
16 For reviews on the Pauson–Khand reaction of electron-deﬁcientalkenes, see: a) M. R. Rivero, J. Adrio, J. C. Carretero, Synlett
2005, 26. b) M. R. Rivero, J. Adrio, J. C. Carretero, Eur. J. Org.
Chem. 2002, 2881. See also: c) L. V. R. Boñaga, M. E. Kraﬀt,
Tetrahedron 2004, 9795.
17 The conﬁguration of the major isomer was determined to be anti by
X-ray crystallography of the cyclopentanone, derived via reductionof 9a.
18 The Pauson–Khand reaction of a similar N-containing 1,6-enyne
with a CF3 group at C-1 was reported to be unsuccessful. M.
Ishizaki, D. Suzuki, O. Hoshino, J. Fluorine Chem. 2001, 111, 81.

Published on the web (Advance View) December 2, 2006; doi:10.1246/cl.2007.22