Rapid and slow generation of 1-trifluoromethylvinyllithium: syntheses and applications of CF3-containing allylic alcohols, allylic amines, and vinyl ketones

Article abstract of DOI:10.1002/asia.201000139

1-(Trifluoromethyl)vinylation is accomplished in two protocols by the in situ generation of thermally unstable 3,3,3-trifluoroprop-1-en-2-yllithium (1):1) a rapid lithium-halogen-exchange reaction of 2-bromo-3,3,3-trifluoroprop- 1-ene (2) takes effect wit

Full text of DOI:10.1002/asia.201000139

DOI: 10.1002/asia.201000139
Rapid and Slow Generation of 1-Trifluoromethylvinyllithium: Syntheses and
Applications of CF3-Containing Allylic Alcohols, Allylic Amines, and Vinyl
Ketones
Ryo Nadano,[b] Kohei Fuchibe,[a] Masahiro Ikeda,[a] Hiroki Takahashi,[a] and
Junji Ichikawa*[a]
Abstract: 1-(Trifluoromethyl)vinylation
is accomplished in two protocols by the
in situ generation of thermally unstable
3,3,3-trifluoroprop-1-en-2-yllithium (1):
1) a rapid lithium–halogen-exchange
reaction of 2-bromo-3,3,3-trifluoro-
prop-1-ene (2) takes effect with sec-
BuLi at À1058C to generate vinyllithi-
um 1, which reacts with more reactive
electrophiles, such as aldehydes and N-
tosylimines before its decomposition,
to afford 2-(trifluoromethyl)allyl alco-
hols and N-[2-(trifluoromethyl)allyl]
sulfoamides in good yield; 2) treatment
of 2 with nBuLi at À1008C causes a
slow lithium–halogen exchange of 2,
which gives rise to a mixture of 1 and
nBuLi. Vinyllithium 1 is preferentially
trapped with less reactive electrophiles,
such as N,N-dimethylamides in the
presence of BF3·OEt2, to afford 1-(tri-
fluoromethyl)vinyl ketones in good
yield. Versatility of the products
toward syntheses of CF3-containing
ring-fused cyclopentenones is also dem-
onstrated by the Pauson–Khand reac-
tion and the Nazarov cyclization.
Keywords: allylic compounds
·
cyclization · fluorine · ketones ·
lithium
Introduction
lar devices, and trifluoromethylated building blocks have
been developed.[2] Among these, the 3,3,3-trifluoroprop-1-
en-2-yl group [1-(trifluoromethyl)vinyl group] is very versa-
tile: (trifluoromethyl)vinyl compounds readily undergo cy-
cloaddition with dienes and 1,3-dipoles to construct hetero-
and carbocyclic ring systems bearing a trifluoromethyl
group.[3] Furthermore, they serve as monomers for the syn-
thesis of trifluoromethyl-containing polymers.[4]
We recognized that a 1-(trifluoromethyl)vinyl group func-
tions as a potential synthetic unit because of its electron-
withdrawing CF3 group, double bond that is reactive toward
nucleophiles, and allylic fluorine atoms with leaving-group
ability. These properties allow transformations to com-
pounds with fluorinated one-carbon units. Related to this,
we have already reported flexible synthetic routes to the fol-
lowing: 1) 1,1-difluoro-1-alkenes by an SN2’-type reaction[5]
of 1-(trifluoromethyl)vinyl compounds,[6] 2) fluorocarbon-
substituted heterocycles by intramolecular nucleophilic reac-
tions of functionalized 2-trifluoromethyl-1-alkenes,[7] and
3) 5-trifluoromethyl-2-cyclopentenones by a regioselective
Nazarov cyclization of 1-(trifluoromethyl)vinyl ketones.[8]
Because of the synthetic potential of the 1-(trifluorome-
thyl)vinyl system, extensive efforts have been made to de-
velop synthetic methods for 2-trifluoromethyl-1-alkenes [1-
(trifluoromethyl)vinyl compounds].[9–16] Trifluoromethylated
Trifluoromethyl compounds have now become essential in
agricultural and medicinal chemistry, and in materials sci-
ence.[1] It is well-known that the introduction of a trifluoro-
methyl group into bioactive compounds has a significant
effect on their transport, metabolism, and distribution
within organisms. An electron-withdrawing trifluoromethyl
group is also finding wide use in optical and electronic devi-
ces. A building-block strategy is now fully recognized as an
efficient approach for the selective introduction of fluorine-
containing substituents into bioactive molecules and molecu-
[a] Dr. K. Fuchibe, M. Ikeda, H. Takahashi, Prof. Dr. J. Ichikawa
Department of Chemistry, Graduate School of Pure and Applied
Sciences
University of Tsukuba
Tsukuba 305-8571 (Japan)
Fax : (+81)29-853-4237
E-mail: junji@chem.tsukuba.ac.jp
[b] Dr. R. Nadano
Department of Chemistry, Graduate School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000139.
Chem. Asian J. 2010, 5, 1875 – 1883
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPERS
vinylmetal species are straightforward reagents for providing
a variety of compounds bearing a (trifluoromethyl)vinyl
moiety. 1-(Trifluoromethyl)vinyl compounds with a conju-
gated system can be prepared by palladium-catalyzed cou-
pling reactions of relatively stable 1-(trifluoromethyl)vinyl-
metals, such as [1-(trifluoromethyl)vinyl]zinc,[10] -tin,[11] and
-boronic acid,[12] with the appropriate unsaturated organoha-
lides. The Suzuki[13a] and the Sonogashira coupling reac-
tions,[13b,c] and a carbonylation reaction[13d] are also amenable
to the synthesis of conjugated 1-(trifluoromethyl)vinyl com-
pounds by 1-(trifluoromethyl)vinylpalladium, generated
from the corresponding bromide. In contrast, methods for
the preparation of nonconjugated 1-(trifluoromethyl)vinyl
compounds are still rather limited because of the thermal in-
stability of 1-(trifluoromethyl)vinyl metal species.[14]
Tarrant reported that 3,3,3-trifluoroprop-1-en-2-yllithium
[1-(trifluoromethyl)vinyllithium] (1), generated upon treat-
ment of 2-bromo-3,3,3-trifluoropropene (2) with nBuLi, re-
acted with aldehydes or ketones to afford 2-(trifluoromethy-
l)allyl alcohols [Eq. (1)].[15] Although the lithium reagent
was sufficiently reactive to allow the preparation of noncon-
jugated 1-(trifluoromethyl)vinyl compounds, this approach
had the following serious drawbacks:[15c] 1) the generated
lithium species 1 was highly unstable and readily underwent
elimination of lithium fluoride, even at À788C, leading to
1,1-difluoroallene [Eq. (1)],[17] and thus, the reaction re-
quired the alternate addition of nBuLi and a carbonyl sub-
strate to 2 in several aliquots; 2) the product alcohols were
obtained only in 30–50% yields along with butyl carbinols
derived from nBuLi, indicating incomplete lithium–halogen
exchange.
ring opening of oxiranes or oxetanes with vinyllithium 1
[Eq. (2)].[18a] In this synthesis, the lithium–halogen-exchange
reaction takes place upon treatment of bromide 2 with
nBuLi at À1008C, under which conditions a slow lithium–
halogen exchange gave rise to a mixture of vinyllithium 1
and nBuLi. We succeeded, however, in the selective trap-
ping of 1 with appropriate electrophiles, such as oxiranes
and oxetanes, in the presence of BF3·OEt2 to obtain the de-
sired alcohols.[19] This selectivity might be explained by the
subtle difference between the reactivities of the two lithium
species. While nBuLi shows lower reactivity, probably be-
cause of its high aggregation state,[20] the reactivity of vinyl-
lithium 1 would be relatively enhanced by its low aggrega-
tion state, which might be caused by its sp2-hybridization,
the steric effect, and/or the lithium–fluorine interaction[21] of
the trifluoromethyl group.
In our previous paper, we reported on the efficient syn-
thesis of 1-(trifluoromethyl)vinyl-substituted alcohols by the
For general applicability of the 1-(trifluoromethyl)vinyla-
tion with vinyllithium 1, there remained a problem to be
solved with regard to its reaction with highly reactive elec-
trophiles. The vinylation of aldehydes led to the nonselec-
tive addition of vinyllithium 1 and nBuLi, as mentioned
above.[15,22] In this paper, we describe full details of the two
protocols for the general (trifluoromethyl)vinylation with
both more and less reactive electrophiles (Scheme 1): 1) one
involving a rapid lithium–halogen exchange for more reac-
tive electrophiles, such as aldehydes and imines,[18b] and
2) the other one involving the combination of a slow lithi-
um–halogen exchange and a selective trapping of vinyllithi-
Abstract in Japanese:
Scheme 1. Concept for 1-(trifluoromethyl)vinylation.
1876
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Rapid and Slow Generation of 1-Trifluoromethylvinyllithium
Table 2. Synthesis of 2-(trifluoromethyl)allyl alcohols 5.
um 1 with less reactive electrophiles other than oxiranes and
oxetanes,[18a] namely, carboxamides. Furthermore, 1-(trifluor-
omethyl)vinyl compounds obtained by using the two meth-
ods mentioned above were used to construct more complex
structures bearing a trifluoromethyl group, such as pyrroli-
dine ring-fused or furan ring-fused cyclopentenones and in-
danones by the Pauson–Khand reaction and the Nazarov
cyclization, respectively.
Entry
1
R
Product
Yield [%]
73
Ph
5a
5b
2
C6H
G
82
Results and Discussion
Generation of 1-(Trifluoromethyl)vinyllithium 1 by the
Rapid Lithium–Halogen-Exchange Reaction: Synthesis of 2-
(Trilfuoromethyl)allyl Alcohols 5
3
4
5
6
2-furyl
5c
5d
5e
5 f
58
93
92
76
We first re-examined the generation of vinyllithium 1 from
bromotrifluoropropene 2 upon treatment with several alkyl-
lithiums at temperatures ranging from À788C to À1058C
over 15 min. After quenching with methanol, the product
distributions were observed by 19F NMR (Table 1).[23] When
(E)-cinnamyl
(E)-a-methylcinnamyl
CH2CH2Ph
Table 1. Generation of 1-(trifluoromethyl)vinyllithium 1.
(Entries 2–6). Thus, the more rapid lithium–halogen ex-
change allowed the reaction with reactive electrophiles.
Entry
R
T [8C]
3 [%]
4 [%]
Recovery of 2 [%]
1
2
3
4
5
nBu
nBu
nBu
sec-Bu
tert-Bu
À78
20
31
14
60
50
54
11
1
26
35
17
58
76
10
5
Synthesis of N-[2-(Trifluoromethyl)allyl] Amines 7
À96
Allyl amine derivatives have been used as useful compo-
nents for the synthesis of N-heterocycles.[24] This fact
prompted us to investigate the reaction of vinyllithium 1
with imines (as other, more reactive, electrophiles), leading
to the synthesis of 2-(trifluoromethyl)allyl amine derivatives
7 [Eq. (3)].[9c–e] Although N-benzylimine 6a was not suffi-
ciently reactive toward 1, BF3·OEt2 promoted the desired
reaction to afford allyl amine 7a in 81% yield. When much
more reactive electrophiles, N-benzoylimine[25] 6b and N-to-
sylimine[26] 6c, were used, the corresponding allyl amines 7b
and 7c were obtained in 97% and 90% yield, respectively.
À105
À105
À105
the reaction was carried out with nBuLi at À788C, the de-
composition of vinyllithium 1 took place to afford 1,1-di-
fluoroallene (4) in 54% yield by the elimination of lithium
fluoride (Entry 1). On the other hand, performing the reac-
tion at À1058C suppressed the decomposition; here, we ob-
served only a 14% yield of 3,3,3-trifluoroprop-1-ene (3),
along with a 76% recovery of 2 (Entry 3). These results in-
dicate that either incomplete conversion of 2 or decomposi-
tion of 1 is inevitable in the reaction with nBuLi, because of
the slow exchange rate of 2 and the thermal instability of 1.
In contrast, the lithium–halogen-exchange reaction with sec-
BuLi proceeded rapidly even at À1058C to consume 90%
of 2, which generated 1 in at least 60% yield along with
26% of 4 (Entry 4).
We then attempted the reaction of vinyllithium 1 with al-
dehydes. Vinyllithium 1 was generated in situ from excess
amounts of vinyl bromide
2 (2.0 equiv) and sec-BuLi
(2.0 equiv), taking the partial decomposition of 1 into con-
sideration. Treatment of the ether solution of 1 with benzal-
dehyde afforded the desired 2-(trifluoromethyl)allyl alco-
hol[14] 5a in 73% yield (Table 2, Entry 1). Aryl, heteroaryl,
alkenyl, and alkyl aldehydes reacted in a similar manner to
give the corresponding allylic alcohols 5b–f in high yield
We further examined the 1-(trifluoromethyl)vinylation of
several other imines 6d–g. We chose N-tosylimines in view
of their availability, ease of handling, and the synthetic ap-
plicability of the products. The results are summarized in
Table 3. All examined N-tosylimines 6c–g provided the cor-
responding N-[2-(trifluoromethyl)allyl] amines 7c–g in good
Chem. Asian J. 2010, 5, 1875 – 1883
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1877

J. Ichikawa et al.
FULL PAPERS
Table 3. Synthesis of N-[2-(trifluoromethyl)allyl] amines 7.
presence of BF3·OEt2 (1.0 equiv), to afford the desired
ketone 9a but in only 7% yield. No products were obtained
in the absence of Lewis acid (Table 4, Entries 1 and 2). To
improve the yield of 9a, we investigated the effect of the
molar ratio of reagents. By using 3 equiv each of 2 and
nBuLi, the yield was increased to 44%, while 2 equiv of
BF3·OEt2 gave a poor result (Entries 5 and 6). To avoid side
reactions, 5 equiv of 2 was used, which improved the yield
of 9a to 55% (Entry 7). In this reaction, only a trace
amount of butyl adduct 1-(1-naphthyl)pentan-1-one was ob-
served, which indicated that vinyllithium 1 was selectively
trapped with amide 8a. When 8a was treated with 1 gener-
ated from 2 and sec-BuLi at À1058C in the presence of
BF3·OEt2, the reaction gave an inferior result (29% yield of
9a), compared with the result with nBuLi (Entry 4). The
rapid lithium–halogen exchange would cause competitive
Entry
1
N-Tosylimine
Product
Yield [%]
90
6c
6d
6e
6 f
6g
7c
7d
7e
7 f
7g
2
3
4
5
89
77
96
76, 91[a]
[a] Bromide 2 (3.5 equiv) and sec-BuLi (3.2 equiv) were used.
Table 4. (Trifluoromethyl)vinylation of amides and thioester 8a, 10–13.[a]
to excellent yield (Entries 1–5).
Butanimine 6e gave 7e in good
yield, even though it had acidic
a-protons (Entry 3). Although
1,1-diphenylmethanimine
6g
Entry
2 (equiv)
nBuLi (equiv)
BF3·OEt2 (equiv)
X
Electrophile
Yield [%]
showed modest reactivity, the
yield of 7g was improved to
91% when using greater
amounts of 1, generated from 2
1
2
1.5
1.5
2.0
2.2
3.0
3.0
5.0
1.5
1.5
2.0
2.0[c]
3.0
3.0
2.0
0
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
8a
8a
8a
8a
8a
8a
8a
0
7
39
29
44
9
1.0
1.0
1.0
1.0
2.0
1.0
3[b]
4
(3.5 equiv)
and
sec-BuLi 5[b]
6
7
(3.2 equiv) (Entry 5).
55
8
3.0
3.0
1.0
10
35
Generation of 1-
(Trifluoromethyl)vinyllithium 1
by the Slow Lithium-Halogen-
Exchange Reaction: Synthesis
of 1-(Trifluoromethyl)vinyl
Ketones 9
9
10
3.0
3.0
3.0
3.0
1.0
1.0
NMePh
11
12
5
23
NMe
G
11
3.0
3.0
1.0
13
–
[a] Reagents were added in the following order: 2, BF3·OEt2, nBuLi, and 8a. [b] Amide 8a was recovered in
42% (Entry 3) and in 23% (Entry 5). [c] sec-BuLi was used instead of nBuLi. Reagents were added in the fol-
lowing order: 2, sec-BuLi, 8a, and BF3·OEt2.
Recently, a,b-unsaturated car-
bonyl compounds with an a-tri-
fluoromethyl group have been attracting much attention, es-
pecially in the field of materials science. While many tri-
fluoromethacrylic acid derivatives were developed as build-
ing blocks[27] and monomers,[4] reports on the corresponding
ketones are rather limited.[28] Huang and co-workers report-
ed the synthesis of 1-(trifluoromethyl)vinyl ketones by the
Stille coupling of 1-(trifluoromethyl)vinyltin with acyl chlor-
ides.[11] The disadvantages associated with this reaction were
toxicity and low atom economy, attributed to the trialkyltin
group. We therefore focused on the (trifluoromethyl)vinyla-
tion of amide electrophiles using the slow lithium–halogen-
exchange protocol, expecting to synthesize 1-(trifluorome-
thyl)vinyl ketones 9. Amides, like oxiranes,[18] are less reac-
tive electrophiles and might react preferentially with vinyl-
lithium 1 in the presence of nBuLi.
decomposition of vinyllithium 1, when the reaction with
electrophiles is not facile.
Several other amides and thioesters 10–13 were examined,
in vain, as shown in Table 4.[29] N-Acylmorpholine 10 result-
ed in a nonselective reaction of vinyllithium 1 and nBuLi
(Entry 8). N-Methy-N-phenylamide 11 afforded only 5%
yield of ketone 9a. This is probably arising from its bulki-
ness, which prevents an attack of the lithium species
(Entry 9). The Weinreb amide 12 afforded 9a in 23% yield,
together with its conjugate addition product of N-methoxy-
methanamine (Entry 10). The reaction of 2-pyridylthioester
13 gave a complex mixture of trifluoromethyl compounds
(Entry 11).
We examined other substrates 8 to synthesize 1-(trifluoro-
methyl)vinyl ketones 9 under the reaction conditions de-
scribed above (Table 4, Entry 7). The results are summar-
ized in Table 5. The reactions of 8a–d bearing aryl groups
afforded the corresponding ketenes 9 in moderate to good
Vinyl bromide 2 (1.5 equiv) was treated with nBuLi
(1.5 equiv) to generate 1, which was in turn trapped with
N,N-dimethyl-1-naphthylcarboxamide (8a) at À1008C in the
1878
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Rapid and Slow Generation of 1-Trifluoromethylvinyllithium
Table 5. Synthesis of 1-(trifluoromethyl)vinyl ketones 9.
vinyl alkyl ketone 9l in 42% yield. Highly electrophilic 1-
(trifluoromethyl)vinylketones 9 were efficiently prepared by
a nucleophilic addition reaction of vinyllithium species, with-
out affecting the products.
Entry
1
Dimethylamide
Product
Yield [%]
2-(Trifluoromethyl)allyl Alcohols, N-[2-
(Trifluoromethyl)allyl] Amides, and 1-
(Trifluoromethyl)vinyl Ketones as Trifluoromethyl-group-
containing Synthones
8a
8b
8c
8d
8e
9a, 55
2
3
4
5
9b, 61
9c, 65
9d, 57
9e, 24[a]
The (trifluoromethyl)vinylated compounds obtained above,
2-(trifluoromethyl)allyl alcohols 5, N-[2-(trifluoromethyl)all-
yl] amides 7, and 1-(trifluoromethyl)vinyl ketones 9, were
expected to serve as versatile synthones for creating a varie-
ty of valuable trifluoromethyl-substituted compounds be-
cause of their reactive vinyl groups. To demonstrate the via-
bility of this building-block strategy, we converted the prod-
ucts to trifluoromethylated cyclopentenone derivatives by
an intramolecular Pauson–Khand reaction or the Nazarov
cyclization.
6
7
8 f
8g
9 f, 65
Synthesis of Bicyclic Cyclopentenones with an Angular
Trifluoromethyl Group by an Intramolecular Pauson–Khand
Reaction
9g, 51[a]
In steroid and alkaloid syntheses, much effort has been de-
voted to the construction of fused-ring systems involving an
angular methyl group,[30] as exemplified by dendrobine,[31]
the framework of which is formed by an intramolecular
Pauson–Khand reaction.[32] Whereas the introduction of an
angular trifluoromethyl group is one of the most promising
approaches for the analog synthesis of steroids and alka-
loids, it remains a challenging task.[3,33] Furthermore, there is
only one example of the Pauson–Khand reaction of enynes
bearing a trifluoromethyl group on the vinylic carbons, and
it gave an unsuccessful result.[34] These facts prompted us to
investigate the Pauson–Khand reaction of 1,6-enynes bear-
ing a trifluoromethyl group. The enyne substrates N-allyl-N-
propargylamides 14a–c and allyl propargyl ether 14d were
prepared from 2-(trifluoromethyl)allyl amides 7c,e and alco-
hol 5a, respectively, simply by propargylation [Eq. (4)].
8
8h
8i
9h, 38
9i, 66
9
10[a,b]
11[c]
12[c]
8j
8k
8l
9j, 73
9k, 78
9l, 42[a]
[a] 19F NMR yield relative to internal CF3C6H5 standard. [b] Vinyl bro-
mide 2 (2.0 equiv) was used. [c] BF3·OEt2 (1.3 equiv) was used.
yield. 4-(Trifluoromethyl)benzamide 8e resulted in 24%
yield of 9e. This is probably arising from the high reactivity
of the product 9e, caused by the strong electron-withdraw-
ing CF3 group. Ketones 9 f and 9g bearing a heteroaryl
group, such as the 2-thienyl and 2-furyl groups, were ob-
tained in 65% and 51% yield, respectively. (Trifluorome-
thyl)vinylation of cinnamamide 8h afforded 9h in 38%
yield. The reason for this is the susceptibility of the styryl
group to nucleophilic attack. Introduction of a methyl group
at the a-position suppressed the attack on the product 9i,
leading to an improved yield of 66%. Among the alkyl
ketone products, adamantyl ketone 9j and 1-phenylpropan-
2-yl ketone 9k were obtained in 73% and 78% yield, re-
spectively, and amide 8l bearing a primary alkyl group gave
Enyne 14a was treated with dicobalt octacarbonyl to
afford the cobalt alkyne complex, which was then heated in
CH3CN. The expected intramolecular Pauson–Khand reac-
tion smoothly proceeded to afford the desired angularly tri-
fluoromethylated cyclopentenone 15a in high yield (81%)
and with high diastereoselectivity (anti/syn=94:6) (Table 6,
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J. Ichikawa et al.
FULL PAPERS
Table 6. Synthesis of angularly trifluoromethylated cyclopentenones 15.
Synthesis of 2-Trifluoromethylindanones 17 by the Nazarov
Cyclization
As an application of the aryl (trifluoromethyl)vinyl ketones
9 obtained above, we attempted the Nazarov cyclization,[8,36]
which would provide 1-indanones bearing a trifluoromethyl
group at the a-position of the carbonyl group. a-Trifluoro-
methylation of ketones has been accomplished by radical[37]
and electrophilic[38] trifluoromethylation of enolate deriva-
tives. As these methods are often inefficient, a method for
the preparation of a-trifluoromethylated cyclopentanones
would be valuable.
Entry 1,6-Enyne
t [h] Product
Yield [%] anti/
syn[a]
1
14a
14b
3
15a 81
94:6[b]
83:17
2
2
15b 85
A solution of ketone 9c was treated with several Lewis
and Brønsted acids in 1,1,1,3,3,3-hexafluoropropan-2-ol
(HFIP) as a solvent at room temperature.[8,39] Whereas
Lewis acids, such as ferric chloride and trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf), hardly promoted the re-
action and gave only a trace amount of the desired 2-tri-
fluoromethylindan-1-one 17c (Table 7, Entries 1 and 2),
10 equiv of trifluoromethanesulfonic acid (TfOH) success-
fully afforded 17c in 87% yield (Entry 4).[40]
3
14c
14d
3
5
15c 71
15d 53
86:14
64:36
4[c]
[a] Isomer ratio was determined by 19F NMR. [b] Configuration of the major isomer
was determined to be anti. See text. [c] Substrate 14d was treated with Co2(CO)8 in
toluene at room temperature for 1 h, and then heated at reflux.
Table 7. The Nazarov cyclization of 1-(trilfuoromethyl)vinyl ketone 9c.
Entry 1). The cyclization of internal alkyne substrate 14b
and substrate 14c with an alkyl group at the allylic position
yielded pyrrolidine ring-fused cyclopentenones 15b and 15c
in 85% and 71% yield, respectively (Entries 2 and 3). Al-
though enyne 14d bearing an ether linkage instead of a sul-
fonamide linkage gave a poorer result under the above con-
ditions, refluxing the cobalt complex in toluene improved
the yield of the desired furan ring-fused cyclopentenone 15d
to 53%.
Entry
Acid (equiv)
t [h]
Yield [%]
1
2
3
4
FeCl3 (3.0)
20
20
20
3 days
3
TMSOTf (3.0)
TfOH (3.0)
TfOH (10)
trace
18
87
The configuration of the major isomer of 15a was deter-
mined to be anti by X-ray crystallography of 16, which is de-
rived from 15a by hydrogenation of the double bond
(Figure 1).[35] The relative configurations of 15b–d were as-
signed by analogy with 15a, and supported by comparing
The synthesis of several other substituted indanones was
achieved by the TfOH-mediated Nazarov cyclization
(Table 8). The cyclization of naphthyl ketones 9a,b proceed-
ed considerably faster than that of phenyl ketone 9c (En-
tries 1,2 vs 3). The cyclization of naphthyl ketones proceed-
ed in a regioselective manner. Treatment of 1-naphthyl
ketone 9a with TfOH exclusively gave the Nazarov product
17a in 73% yield without the formation of dihydrophenale-
none 18, which suggests that the Nazarov cyclization is pre-
ferred to a Friedel–Crafts-type cyclization. When 2-naphthyl
isomer 9b was subjected to the reaction conditions, inda-
none 17b was regioselectively obtained in quantitative yield.
Thiophene-fused cyclopentenone was also synthesized in
moderate yield (Entry 4). Di-
1
the H and 19F NMR data of each isomer.
vinylketone 9h, without sub-
stituent at the a position, un-
derwent the ring formation by
the use of TfOH, whereas the
cyclization of methylated 9i
proceeded
smoothly
with
Figure 1. X-ray crystal structure of cyclopentanone 16.
TMSOTf (Entries 5–7).[8a]
1880
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 1875 – 1883

Rapid and Slow Generation of 1-Trifluoromethylvinyllithium
Table 8. Synthesis of trifluoromethylated indanones 17.
2-bromo-3,3,3-trifluoroprop-1-ene (2), which is a versatile
fluorinated C3 building block.
Experimental Section
Entry
1
9
t
Product
Yield [%]
17a 73[a]
General
IR spectra were recorded by ATR (attenuated total reflectance) method.
NMR spectra were recorded in CDCl3 at 500 MHz (1H NMR), 126 MHz
(13C NMR), and 470 MHz (19F NMR). Chemical shift values were given
in ppm relative to internal Me4Si (for 1H NMR: d=0.00), CDCl3 (for
13C NMR: d=77.0), and C6F6 (for 19F NMR: d=0.0). Column chromatog-
raphy and preparative thin-layer chromatography (PTLC) were per-
formed on silica gel. Diethylether (Et2O), N,N-dimethylformamide
(DMF), and CH2Cl2 were dried by passing over a column of activated
alumina (A-2, Purity) followed by a column of Q-5 scavenger (Engel-
hard). 1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was distilled from mo-
lecular sieves 4 ꢁ, and stored over molecular sieves 4 ꢁ. Acetonitrile
(CH3CN) was distilled from P2O5 and then from CaH2, and stored over
molecular sieves 3 ꢁ. 2-Bromo-3,3,3-trifluoroprop-1-ene (2) was distilled
prior to use. BF3·OEt2 was distilled from CaH2 prior to use. All reactions
were conducted under argon. nBuLi (hexane solution), sec-BuLi (cyclo-
hexane solution), CF3SO3H, NaH (55% dispersion in mineral oil), prop-
argyl bromide, Co2(CO)8, and palladium on activated charcoal (5% Pd/
C) were purchased and used without further purification. N,N-Dimethyl-
carboxamides were prepared by the reaction of the corresponding acyl
chlorides with dimethylamine (50% solution in water) in CH2Cl2, and pu-
rified by distillation with bulb-to-bulb apparatus under reduced pressure.
N-benzoylimine 6b[25] and N-(4-methylbenzenesulfonyl)imine 6c–g[26]
were prepared according to the literatures.
9a 1 h
2
9b 1 h
17b Quant.
3
4
9c 3 days
9 f 3 days
17c 87
17 f 30[b]
5
6
9h 3 days
9h 3 days
17h 46
[c]
17h
–
7
9i 10 min
17i 86[c]
[a] Dihydrophenalenone 18 was not observed. [b] (Trifluoromethyl)vinyl
ketone 9 f was recovered in 21% yield. [c] TMSOTf (1 equiv) was used in
place of TfOH (CH2Cl2/HFIP=1:1, RT).
Syntheses
2-(Trifluoromethyl)allyl alcohols (5): To a solution of 2-bromo-3,3,3-tri-
fluoroprop-1-ene (2, 2.0 mmol) in Et2O (10 mL) was added a solution of
sec-BuLi (1.07m in cyclohexane, 2.0 mmol) in Et2O (2 mL, pre-chilled
with a À788C bath) at À1058C (internal temperature) over 5 min. After
stirring for an additional 5 min, a solution of an aldehyde (1.0 mmol) in
Et2O (2 mL) was transferred by using a cannula into the solution of the
generated vinyllithium reagent. The reaction mixture was allowed to
warm up to À508C over 2 h. After the reaction was quenched with phos-
phate buffer (pH 7, 10 mL), organic materials were extracted with Et2O.
The combined extracts were washed with brine, and dried over MgSO4.
After removal of the solvent under reduced pressure, the residue was pu-
rified by column chromatography (hexane-EtOAc, 10:1) to give 5.
Conclusions
We develop two protocols for the synthesis of 1-(trifluoro-
methyl)vinyl compounds by rapid and slow lithium–halogen-
exchange processes that generate thermally unstable 1-(tri-
fluoromethyl)vinyllithium (1). The rapid lithium–halogen-
exchange reaction of 2-bromo-3,3,3-trifluoroprop-1-ene (2)
takes place by using sec-BuLi at À1058C to suppress the de-
composition of 1. The reaction with more reactive electro-
philes, aldehydes and N-tosylimines, can now proceed to
afford 2-(trifluoromethyl)allyl alcohols 5 and amines 7 in
good to excellent yield. The slow lithium–halogen exchange
of 2 with nBuLi gives a mixture of vinyllithium 1 and
nBuLi, in which 1 is preferentially trapped by N,N-dimethy-
lamide to yield 1-(trifluoromethyl)vinyl ketones 9 efficiently.
These two (trifluoromethyl)vinylation methods are consid-
ered to be complementary, which broadens their applicabili-
ty to various electrophiles.
Furthermore, we succeed in the construction of pyrroli-
dine ring-fused or furan ring-fused cyclopentenones 15 bear-
ing an angular trifluoromethyl group and 2-trifluoromethyl-
substituted indanones 17 by: 1) the cobalt octacarbonyl-
mediated Pauson–Khand reaction of 1,6-enynes 14, derived
from 2-(trifluoromethyl)allyl amides 7 or alcohols 5, and
2) the Nazarov cyclization of aryl 1-(trifluoromethyl)vinyl
ketones 9, respectively. These complex trifluoromethyl-con-
taining structures are constructed in a couple of steps from
1-Phenyl-2-trifluoromethylprop-2-en-1-ol (5a): A colorless liquid (73%).
IR (neat): n˜ =3357, 3066, 3035, 2922, 2850, 1321, 1167, 1115, 1022, 957,
698 cmÀ1; H NMR (500 MHz, CDCl3, 258C, TMS): d=2.20–2.22 (m, 1H;
1
OH), 5.43 (d, 3J(H,H) =2.9 Hz, 1H; CH), 5.80 (q, 4J(H,F) =1.4 Hz, 1H;=
CH2), 5.93 (q, 4J(H,F) =0.7 Hz, 1H;=CH2), 7.33–7.39 ppm (m, 5H; ArH);
13C NMR (126 MHz, CDCl3, 258C): d=71.3, 119.8 (q, 3J(C,F) =5 Hz),
123.1 (q, 1J(C,F) =275 Hz), 126.8, 128.6, 128.7, 140.2, 140.8 ppm (q, J(C,F)
=
2
28 Hz); 19F NMR (470 MHz, CDCl3, 258C, C6F6): d=96.5 ppm (br s);
HRMS (FAB): m/z (%) calcd for C10H10F3O: 203.0684 [M+H]+; found:
203.0687.
[2-(Trifluoromethyl)allyl] amines (7b–g): To a solution of 2 (0.88 mmol)
in Et2O (8 mL), was added a solution of sec-BuLi (1.07m in cyclohexane,
0.80 mmol) in Et2O (2 mL) at À1058C. After stirring for 10 min, a solu-
tion of N-benzoylimine 6b[25] or N-(4-methylbenzenesulfonyl)imine 6c–
g[26] (0.40 mmol) in Et2O (5–20 mL) was added dropwise. The reaction
mixture was allowed to warm up to À508C over 2 h. The reaction was
quenched with phosphate buffer (pH 7, 10 mL), and organic materials
were extracted with EtOAc. The combined extracts were washed with
brine, and dried over MgSO4. After removal of the solvent under re-
duced pressure, the residue was purified by column chromatography to
give 7b–g.
4-Methyl-N-[1-phenyl-2-(trifluoromethyl)prop-2-en-1-yl]benzenesulfona-
mide (7c): Colorless crystals (90%); m.p.: 111–1148C; IR (neat): n˜ =
Chem. Asian J. 2010, 5, 1875 – 1883
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1881

J. Ichikawa et al.
FULL PAPERS
3261, 3064, 2929, 1435, 1323, 1159, 1115, 1090, 968, 914, 771, 660 cmÀ1
;
The Nazarov cyclization of 9: To a solution of 9 (0.29 mmol) in HFIP
(1 mL) was added TfOH (3 mmol) at room temperature. After stirring
for 1 h, the reaction was quenched with phosphate buffer (pH 7, 5 mL).
Organic materials were extracted with EtOAc. The combined extracts
were washed with brine, and dried over MgSO4. After removal of the sol-
vent under reduced pressure, the residue was purified by column chroma-
tography (hexane/EtOAc, 10:1) to give 17.
1H NMR (500 MHz, CDCl3, 258C, TMS): d=2.41 (s, 3H; CH3), 5.12 (d,
2J(H,H) =7.2 Hz, 1H;=CH2), 5.43 (d, 2J
ACTHNUTRGEN(NUG H,H)=7.2 Hz, 1H;=CH2), 5.73
(s, 1H), 5.88 (s, 1H), 7.04 (d, 3J(H,H) =6.5 Hz, 2H; ArH), 7.18–7.25 (m,
5H; ArH), 7.63 ppm (d, 3J(H,H) =8.2 Hz, 2H; ArH); 13C NMR (126 MHz,
1
CDCl3, 258C): d=21.5, 56.5, 121.6 (q, 3J(C,F) =5 Hz), 122.8 (q, J(C,F)
=
2
275 Hz), 127.1, 127.2, 128.4, 128.8, 129.5, 136.8, 137.2, 138.0 (q, J(C,F)
=
29 Hz), 143.7 ppm; 19F NMR (470 MHz, CDCl3, 258C, C6F6): d=
96.5 ppm (brs); elemental analysis: calcd (%) for C17H16F3NO2S (341.4):
C 57.46, H 4.54, N 3.94; found: C 57.72, H 4.73, N 3.74.
2-(Trifluoromethyl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one
(17a): m.p.: 102–1048C; IR (neat): n˜ =3059, 2945, 1705, 1574, 1514, 1439,
1
1344, 1250, 1184, 1153, 1088, 955 cmÀ1; H NMR (500 MHz, CDCl3, 258C,
TMS): d=3.34–3.43 (m, 1H), 3.48–3.57 (m, 2H), 7.53 (d, 3J(H,H) =8.4 Hz,
1-(Trifluoromethyl)vinylketones (9): To
a
solution of BF3·OEt2
1H; ArH), 7.60 (dd, 3J(H,H) =7.8, 7.8 Hz, 1H; ArH), 7.71 (dd, 3J(H,H) =7.8,
(1.0 mmol) and 2 (5.0 mmol) in Et2O (10 mL) was added a solution of
nBuLi (1.53m in hexane, 2.0 mmol) in Et2O (3 mL) at À1008C. After stir-
ring for 10 min, a solution of N,N-dimethylcarboxamide 8 (1.0 mmol) in
Et2O (5 mL) was added. The reaction mixture was allowed to warm up
to À508C over 2 h. Phosphate buffer (pH 7, 10 mL) was added to quench
the reaction, and organic materials were extracted with EtOAc. The com-
bined extracts were washed with brine, and dried over MgSO4. After re-
moval of the solvent under reduced pressure, the residue was purified by
column chromatography (hexane-EtOAc, 10:1) to give 9.
3
7.8 Hz, 1H; ArH), 7.91 (d, 3J(H,H) =7.8 Hz, 1H; ArH), 8.10 (d, J(H,H)
=
8.4 Hz, 1H; ArH), 9.09 ppm (d, 3J(H,H) =7.8 Hz, 1H; ArH); 13C NMR
2
(126 MHz, CDCl3, 258C): d=27.9 (q, 3J(C,F) =2 Hz), 50.1 (q, J(C,F)
=
27 Hz), 123.3, 123.9, 125.0 (q, 1J(C,F) =279 Hz), 127.2, 128.3, 129.3, 129.6,
130.1, 132.8, 137.1, 155.7, 197.1 ppm; 19F NMR (470 MHz, CDCl3, 258C,
C6F6): d=93.9 ppm (d, 3J
ACTHNUGRTENUNG(F,H)=9 Hz); elemental analysis: calcd (%) for
C14H9F3O (250.2): C 67.20, H 3.63; found: C 67.18, H 3.83.
1-(1-Naphthyl)-2-(trifluoromethyl)prop-2-en-1-one (9a): A pale brown
liquid (55%). IR (neat): n˜ =3059, 1668, 1508, 1340, 1132, 1055, 793 cmÀ1
;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=6.14 (q, 4J(H,F) =1.6 Hz,
1H), 6.67 (s, 1H;=CH2), 7.50 (dd, 3J(H,H) =8.2, 7.2 Hz, 1H; ArH), 7.56
(dd, 3J(H,H) =7.4, 7.4 Hz, 1H; ArH), 7.59 (dd, 3J(H,H) =7.4, 7.4 Hz, 1H;
ArH), 7.62 (d, 3J(H,H) =7.2 Hz, 1H; ArH), 7.91 (d, 3J(H,H) =7.4 Hz, 1H;
Acknowledgements
ArH), 8.02 (d, 3J(H,H) =8.2 Hz, 1H; ArH), 8.18 ppm (d, 3J(H,H) =7.4 Hz,
We thank Dr. N. Kano (the University of Tokyo) for the X-ray crystal
structure analysis. We are grateful to the Ogasawara Foundation for the
Promotion of Science and Engineering and Central Glass Co., Ltd. for fi-
nancial support, and to Tosoh F-Tech, Inc. for a generous gift of 2-
bromo-3,3,3-trifluoroprop-1-ene.
1
1H; ArH); 13C NMR (126 MHz, CDCl3, 258C): d=121.8 (q, J(C,F)
=
276 Hz), 124.1, 125.1, 126.8, 127.9, 128.4, 128.5, 130.5, 132.6, 133.7 (q,
3J(C,F) =5 Hz), 133.7, 134.2, 139.4 (q, 2J(C,F) =29 Hz), 192.7 ppm; 19F NMR
(470 MHz, CDCl3, 258C, C6F6): d=96.9 ppm (brs); HRMS (FAB): m/z
(%) calcd for C14H10F3O: 251.0684 [M+H]+; found: 251.0691.
The Pauson–Khand reaction of N-propargyl-N-[2-(trifluoromethyl)allyl]
amines (14a-c): To a solution of 14a–c (0.339 mmol) in CH2Cl2 (10 mL)
was added Co2(CO)8 (0.41 mmol), and the solution was stirred for 30 min
at room temperature. The solvent was removed under reduced pressure,
and then acetonitrile (15 mL) was added. After heating the solution at
608C for 2–3 h, the solvent was removed under reduced pressure. The
residue was purified by column chromatography (hexane/EtOAc, 3:1) to
give 15a–c.
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ACHTUNGTRENUN(NG 1H)-one (15a): A pale yellow liquid (81%;
anti/syn=94:6). Major product: anti isomer: IR (neat): n˜ =3032, 2943,
2868, 1730, 1348, 1147, 1059, 912, 802, 667, 563, 542 cmÀ1 1H NMR
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2
2.37 (d, 2J(H,H) =18.0 Hz, 1H; CH2), 2.40 (s, 3H; CH3), 4.41 (d, J(H,H)
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2
15.0 Hz, 1H; CH2), 4.58 (d, J(H,H) =15.0 Hz, 1H; CH2), 5.34 (s, 1H; CH),
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7.34–7.41 (m, 1H; ArH), 7.57 ppm (d, 3J(H,H) =8.1 Hz, 2H; ArH);
2
13C NMR (126 MHz, CDCl3, 258C): d=21.5, 41.4, 47.8, 62.2 (q, J(C,F)
=
26 Hz), 64.0, 125.1 (brs), 125.9 (q, 1J(C,F) =284 Hz), 127.2, 127.5 (brs),
128.8, 129.0 (brs), 129.2 (brs), 129.6, 131.5, 135.0, 136.8, 143.9, 168.3,
203.1 ppm; 19F NMR (470 MHz, CDCl3, 258C, C6F6): d=87.6 ppm (br s);
HRMS (FAB): m/z (%) calcd for C21H19F3NO3S: 422.1038 [M+H]+;
found: 422.1050. Minor product: syn isomer: IR (neat): n˜ =3066, 3033,
2922, 2852, 1732, 1354, 1165, 1092, 1032 cmÀ1 1H NMR (500 MHz,
;
CDCl3, 258C, TMS): d=2.43 (s, 3H; CH3), 2.47 (d, 2J(H,H) =17.8 Hz, 1H;
CH2), 2.72 (d, 2J(H,H) =17.8 Hz, 1H; CH2), 4.45 (s, 1H; CH), 4.57 (d,
2J(H,H) =16.0 Hz, 1H; CH2), 4.69 (d, 2J(H,H) =16.0 Hz, 1H; CH2), 6.13 (s,
1H;=CH), 7.07–7.18 (m, 1H; ArH), 7.27 (d, 3J(H,H) =8.3 Hz, 2H; ArH),
7.28–7.35 (m, 3H; ArH), 7.54 (d, 3J(H,H) =8.3 Hz, 2H; ArH), 7.54–
7.64 ppm (m, 1H; ArH); 13C NMR (126 MHz, CDCl3, 258C): d=21.6,
43.5, 49.3, 62.4 (q, 2J(C,F) =26 Hz), 71.0, 124.9 (q, 1J(C,F) =285 Hz), 127.9,
128.1 (br s), 128.1 (br s), 128.8, 129.8, 130.0, 133.3, 133.7, 144.6, 168.9,
202.9 ppm; 19F NMR (470 MHz, CDCl3, 258C, C6F6): d=94.0 ppm (brs);
HRMS (FAB): m/z (%) calcd for C21H19F3NO3S: 422.1038 [M+H]+;
found: 422.1010.
1882
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 1875 – 1883

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Received: February 20, 2010
Published online: June 22, 2010
Chem. Asian J. 2010, 5, 1875 – 1883
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1883