Synthesis of αβ-unsaturated trifluoromethyl ketones from 4-Dimethylamino-1,1,1-trifluorobut-3-ene-2-one by addition of grignard reagents

Article abstract of DOI:10.1016/S0040-4020(00)00597-4

Enaminones are available by reaction of 4-ethoxy-1,1,1-trifluorobut-3-ene-2-one with amines such as dimethylamine and they react with Grignard reagents to give αβ-unsaturated trifluoromethyl ketones in good yield by 1,4-addition followed by elimination. The generality of this procedure is contrasted with reactions based either on the use of organolithium nucleophiles, or the use of 4-alkoxy-αβ-unsaturated trifluoromethyl ketones as electrophilic partners. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00597-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7261–7266
Synthesis of ab-Unsaturated Trifluoromethyl Ketones from
4-Dimethylamino-1,1,1-trifluorobut-3-ene-2-one by Addition of
Grignard Reagents
*
Rebecca J. Andrew and John M. Mellor
Department of Chemistry, Southampton University, Southampton, SO17 1BJ, UK.
Received 22 March 2000; revised 8 June 2000; accepted 22 June 2000
Abstract—Enaminones are available by reaction of 4-ethoxy-1,1,1-trifluorobut-3-ene-2-one with amines such as dimethylamine and they
react with Grignard reagents to give ab-unsaturated trifluoromethyl ketones in good yield by 1,4-addition followed by elimination. The
generality of this procedure is contrasted with reactions based either on the use of organolithium nucleophiles, or the use of 4-alkoxy-ab-
unsaturated trifluoromethyl ketones as electrophilic partners. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
and in additions to b-substituted-ab-unsaturated ketones,
such as the ketones (2) and (3). Organocuprate additions
to acetylenic trifluoromethylketones afford7 products by
both 1,2- and 1,4-addition. Again organometallic additions
to b-substituted unsaturated trifluoromethyl ketones (2) and
(3) might lead to products of 1,2- or 1,4-addition. A well
investigated route with non-fluorinated analogues has
concerned the displacement of alkoxy groups. The ketones
(2) are readily available by acylation of the alkylvinyl ethers
with trifluoroacetic anhydride, but the value of this route is
limited. Reaction6 of phenylmagnesium bromide with the
ketone (2, RˆEt) at 0ЊC gives an unsaturated ketone, a
product of 1,2-addition, in only 20–30% yield. Side
reactions by direct attack at the carbonyl group occur. Simi-
larly additions of organozinc reagents to the ketones (2) are
complicated by the dominance of 1,2-addition giving
undesired products. Addition elimination sequences based
on b-halo- or b-alkylthio- analogues have been investi-
gated, but not developed for the synthesis of unsaturated
trifluoromethyl ketones.
The present strongly developed interest1 in organofluorine
chemistry, and particularly the construction of simple
fluorine building blocks appropriate for subsequent
synthetic elaboration, has led to considerable study of, in
general, trifluoromethylketones2 and, in particular, a,b-
unsaturated3–11 trifluoromethylketones (1). Such ketones
have been used as intermediates in heterocyclic synthesis12
and have also been viewed as synthetic targets13 because of
their possible pharmacological interest. Whilst trifluoro-
methyl ketones constitute a particularly well documented
class of serine protease inhibitors which have proven attrac-
tive against elastase, chymotrypsin and CMV protease14 and
aromatic trifluoromethyl ketones are found to be inhibitors
of helicobacter pylori,15 the published routes to such a,b-
unsaturated trifluoromethylketones (1) are fraught with
difficulties. These are highlighted by the comments,
methods for the synthesis of trifluoromethyl ketones are
scarce16 and in reference to the most developed route of
nucleophilic trifluoromethylation of esters, there were
until recently few reports of successful synthetic method-
ology.17 Some routes3 require organofluorine reagents less
readily available than trifluoroacetic anhydride and other
routes5 are multi-step. Aldol condensation8 of trifluoro-
methylketones with aldehydes is inefficient. An earlier
route9 depends upon the addition of vinyl Grignard reagents
to trifluoroacetic acid and proceeds in low yield. Two poten-
tially promising routes are the use of organometallic
reagents in additions to acetylenic trifluoromethylketones
An alternative route using the readily available18–20
4-dialkylamino-ab-unsaturated ketones (3) has recently
been studied. With non-fluorinated analogues of (3)
some success has been achieved in such addition elimina-
tion reactions using not only Grignard,21,22 organolithium23
and organocuprate24 reagents, but more recently25 with
organocerium reagents. In the synthesis of a,b-unsaturated
Keywords: addition; Grignard reagents; organolithium; trifluoromethyl-
ketones.
* Corresponding author. Tel.: ϩ44-(0)23-8059-2392; fax: ϩ44-(0)23-
8059-6805; e-mail: jmm4@soton.ac.uk
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00597-4

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R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7261–7266
trifluoromethylketones (1) Balenkova et al.11 have recently
shown that aryllithiums add to the 4-dimethylamino-ab-
unsaturated trifluoromethylketone (4) by 1,4-addition. In
contrast in the one reported example using a Grignard
reagent the diketone (5) was transformed11 to the hydroxy-
ketone (6) in only 18% yield. There are other reports of the
contrasting behaviour of Grignard reagents and organo-
lithium reagents with b-substituted-ab-unsaturated
ketones. In a recent study21 with b-dialkylamino-ab-
unsaturated ketones although alkyllithiums undergo
1,4-addition, 1,2-addition is observed with Grignard
reagents. There is a single example,6 albeit in moderate
yield, of 1,4-addition of a Grignard reagent to a b-dialkyl-
amino-ab-unsaturated trifluoromethylketone (3). With non-
fluorinated analogues 1,4-additions of Grignard reagents22
are well described. Not only is the distinction in the regio-
chemistry of additions to methyl- and trifluoromethyl-
ketones unclear, but the contrasting 1,4-addition of phenyl
magnesium bromide to acyclic b-alkoxy-ab-unsaturated
ketones and the preferential 1,2-addition of the same reagent
to cyclic b-alkoxy-ab-unsaturated ketones, indicates that
the expected outcome of Grignard additions to ketones
such as (2) and (3) is unclear. In the light of our studies26,27
with the readily available b-alkoxy- and b-dialkyl-dialkyl-
amino-ab-unsaturated trifluoromethylketones (3), we
considered that reaction with a variety of Grignard reagents
might provide a route to b-aryl-ab-unsaturated trifluoro-
methylketones and b-alkyl-ab-unsaturated trifluoro-
methylketones (1). In this paper we establish such
procedures based both on Grignard and organolithium
reagents.
bromide gave the alcohol (15) in addition to the expected
ketone (16). An interesting difference was observed in the
products of overaddition. With an excess of phenyl mag-
nesium bromide, greater than 2 equiv., the product of further
reaction was observed to be the ketone (17). In contrast the
product of further reaction of methyl magnesium bromide
with the ketone (10) was the alcohol (18). To illustrate the
reaction of Grignard reagents derived from terminal alkyl-
acetylenes, the Grignard derived from 1-decyne was
reacted. A small amount of further reaction to afford the
alcohol (19) was observed, but the unsaturated ketone (20)
was obtained in 61% yield.
The addition of organometallic reagents other than Grignard
reagents was briefly examined. A procedure using cerium-
(III) chloride, previously developed25 with non-fluorinated
enaminoketones, was examined. Using phenylmagnesium
bromide we find that reaction with the enaminoketone (4)
in the presence of CeCl3 gives the unsaturated ketone (10),
but with no enhancement of yield relative to the use of
phenylmagnesium bromide alone. The reaction of ethyl
bromoacetate with the enaminone (4), under Reformatsky
conditions using zinc failed. However reaction with organo-
lithium reagents is effective, but has no advantage over the
addition of organomagnesium reagents. In the recent study
of the addition of aryllithiums to the 4-dimethylamino-
trifluoromethylketone (4) and to the dione (5) Balenkova
et al.11 report that reaction of butyllithium, in both cases,
affords complex mixtures, and the expected products,
unsaturated trifluoromethyl ketones could not be isolated.
We find that reaction of 4-dimethylamino-trifluoromethyl-
ketone (4) with phenyl lithium afforded the ketone (10) in
42% yield and the lithium derivative of phenylacetylene
gave the ketone (16) in 37% yield. By contrast with these
examples, our results shown in Table 1 of reactions with a
variety of magnesium reagents derived from alkyl- and aryl-
derivatives, establish the preference in preparation of
unsaturated trifluoromethyl ketones of the use of Grignard
reagents.
Results and Discussion
Reaction of enaminone (4) with the Grignard reagent
prepared from 1-bromooctane and chromatographic puri-
fication gave the ketone (7) in 67% yield (see Table 1). In
contrast to the analogous addition to the alkoxy analogues
reaction is highly selective. Only 1,4-addition is observed
and neither 1,2-addition products, nor products of further
addition are isolated when 2 equiv. or less of Grignard
reagent are used. Formation of the product (7) is also stereo-
selective. No cis product is observed. In a similar manner
1-bromoundecane and 1-bromododecane gave the ketones
(8) and (9) respectively. Reaction is also efficient with
Grignards derived from aryl halides. Bromobenzene,
p-bromoanisole, 1-bromo-4-fluorobenzene, 3-bromotoluene
and 1-bromonaphthalene gave the ketones (10), (11), (12),
(13), and (14) respectively. Acetylenic Grignard reagents
also react, but in contrast to those cases of addition of
alkyl and aryl Grignard reagents where no reaction at the
carbonyl centre is observed using 2 equiv. of a Grignard
reagent, overreaction with phenylacetylenic magnesium
In the two accompanying papers26,27 we show that the
4-dialkylamino-ab-unsaturated trifluoromethylketones (3)
are less reactive than the analogous 4-alkoxy-ab-unsatu-
rated trifluoromethylketones (2). We describe cases where
it is necessary to use the latter with less reactive nucleo-
philes in order to achieve satisfactory transformations. In
contrast with more reactive organometallic nucleophiles
there is merit in matching less reactive partners. Thus in

R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7261–7266
Table 1. Synthesis of unsaturated trifluoromethyl ketones
7263
Enaminone substrate
Nucleophile
Product
Yields (%)
67
(4)
n-C8H17MgBr
(4)
(4)
n-C11H21MgBr
n-C12H25MgBr
60
38
(4)
(4)
PhMgBr
PhLi
47a
42
(4)
(4)
p-MeOC6H4MgBr
p-FC6H4MgBr
58
50
(4)
(4)
m-CH3C6H4MgBr
62
80
a-Naphthyl magnesium bromide
(4)
(4)
(4)
PhCCMgBr
PhCCLi
37a
37
C8H17CCMgBr
61a
a See text for additional products.
reaction of 4-dialkylamino-ab-unsaturated trifluoro-
methylketones (3) and 4-alkoxy-ab-unsaturated trifluoro-
methylketones (2) with aryllithium nucleophiles the less
reactive 4-dialkylamino-ab-unsaturated trifluoromethyl-
ketones (3) can be used more effectively. However instead
of using the more reactive alkyllithiums with 4-dialkyl-
amino-ab-unsaturated trifluoromethylketones (3) there is
preference for using organomagnesium reagents in trans-
formations to give various ab-unsaturated trifluoromethyl
ketones. In particular such a strategy avoids the complica-
tions found in reactions of the 4-alkoxy-ab-unsaturated
trifluoromethylketones (2), where undesired side-products
complicate the 1,4-mode of addition. In view of the current
interest in trifluoromethyl ketones the methodology
developed in this paper based on cheap readily available
starting materials is likely to have many applications.
Experimental
General experimental methods are described in the previous
paper.27
General procedure for the synthesis of
trifluoromethylated a,b-unsaturated ketones (1)
A solution of the alkyl magnesium bromide was prepared
from the corresponding alkyl (aryl) bromide (2.4–
3.0 mmol) and dry magnesium turnings (2.4–3.0 mmol) in
anhydrous diethyl ether (1.0 ml) by dropwise addition of the
alkyl (aryl) halide followed by gentle heating until all the
magnesium was consumed. A solution of 4-dimethylamino-
1,1,1-trifluoro-3-buten-2-one (4) (0.20 g, 1.2 mmol) in
anhydrous ether (6 ml) was then added to the solution of

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R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7261–7266
the Grignard reagent at room temperature with stirring. The
resulting mixture was heated under reflux for 2 h before the
cold reaction mixture was poured into ice cold 2 M hydro-
chloric acid (14.5 ml). The ether layer was separated and the
aqueous layer further extracted with ether (2×12 ml). The
combined ether phases were washed with water (12 ml),
dried over Na2SO4 and the solvent removed in vacuo. The
crude product was purified by column chromatography
(silica gel, neat petroleum ether) to afford the appropriate
trifluoro substituted unsaturated ketone.
magnesium (0.06 g) afforded as a yellow oil in 80% yield
the known 4-(4-methoxyphenyl)-1,1,1-trifluoro-3-buten-2-
one (11). Flash chromatography (eluant petroleum ether)
and recrystallisation (ethanol) afforded in 58% yield the
known28 title compound as yellow crystals, (0.16 g) mp
47–48ЊC (lit. mp 38ЊC) dH 7.93 (1H, d Jˆ15.8 Hz, H-4),
7.0 (2H, dd, Jˆ6.6, 1.8 Hz, H-20), 6.95 (2H, dd Jˆ7.0,
1.8 Hz, H-30, H-50), 6.88 (1H, dd Jˆ15.8, 0.7, H-3), 3.87
(3H, s, OCH3); dC 55.66 (OCH3), 114.17 (C-3), 114.90
(C-30, C-50), 116.33 (q, C-1), 126.31 (C-10), 131.56 (C-2,
C-60), 150.13 (C-4), 163.34 (C-40), 180.06 (q, C-2); dF
Ϫ84.34 (CF3); nmax 3012, 2937, 2841, 1704, 1590 and
1,1,1-Trifluoro-3-dodecen-2-one (7). The Grignard
reagent from 1-bromooctane (0.46 g) and magnesium
(0.06 g) afforded as a colourless oil in 67% yield the
known5 1,1,1-trifluoro-3-dodecen-2-one (7) (0.19 g) dH
7.34 (1H, dt Jˆ15.8, 7.0 Hz, H-4), 6.41 (1H, dd
Jˆ15.8 Hz, 1.1, H-3), 2.34 (2H, dq Jˆ1.5, 7.0 Hz, H-5),
1.52 (2H, m, H-6), 1.28 (s, 10H), 0.89 (3H, t Jˆ6.6 Hz,
H-12); dC 14.18 (C-12), 22.76 (C-11), 27.74 (C-10), 29.27
(C-8, C-9), 29.40 (C-7), 31.93 (C-6), 33.40 (C-5), 116.38 (q,
C-1), 121.48 (C-3), 157.10 (C-4), 179.92 (q, C-2); dF
1568 cmϪ1
.
4-(4-Fluorophenyl)-1,1,1-trifluoro-3-buten-2-one (12).
The Grignard reagent from 1-bromo-4-fluorobenzene
(0.52 g) and magnesium (0.07 g) afforded in 50% yield
the known29 4-(4-fluorophenyl)-1,1,1-trifluoro-3-buten-2-
one (12) as white crystals (0.13 g) mp 39–41ЊC (ethanol-
water) dH 7.94 (1H, d Jˆ15.8 Hz, H-4), 7.66 (2H, dd,
Jˆ8.8, 5.1, 1.8 Hz, H-20, H-60), 7.15 (2H, dt Jˆ8.5, 8.5,
1.8 Hz, H-30, H-50), 6.95 (1H, d Jˆ15.8 Hz, H-3); dC
116.50 (q, C-1), 116.46 (C-3), 116.72 (d C-30, C-50),
129.80 (d, C-10), 131.54 (C-20, C-60), 148.87 (C-4),
165.25 (d, C-40), 180.01 (q, C-2); dF Ϫ84.16 (CF3),
Ϫ56.20 (ArF); nmax 1716, 1613 and 1589 cmϪ1; found
Mϩ 218.0350. C10H6F4O requires Mϩ 218.0355 m/z 218
(51), 149 (100), 121 (44) and 97 (36).
Ϫ84.29 (CF3); nmax 2929, 2858, 1731, 1711 and 1628 cmϪ1
.
1,1,1-Trifluoro-3-pentadecen-2-one (8). The Grignard
reagent from 1-bromoundecane (0.56 g) and magnesium
(0.06 g) afforded as a colourless oil in 60% yield 1,1,1-
trifluoro-3-pentadecen-2-one (8) (0.20 g) dH 7.34 (1H, dt
Jˆ15.8 Hz, 7.0, H-4), 6.41 (1H, dd Jˆ15.8, 0.7 Hz, H-3),
2.34 (2H, dq Jˆ1.4, 7.0 Hz, H-5), 1.52 (2H, m, H-6), 1.27
(s, 16H), 0.88 (3H, t Jˆ6.6 Hz, H-15); dC 14.21 (C-15),
22.82 (C-14), 27.75 (C-13), 29.29 (C-12), 29.46 (C-11,
C-10), 29.60 (C-9), 29.73 (C-7, C-8), 32.04 (C-6), 33.40
(C-5), 116.38 (q, C-1), 121.48 (C-3), 157.10 (C-4), 179.92
(q, C-2); dF Ϫ84.27 (CF3); nmax 2926, 2854, 1730, 1710 and
1628 cmϪ1; found Mϩ 278.1895. C15H25F3O requires Mϩ
278.1858 m/z 278 (12), 249 (3), 235 (3), 221 (4), 209
(88), 179 (17), 165 (22), 97 (47), 69 (61) and 43 (100).
4-(3-Tolyl)-1,1,1-trifluoro-3-buten-2-one
(13).
The
Grignard reagent from 3-bromotoluene (0.51 g) and magne-
sium (0.07 g) afforded as a yellow oil in 62% yield 4-(3-
tolyl)-1,1,1-trifluoro-3-buten-2-one (13) (0.16 g) dH 7.94
(1H, d Jˆ15.8 Hz, H-4), 7.44–7.30 (4H, m, aromatic),
7.00 (1H, dd Jˆ15.8, 0.7 Hz, H-3), 2.40 (3H, s, CH3); dC
21.38 (CH3), 116.55 (C-3), 116.57 (q, C-1), 126.72 (C-60),
129.27 (C-40), 129.93 (C-50), 133.40 (C-20), 139.19 (C-10,
C-30), 150.57 (C-4), 180.17 (q, C-2); dF Ϫ84.28 (CF3); nmax
3030, 2926,1717, 1609 and 1583 cmϪ1; found Mϩ
214.0611. C11H9F3O requires Mϩ 214.0605 m/z 214 (79),
199 (56) and 145 (100).
1,1,1-Trifluoro-3-hexadecen-2-one (9). The Grignard
reagent from 1-bromododecane (0.60 g) and magnesium
(0.06 g) afforded as a colourless oil in 38% yield the
known5 1,1,1-trifluoro-3-hexadecen-2-one (9) (0.13 g) dH
7.34 (1H, dt Jˆ15.8, 7.2 Hz, H-4), 6.41 (1H, dd Jˆ15.8,
1.1 Hz, H-3), 2.33 (2H, dq Jˆ1.5, 7.2 Hz, H-5), 1.52 (2H,
m, H-6), 1.26 (s, 18H), 0.88 (3H, t Jˆ6.8 Hz, H-16); dC
14.21 (C-16), 22.82 (C-15), 27.74 (C-14), 29.29 (C-13),
29.45 (C-12), 29.47 (C-11), 29.68 (C-10), 29.73 (C-9),
29.76 (C-7, C-8), 32.05 (C-6), 33.40 (C-5), 116.38 (q,
C-1), 121.47 (C-3), 157.08 (C-4), 179.91 (q, C-2); dF
4-(1-Naphthyl)-1,1,1-trifluoro-3-buten-2-one (14). The
Grignard reagent from 1-bromonaphthalene (0.50 g) and
magnesium (0.06 g) afforded as a yellow oil in 80% yield
4-(1-naphthyl-1,1,1-trifluoro-3-buten-2-one (14) (0.24 g)
dH 8.80 (1H, d Jˆ15.8 Hz, H-4), 8.14 (1H, d Jˆ8.5 Hz,
H-20), 7.95 (1H, d Jˆ7.5 Hz, H-40), 7.87 (1H, d Jˆ6.6,
H-50), 7.86 (1H, d Jˆ8.0, H-80), 7.59 (1H, dt Jˆ7.5 Hz,
1.5, H-30), 7.56 (1H, dt Jˆ8.1, 1.1 Hz, H-60), 7.48 (1H, dt,
Jˆ8.0, 1.1 Hz, H-70), 7.10 (1H, d Jˆ15.8 Hz, H-3), dC
116.70 (q, C-1), 118.65 (C-3), 122.96, 125.55, 126.24,
126.81, 127.82, 129.19, 130.47, 131.94, 132.98, 133.93
(naphthyl), 146.83 (C-4), 180.06 (q, C-2); dF Ϫ84.32
(CF3); nmax 3059, 2928, 1715, 1604 and 1570 cmϪ1; found
Mϩ 250.0590. C14H9F3O requires Mϩ 250.0605 m/z 250
(79), 181 (100), 153 (51), 127 (7) and 76 (27).
Ϫ84.23 (CF3); nmax 2926, 2855, 1730, 1711 and 1629 cmϪ1
.
4-Phenyl-1,1,1-trifluoro-3-buten-2-one (10). The
Grignard reagent from bromobenzene (0.38 g) and magne-
sium (0.06 g) afforded as a yellow oil in 47% yield the
known28
4-phenyl-1,1,1-trifluoro-3-buten-2-one
(10)
(0.34 g) dH 7.98 (1H, d Jˆ15.8 Hz, H-4), 7.57 (5H, m,
phenyl), 7.03 (1H, dq Jˆ15.8, 0.7 Hz, H-3), dC 116.55 (q,
C-1), 116.76 (C-3), 129.39, 132.49, 133.46, 141.41
(phenyl), 150.31 (C-4), 180.16 (q, C-2); dF Ϫ84.23 (CF3);
6-Phenyl-1,1,1-trifluoro-3-hexen-5-yne-2-one (16) and
1,7-diphenyl-3-hydroxy-3-trifluoromethyl-4-hepten-1,6-
diyne (15). A solution of phenylacetylenic magnesium
bromide was prepared from phenylacetylene (0.24 g) in
anhydrous diethyl ether (4.0 ml) and 3 M ethylmagnesium
nmax 3065, 3031, 1720, 1610 and 1576 cmϪ1
.
4-(4-Methoxyphenyl)-1,1,1-trifluoro-3-buten-2-one (11).
The Grignard reagent from p-bromoanisole (0.45 g) and

R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7261–7266
7265
bromide in diethyl ether (0.80 ml) under nitrogen. A solu-
tion of 4-dimethylamino-1,1,1-trifluoro-3-buten-2-one (4)
(0.20 g) in anhydrous diethyl ether (3.0 ml) was then
added to the stirred solution of the Grignard reagent at
room temperature. The resulting mixture was heated under
reflux for 2.5 h, and after cooling was poured into ice cold
2 M hydrochloric acid (14.5 ml). The ether layer was sepa-
rated and the aqueous layer was further extracted with
diethyl ether (2×12 ml). The combined ether phases were
washed with water (12 ml), dried (MgSO4) and the solvent
removed in vacuo. The resulting products were purified by
chromatography (silica gel, neat petroleum ether) to give
first as a yellow oil in 37% yield 6-phenyl-1,1,1-trifluoro-
3-hexen-5-yne-2-one (16) (0.10 g) dH 7.55 (2H, dd, Jˆ5.9,
1.8 Hz, ortho), 7.41 (3H, m, aromatic), 7.28 (1H, d
Jˆ15.8 Hz, H-4). 6.87 (1H, d 15.8, H-3); dC 87.30 (C-6),
104.97 (C-5), 116.32 (q, C-1), 121.58 (ArC-1), 127.87
(C-3), 128.84 (ArC-3, ArC-5), 130.52 ArC-4), 131.09
(C-4), 132.60 (ArC-2, ArC-6), 179.42 (q, C-2); dF
Ϫ84.05; nmax 2194, 1722 and 1602 cmϪ1; found Mϩ
224.0444. C12H7F3O requires Mϩ 224.0449 m/z 224 (66),
155 (100), 127 (39), 101 (6) and 77 (16); and then as a
yellow oil in 18% yield 1,7-diphenyl-3-hydroxy-3-trifluoro-
methyl-4-hepten-1,6-diyne (15) (0.07 g) dH 7.45 (10H, m,
aromatic), 6.59 (1H, d Jˆ15.4 Hz, H-4). 6.34 (1H, d 15.4,
H-4), 2.98 (1H, brs, OH); dC 72.06 (q, C-3), 81.92 (C-6),
86.01(C-1), 89.14 (C-2), 93.79 (C-7), 116.46 (C-5), 120.81
(ArC-1), 122.76 (ArC-1), 123.27 (q, CF3), 128.58, 128.65,
128.96, 129.85, 131,87, 132.25, (ArC) 134.61 (C-4); dF
Ϫ81.28; nmax 3442, 3059, 2236 and 2205 cmϪ1; found
Mϩ 326.0906. C20H13F3O requires Mϩ 326.0918 m/z 326
(29), 309 (6), 257 (100), 249 (2), 127 (10), 101 (6) and 77
(9).
(4H, m, H-6, H-18) 1.29 (16H, br s H-2, H-3, H-4, H-5,
H-19, H-20, H-21, H-22), 0.89 (6H, t, Jˆ6.4 Hz, H-1,
H-23); dC133.78 (C-12), 123.17 (q, JCFˆ285 Hz, CF3),
116.58 (C-13), 94.99 (CC), 90.47 (CC), 77.21 (CC), 73.67
(CC), 71.42 (q, JCFˆ33 Hz, C-11), 31.82, 31.76, 29.16,
29.10, 29.07, 28.94, 28.89, 28.72, 28.50, 28.02 and 22.63
(C-2, C-3, C-4, C-5, C-6, C-7, C-17, C-18, C-19, C-20, C-21
and C-22), 19.44 and 18.55 (C-8 and C-16) and 14.06 (C-1,
C-23); dF Ϫ80.73; nmax 3450, 2928, 2857, 2243 and
2212 cmϪ1; found Mϩ 398.2785. C24H37F3O requires Mϩ
398.2797 m/z 398 (1), 341 (1), 329 (100), 299 (4), 273 (4)
and 163 (6).
6-Phenyl-1,1,1-trifluoro-3-hexen-5-yne-2-one (16). To a
stirred solution of phenylacetylene (0.24 g) in dry ether
was added dropwise at Ϫ78ЊC under nitrogen 1.6 M butyl-
lithium in hexanes (1.5 ml). After stirring for 10 min, the
mixture was allowed to warm to room temperature and a
solution of 4-dimethylamino-1,1,1-trifluoro-3-buten-2-one
(4) (0.20 g) in dry ether (4 ml) added. The resulting mixture
was heated under reflux for 2 h, worked up and the resulting
oil was purified by flash chromatography to afford as a
yellow oil 6-phenyl-1,1,1-trifluoro-3-hexen-5-yne-2-one
(16) (0.10 g) in 37% yield.
4-Phenyl-1,1,1-trifluoro-3-buten-2-one (10) and 4,4-
diphenyl-1.1.1-trifluorobutan-2-one (17). A solution of
phenylmagnesium bromide was prepared in anhydrous
ether from bromobenzene (1.88 g) and dry magnesium
turnings (0.29 g). A solution of 4-dimethylamino-1,1,1-
trifluoro-3-buten-2-one (4) (0.40 g) in anhydrous ether
(12 ml) was added with stirring to the solution of the
Grignard reagent at room temperature. The resulting
mixture was heated under reflux for 2 h and the cold solu-
tion was poured on to 2 M hydrochloric acid (29 ml). The
ether layer was separated and the aqueous layer further
extracted with diethyl ether (2×24 ml). The combined
ether phases were washed with water (24 ml), dried over
Na2SO4 and the solvent removed in vacuo. The resulting
products were purified by chromatography (silica gel, petro-
leum ether) to give first as a yellow oil in 31% 4-phenyl-
1,1,1-trifluoro-3-buten-2-one (10) (0.15 g) (see above for
physical data); and then as a colourless oil in 15% yield
4,4-diphenyl-1.1.1-trifluorobutan-2-one (17) (0.10 g) dH
7.09 (10H, m, aromatic), 4.51 (1H, t, Jˆ7.4 Hz, H-4),
3.33 (2H, d Jˆ7.4 Hz, H-3); dC 42.65 (C-3), 44.78 (C-4),
115.64 (q, C-1), 127.11, 127.70, 128.99, 142.65 (ArC),
189.49 (q, C-2); dF Ϫ82.44; nmax 3030, 2903 and1765
1,1,1-Trifluoro-3-tetradecen-5-yn-2-one (20) and 11-
(trifluoromethyl)-12-tricosen-9,14-diyn-11-ol (19). To a
stirred solution of 1-decyne (0.33 g) in dry ether (4 ml)
was added dropwise at room temperature under nitrogen
3 M ethylmagnesium bromide in dry ether (1.60 ml). The
mixture was heated under reflux for 1 h and allowed to cool
to room temperature. To the stirred solution was added
dropwise at room temperature a solution of 4-dimethyl-
amino-1,1,1-trifluoro-3-buten-2-one (4) (0.20 g) in dry
ether (3 ml). After heating under reflux for 2 h the reaction
was worked up and flash chromatography afforded as a
yellow oil in 61% yield 1,1,1-trifluoro-3-tetradecen-5-yn-
2-one (20) (0.19 g) dH 7.05 (1H, dt, Jˆ15.8, 2.2 Hz, H-4),
6.70 (1H, d Jˆ15.8 Hz, H-3). 2.45 (2H, dt 2.2, 7.0, H-7),
1.59 (2H, quin, Jˆ7.1 Hz, H-8) 1.40 (2H, m, H-9), 1.29 (8H,
br s H-10, H-11, H-12, H-13), 0.89 (3H, t, Jˆ6.6 Hz, H-14);
dC179.56 (q, JCFˆ36 Hz, C-2), 132.41 (C-4), 127.68 (C-3),
116.27 (q, JCFˆ290 Hz, C-1), 108.51 (C-6), 79.07 (C-5),
31.93, 29.26, 29.15, 29.03, 28.21 and 22.77 (C-8, C-9,
C-10, C-11, C-12, C-13), 20.27 (C-7) and 14.18 (C-14);
dF Ϫ83.89; nmax 2929, 2858, 2210, 1723, 1704 and
1597 cmϪ1; found Mϩ 260.1388. C14H19F3O requires Mϩ
260.1388 m/z 260 (8), 231 (11), 217 (28), 203 (66), 191
(32), 189 (37), 175 (51), 163 (9), 57 (26), 43 (40) and 29
(16) and as a yellow oil in 17% yield 11-(trifluoromethyl)-
12-tricosen-9,14-diyn-11-ol (19) (0.08 g) dH 6.23 (1H, dt,
Jˆ15.8, 2.0 Hz, H-13), 6.04 (1H, d Jˆ15.8 Hz, H-12). 2.78
(1H, br s, OH), 2.33 (2H, dt 1.8, 7.0, H-16), 2.27 (2H, t,
Jˆ7.0 Hz, H-8), 1.54 (2H, quin, Jˆ7.0 Hz, H-7, H-17) 1.39
;
cmϪ1 found Mϩ278.0920. C16H13F3O requires Mϩ
278.0918 m/z 278 (56), 209 (26) and 167 (100).
4,4-Diphenyl-1,1,1-trifluorobutan-2-one (17). A solution
of phenylmagnesium bromide was prepared from bromo-
benzene (0.11 g) and dry magnesium (0.02 g) in ether
(0.5 ml). A solution of 4-phenyl-1,1,1-trifluoro-3-buten-2-
one (10) (0.12 g) in anhydrous ether (3 ml) was added
with stirring at room temperature to the Grignard solution
under nitrogen. The resulting mixture was heated under
reflux for 2 h, and when cold poured into ice cold 2 M
hydrochloric acid (7 ml). the ether layer was separated,
the aqueous layer further extracted with ether (2×6 ml),
the combined ether phases were washed with water (6 ml),
dried over MgSO4 and the solvent removed in vacuo.

7266
R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7261–7266
6. Gorbunova, M. G.; Gerus I. I.; Kukhar V. P. J. Fluorine Chem.
1993, 65, 25; Zhu, S. Z.; Qin, C. Y.; Xu, G. L.; Chu, Q. L.; Huang,
Q. C. J. Fluorine Chem. 1999, 99, 141.
Chromatography afforded 4,4-diphenyl-1,1,1-trifluoro-
butan-2-one (17) in 65% yield (see above for physical data).
7. Linderman, R. J.; Lonikar, M. S. Tetrahedron Lett. 1987, 28,
5271.
8. Mead, D.; Loh, R.; Asato, A. E.; Lin, R. S. Tetrahedron Lett.
1985, 26, 2873.
9. Neunhoffer, O.; Alsdorf, G.; Ulrich, H. Chem. Ber. 1959, 92,
252.
2-Hydroxy-2-methyl-4-phenyl-1,1,1-trifluorobut-3-ene
(18). A solution of methylmagnesium iodide was prepared
from methyl iodide (0.28 g) and dry magnesium turnings
(0.05 g) in anhydrous ether (1.0 ml). A solution of 4-phenyl-
1,1,1-trifluoro-3-buten-2-one (10) (0.18 g) in anhydrous
ether (6 ml) was added with stirring to the solution of the
Grignard reagent at room temperature. The resulting
mixture was heated under reflux for 2 h and when cold
was poured in to ice-cold hydrochloric acid (14.5 ml). The
ether layer was separated and the aqueous layer further
extracted with ether (2×12 ml). The combined organic
phases were washed with water (12 ml), dried over
MgSO4 and the solvent removed in vacuo. Chromatography
afforded in 72% yield as a yellow oil 2-hydroxy-2-methyl-4-
phenyl-1,1,1-trifluorobut-3-ene (18) (0.14 g) dH 7.38 (5H,
m, aromatic), 6.90 (1H, d Jˆ15.8 Hz, H-4), 6.34 (1H, d
Jˆ15.8 Hz, H-3) 2.48 (1H, brs, OH), 1.60 (3H, s, CH3);
dC 22.35 (CH3), 74.18 (q, C-2), 125.72 (q, C-1), 126.44
(C-3), 126.99, 128.61, 128.88 (aromatic), 132.34 (C-4),
135.78 (aromatic); dF Ϫ79.66; nmax 3422, 3030, 2998,
2946 cmϪ1; found Mϩ 216.0751. C11H11F3O requires Mϩ
216.0762 m/z 216 (14), 201 (5) and 147 (40).
10. Nenajdenko, V. G.; Krasovsky, A. L.; Lebedev, M. V.;
Balenkova, E. S. Synlett 1997, 1349; Nenajdenko, V. G.; Sanin,
A. V.; Balenkova, E. S. Molecules 1997, 2, 186.
11. Sanin, A. V.; Nenajdenko, V. G.; Smolko, K. I.; Denisenko,
D. I.; Balenkova, E. S. Synthesis 1998, 842.
12. Nenjdenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ. Chem.
Rev. 1999, 68, 437; Hegde, S. G.; Jones, C. R. Abs. Meeting Am.
Chem. Soc. 1995, 210, Fluo 007.
13. Kawase, M.; Harada, H.; Saito, S.; Cui, J. M.; Tani, S. Biorg.
Med. Chem. Lett. 1999, 9, 193; Boger, D. L.; Sato, H.; Lerner,
A. E.; Austin, B. J.; Patterson, J. E.; Patricelli, M. P.; Cravatt,
B. F. Biorg. Med. Chem. Lett. 1999, 9, 265; Singh, R. P.; Cao,
G. F.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64,
483; Walter, M. W.; Adlington, R. M.; Baldwin, J. E.; Schofield,
C. J. J. Org. Chem. 1998, 63, 5179; Renou, M.; Lucas, P.; Malo, E.;
Quero, C.; Guerrero, A. Chem. Senses 1997, 22, 407; Denieul,
M. P.; QuicletSire, B.; Zard, S. Z. Chem. Commun. 1996, 2511;
Derstine, C. W.; Smith, D. N.; Katzenellenbogen, J. A. J. Am.
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Pharmacol. 1983, 32, 1155.
4-Phenyl-1,1,1,-trifluoro-3-buten-2-one (10). Phenyl-
lithium (1.8 M) in cyclohexane: ether (70:30, 1.33 ml)
was added dropwise with stirring to a solution of
4-dimethylamino-1,1,1-trifluoro-3-buten-2-one (4) (0.20 g)
in ether (6 ml) at room temperature under nitrogen. The
resulting mixture was heated under reflux for 2 h, and
when cold was poured in to ice-cold hydrochloric acid
(14.5 ml). The ether layer was separated and the aqueous
layer further extracted with ether (2×12 ml). The combined
ether phases were washed with water (12 ml), dried over
MgSO4 and the solvent removed in vacuo. Chromatography
afforded in 42% yield as a yellow oil 4-phenyl-1,1,1,-
trifluoro-3-buten-2-one (10) (0.10 g) (see above for spectro-
scopic data).
14. Poupart, M-A.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org. Chem.
1999, 64, 1356.
15. Garrett, G. S.; McPhail, S. J.; Tornheim, K.; Correa, P. E.;
McIver, J. M. Biorg. Med. Chem. Lett. 1999, 9, 301.
16. Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.;
Olah, G. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 820.
17. Yokoyama, Y.; Mochida, K. Synlett 1997, 907.
18. Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1989, 30,
6173.
19. Keller, H.; Schlosser, M. Tetrahedron 1996, 52, 4637.
20. Simchen, G.; Schmidt, A. Synthesis 1997, 117.
21. Shawe, T. T.; Hansen, D. B.; Peet, K. A.; Prokopowicz, A. S.;
Robinson, P. M.; Cannon, A.; Dougherty, K. E.; Ross, A. A.;
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Acknowledgements
We thank EPSRC for a Quota Award (R. J. A.).
22. Fontenas, C.; Ait-Haddou, H.; Bejan, E.; Balavoine, G. G. A.
Syn. Commun. 1998, 1743.
23. Mukaiyama, T.; Oshumi, T. Chem. Lett. 1983, 875.
24. Murahashi, S.; Mitsue, Y.; Tsumiyama, T. Bull. Chem. Soc.
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