Reaction of Benzyl Grignard reagents with trifluoroacetyldihydropyrans and other cyclic β-alkoxy-α,β-unsaturated trifluoromethylketones

Article abstract of DOI:10.1016/S0040-4020(00)00976-5

Benzyl Grignard reagents react with cyclic β-alkoxy-α,β-unsaturated trifluoromethyl ketones by 1,2-addition to afford unsaturated allylic alcohols in high yield. The factors determining the balance between 1,2- and 1,4-addition to unsaturated ketones are

Full text of DOI:10.1016/S0040-4020(00)00976-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10057±10066
Reaction of Benzyl Grignard Reagents with
Tri¯uoroacetyldihydropyrans and Other Cyclic
b-Alkoxy-a,b-Unsaturated Tri¯uoromethylketones
a
b
Simon J. Coles,a John M. Mellor,a, Afaf H. El-Sagheer, Ezz El-Din M. Salem
*
and Reda N. Metwallyc
aDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
bDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt
cDepartment of Science and Maths, Faculty of Petroleum and Mining Engineering, Suez Canal University, Suez, Egypt
Received 18 July 2000; revised 9 October 2000; accepted 12 October 2000
AbstractÐBenzyl Grignard reagents react with cyclic b-alkoxy-a,b-unsaturated tri¯uoromethyl ketones by 1,2-addition to afford unsatu-
rated allylic alcohols in high yield. The factors determining the balance between 1,2- and 1,4-addition to unsaturated ketones are discussed.
The structures of major and minor products are established by single crystal X-ray diffraction studies. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
lenes. Preliminary details5 concerning this synthetic strategy
have been communicated. In this paper we ®rst review the
factors determining the relative importance of 1,2- and
1,4-addition to a,b-unsaturated ketones. Then we describe
the outcome of additions of Grignard reagents derived from
allyl and benzyl halides to the ketones (1±5).
In an earlier paper1 we have described the reaction of
b-dialkylamino-a,b-unsaturated tri¯uoromethyl ketones
and b-alkoxy-a,b-unsaturated tri¯uoromethyl ketones,
such as the acyclic ketone (1) with Grignard reagents
derived from alkyl and aryl halides. Reaction occurs by
1,4-addition followed by elimination to provide a route to
a,b-unsaturated tri¯uoromethyl ketones. In an accompany-
ing paper2 we describe similar 1,4-additions to cyclic
b-alkoxy-a,b-unsaturated tri¯uoromethyl ketones, where
reaction takes a different course. With the ketones (2) and
(3)2 the major products are the cis adducts, although a minor
pathway leads to subsequent ring opening. In the case of the
substituted ketones (4) and (5) initial 1,4-addition at a low
temperature permits the isolation of cis adducts, but the
major pathway at higher temperatures occurs through ring
opening to give a variety of products. We recognised that if
the reaction of Grignard reagents derived from benzyl and
allyl halides were to occur by 1,2-addition a route might be
established to tri¯uoromethylnaphthalenes, based on subse-
quent dehydration and cyclisation by [3,3]benzannulation.3
The successful outcome of this strategy is described in this
and an accompanying paper,4 where we report the reactions
of a variety of Grignard reagents derived from substituted
benzyl halides and the dehydration of the alcohol products
to establish a new route to ¯uorinated substituted naphtha-
The factors6 determining the selectivity in 1,2- and 1,4-
additions to a wide range of a,b-unsaturated carbonyl
compounds have received much attention and in particular
asymmetric conjugate additions7 have been developed. The
hard acid soft base concepts have been used to permit the
generalisations8±10 that among organometallic reagents,
organolithiums, which are hard nucleophiles, react by
1,2-addition, and organocopper reagents, which are softer
Keywords: additions; Grignard reagents; tri¯uoromethylketones.
* Corresponding author. Tel.: 1238059-2392; fax: 1238059-6805;
e-mail: jmm4@soton.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00976-5

10058
S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
Ê
Table 1. Crystal data and re®nement. (All data were collected on a Nonius KappaCCD equipped with a Nonius FR591 molybdenum (l(Moka)ˆ0.71069 A)
rotating anode. Absorption corrections were performed by comparison of multiply measured and symmetry equivalent re¯ections, using Sortav.34 The
structures were solved by direct methods (shelxs-9735) and then subjected to full-matrix least squares re®nement based on F2o (shelxl-9735). Non-hydrogen
Ê
atoms were re®ned anisotropically with hydrogens included in idealised positions (C±H distanceˆ0.97 A) with isotropic thermal parameters riding on those of
the parent atom. The weighting scheme used was wˆ1/[s2(Fo2)]. Data have been deposited with the Cambridge Crystallographic Data Centre, deposition
numbers: CCDC 146994±146997.)
Compound
(9)
(14)
(17)
(21)
Formula
Formula weight
T, K
C16H19F3O3
316.31
150
C19H18F6O4
424.33
150
C15H17F3O3
302.29
150
C16H17F3O2
298.3
293
Crystal system
Space group
Triclinic
Å
P1 (# 2)
Monoclinic
C2/c (#15)
21.241(4)
16.179(3)
10.732(2)
90.0
92.64(3)
90.0
3684.2(12)
8
0.145
14329
4175
0.0656
0.0499/0.1236
0.1220/0.1579
Monoclinic
C2/c (# 15)
20.426(4)
5.5841(11)
25.536(5)
90.0
93.05(3)
90.0
2908.6(10)
8
0.12
15308
3306
0.0734
0.0491/0.1236
0.1169/0.1587
Monoclinic
P21/c (# 14)
9.2288(18)
20.362(4)
7.6375(15)
90.0
91.0(3)
90.0
1435.0(5)
4
1.381
13593
3244
0.0734
0.0571/0.1599
0.0860/0.1774
Ê
a (A)
8.2480(7)
10.7247(9)
19.0148(18)
80.429(5)
88.947(5)
71.679(5)
1573.5(2)
2
0.114
12744
4495
0.1345
Ê
b (A)
Ê
c (A)
a (8)
b (8)
g, (8)
Ê 3
V (A )
Z
m, mm21
Re¯ections measured
Unique re¯ections
Rint
R/wR2 [F2.2s(F2)]
R/wR2 (F2), all data
0.0566/0.0892
0.1592/0.1165
nucleophiles, react by 1,4-addition. Grignard reagents were
seen to lie somewhere between.11,12 Since then there have
been major advances in explaining the selectivity of these
additions. In reactions which proceed by kinetic control
with organometallic reagents having a highly localised
negative charge, a charge controlled 1,2-addition9 can be
expected. In contrast, in additions of nucleophiles having
charge delocalisation, where the reaction is frontier orbital
controlled, a 1,4-addition9 is expected. However other
factors, notably steric-6 and solvent-effects and the nature
of the nucleophile, disturb these simple generalisations. In
particular the nature of the a,b-unsaturated carbonyl
compound in¯uences12±22 the 1,2 to 1,4-ratio, but in the
limited known examples1,22 obtained with acyclic tri¯uoro-
methyl ketones having a b-alkoxy substituent or a b-dialkyl-
amino substituent, 1,4-additions have been reported. Early
results of additions to b-ionone23 established that benzyl
magnesium chloride and methyl magnesium bromide
added by 1,2-addition in 82 and 83% yield, respectively,
but there are other examples24 where benzyl magnesium
bromide reacts preferentially by 1,4-addition. The ratio of
1,2- to 1,4-addition by benzyl Grignard reagents is partly
determined16 by the nature of X in PhCH2MgX, but benzyl
Grignard reagents are very reactive,25 prone to self
coupling26 and likely to produce other side-products.27
Allyl Grignard reagents react28 relatively cleanly with
unsaturated ketones by 1,2-addition. The unusual pattern
of reactivity of benzyl and allyl Grignard reagents is also
observed29±32 in additions to dithioesters where allylic and
benzylic reagents attack at carbon. Such differences have
been attributed by Fukui et al.31 to the relative importance of
a frontier orbital control. In this paper we show that benzyl
Grignard reagents add to the ketones (2±5) by 1,2-addition,
a process favoured31 by charge control. Under the same
conditions, alkyl and aryl Grignard reagents add by
1,4-addition, a process favoured by orbital control.
Results and Discussion
The ketone (2) was reacted with 4 equiv. of benzyl mag-
nesium bromide in ether to give the product of 1,2-addition
(6), which was isolated in 93% yield. By contrast, in reac-
tion of ketone (2) with phenyl magnesium bromide, we have
established that 88% of the products occur from 1,4-addi-
tion and very little 1,2-addition is observed. The ketones (4)
and (5) behaved in a similar manner. The former (4) gave
the two alcohols (7) and (8) in 34 and 61% yields, respec-
tively, and the latter (5) gave the alcohols (9) and (10) in 33
and 65% yields, respectively. The nature of the products
was insensitive to the number of equivalents of Grignard
reagent, which were used. Addition to ketone (3) was less
selective. The alcohol (11), the product of 1,2-addition was
obtained in 34% yield, and the two products of 1,4-addition,
(12) and (13), were obtained in 31 and 30% yield, respec-
tively. In probing the lack of selectivity in reaction of ketone
(3), further reactions using 1.2 and 2 equiv. of benzyl
magnesium bromide were studied. The former conditions
afforded the above three products in lower yields, but
produced a fourth product, the spirocycle (14) and the
same four products were observed using the latter con-
ditions. A single crystal X-ray analysis of the major isomer
(10) (see Table 1), obtained from the ketone (5) con®rmed a
product of 1,2-addition. The second diastereoisomeric alco-
hol (9) obtained from ketone (5) was characterised by spec-
tral comparison with alcohol (10). Similarly the assignment
of structures of the diastereoisomeric pair (7) and (8) was
made by spectral comparison. As expected the major
isomers (8) and (10) have a common stereochemical
relationship. The structures of the products (6), obtained
from the ketone (2), and (11), obtained from ketone (3),
are readily con®rmed to be products of 1,2-addition by
spectral comparison with the products from the ketones
(4) and (5).

S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
10059
Figure 1.
Assignment of the structures to three further products from
reaction of ketone (3) was less easy. The minor product, the
spirocycle (14), required a single crystal X-ray analysis (see
Fig. 1 and Table 1). The spectra of the two saturated ketones
(12) and (13), the products of 1,4-addition, can be compared
with the spectra for other products of 1,4-addition reported2
in the accompanying paper. Their similarity con®rms that
products of 1,4-addition are obtained from ketone (3), in
agreement with the origin of the minor product, the spiro-
cycle (14). Assignment of relative stereochemistry, based
on coupling constant data in a disubstituted tetrahydrofuran,
is less reliable than the assignment in a disubstituted tetra-
hydropyran. We are unable to assign the stereochemistry of
isomers (12) and (13) based on observation of the
2,3-coupling constants. The two isomers are formed in
similar yields re¯ecting the easy cis to trans isomerisation
of 3-acyl-2-substituted terahydrofurans.33
The above results differ from those reported in the accom-
panying paper2 in a number of respects. Most notable is the
dominance of 1,2-addition with benzyl magnesium bro-
mide. A second feature is the different behaviour of the
ketone (3) by comparison with the ketones (2) and (4,5).
Not only is 1,2-addition the minor pathway from ketone (3),
but in contrast to the results of 1,4-addition to ketone (2),
which establish that formation of cis products is highly
stereoselective, ketone (3) affords the two products of 1,4-
addition (12) and (13) unselectively. Finally only from
ketone (3) is a more complex by-product observed. The
1,2-addition described above has been used with substituted
benzyl Grignard reagents to afford, as described in the
accompanying paper,4 a general route to intermediate

10060
S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
Scheme 1.
1,2-adducts and hence to substituted naphthalenes. However
in establishing the generality of the 1,2-addition, we have
observed surprising solvent effects.
Reaction of allyl Grignard reagents, as expected,28 occurred
by 1,2-addition. Reaction of allyl magnesium bromide with
the acyclic ketone (1) in ether gave the alcohol (19) in 81%
yield. Similarly the cyclic ketone (2) gave the alcohol (20)
in 82% yield. It has been well established by Santelli et al.28
that reaction of allyl Grignard reagents normally occurs at
the more substituted site. We ®nd that the Grignard reagents
from cinnamyl chloride and crotyl bromide react with
ketone (2) in such a manner. In the former case the separable
adducts (21) and (22) are obtained, and in the latter case an
inseparable mixture of 1,2-adducts (23) is obtained. The
structure of the minor crystalline adduct (21) was deter-
mined by a single crystal X-ray analysis (see Table 1).
The Grignard reagents from cinnamyl chloride and crotyl
bromide react with ketone (1) in a similar manner. An
unselective addition of cinnamyl magnesium chloride to
ketone (1) gives the alcohols (24) by 1,2-addition. Although
one isomer was isolated as a crystalline solid, the relative
con®gurations of the two isomers have not been de®ned.
Crotyl magnesium bromide similarly affords the alcohols
(25) in an unselective manner. An alternative procedure
for allylation is use of indium. We ®nd that the ketone (3)
can be readily allylated to give the 1,2-adduct (26). Hence
1,2-additions with allyl magnesium halides to these ¯uori-
nated ketones occurs through a variety of methods.
Reaction of benzyl magnesium bromide with the ketone (2)
in tetrahydrofuran±ether (2:1), rather than ether, afforded
mainly the two products of 1,4-addition (15) and (16) as
oils in 46 and 18% yield, respectively; similar results
were obtained in neat tetrahydrofuran in the absence of
ether. Under the former conditions, p-methoxybenzyl
magnesium bromide afforded mainly the crystalline 1,4-
adducts (17) and (18) in 50 and 14% yield, respectively.
Through a single crystal X-ray analysis of the structure of
the adduct (17) (see Table 1), we have been able to assign
unequivocally the cis structure to this adduct. The assign-
ment of the trans structure to the second adduct (18) is based
on spectroscopic comparison. We note that the two major
products (15) and (17) are the cisadducts, which can
partially epimerise33 to give the more stable trans adducts
(16) and (18). The unequivocal assignment of structures to
the 1,4-adducts (17) and (18), based on X-ray analysis,
con®rms the structural assignments to the 1,4-adducts
reported2 in the accompanying paper.
Four aspects of the above results are noteworthy. The most
striking observation is the contrast whereby isolation in high
yield of 1,4-adducts from the ketone (2), as reported in the
accompanying paper,2 with alkyl and aryl Grignard
reagents, may be compared with the results in this paper.

S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
10061
Here we observe formation of 1,2-adducts from reaction of
ketone (2) with benzyl magnesium bromide under identical
conditions. The difference can be explained as a spectacular
example of frontier orbital control in the former case and
charge control in the latter case. However our observation
that reactions conducted in tetrahydrofuran follow a differ-
ent reaction pathway from those in ether suggests that the
precise nature of the species responsible for nucleophilic
attack is solvent dependent, and hence an interpretation
based on charge and frontier orbital controls must be viewed
with caution. The difference in behaviour between ketones
(2) and (3) is also noteworthy. The 1,2-pathway is dominant
for reaction of ketone (2), but the 1,4-pathway is dominant
for reaction of ketone (3) with benzyl magnesium bromide.
Such a difference is not easily explained by an analysis
limited to frontier orbital and charge considerations. The
observation of the trans product (13) in the furan series
can be attributed to a more favoured equilibration from
the kinetically favoured cis adduct (12) relative to the
pyran series. A more rapid equilibration in the ®ve-
membered ring is to be expected.33 Finally the origin of
the minor product (14) is explained in Scheme 1. 1,4-
Addition gives the enolate anion (27), which in the presence
of the unreacted ketone (3) undergoes a further 1,4-addition.
In this addition the new carbon±carbon bond is selectively
formed on the opposite face to that of the benzyl group. A
further cyclisation then affords the spirocyclic hemiketal
product (14).
under re¯ux for another 30 min, allowed to cool to room
temperature and 2 M hydrochloric acid was added until
pH2. The two phases were separated and the aqueous
phase extracted with ether (3£15 ml), the combined organic
phases were collected, washed with water, dried over
MgSO4 and the solvent evaporated in vacuo. The resulting
oil was puri®ed by ¯ash column chromatography [silica gel,
hexane/ethyl acetate (90:10)] to give the title compound (6)
1
as a pale yellow oil (1.40 g, 93%) H NMR (300 MHz,
CDCl3) dˆ7.32 (3H, m, Ph±H), 7.20 (2H, m, Ph±H),
6.48 (1H, s, H-6), 3.92 (2H, m, H-2), 3.11 (2H, s, CH2±
Ph), 2.12 (2H, m, H-4), 2.02 (1H, s, OH), 1.85 (2H, m, H-3);
13C NMR (75 MHz, CDCl3) dˆ144.6 (C-6), 133.8 (C0-1),
130.8, 128.5 and 127.5 (Ph±C), 125.9 (q, JC±Fˆ287.1 Hz,
CF3), 108.1 (C-5), 76.7 (C±CF3), 65.5 (C-2), 39.1 (CH2±
Ph), 21.9 (C-3), 20.8 (C-4); nmax (®lm, cm21) 3550±3200
(OH), 1658 (CvC); LRMS (Scan AP1): m/zˆ255 (M12
OH, 62%), 203 (M12CF3, 100); HRMS (CI1): (M11NH4)
found 290.1344, C14H15F3O2 requires 290.1368.
Reaction of ketone (2) was repeated under the above con-
ditions but using benzyl magnesium bromide (2 equiv.) to
give the alcohol (6) in 79% yield.
Reaction of benzyl magnesium bromide with 2,2,2-
tri¯uoro-1-(2-ethoxy-3,4-dihydro-2H-5-pyranyl)-1-etha-
none (5). Following the above procedure, ketone (5)
(1.00 g, 4.46 mmol) was reacted with benzyl magnesium
bromide and the two isomeric products (9) and (10) were
separated by ¯ash column chromatography [silica gel,
hexane/ethyl acetate (95:5)] to give as the minor product
(2SR,20SR)-1,1,1-tri¯uoro-2-(2-ethoxy-3,4-dihydro-2H-
5-pyranyl)-3-phenyl-2-propanol (9) as a pale yellow oil
The route, by 1,2-addition of benzyl Grignard reagents to
ketones (2) and (3), has been used by us to afford a series of
substituted naphthalenes.4 The addition of benzyl Grignard
reagents gives products of 1,2-addition in high yield, in
marked contrast to the 1,4-additions of aryl Grignard
reagents. These differences might be attributed to the
relative importance of charge control and frontier orbital
effects. However the observation that a change of solvent
from ether to tetrahydrofuran completely alters a reaction
pathway emphasises that a more detailed analysis of the
factors controlling the pathways of reactions reported in
this paper is still required.
1
(0.47 g, 33%); H NMR (300 MHz, CDCl3) dˆ7.21 (3H,
m, Ph±H), 7.12 (2H, m, Ph±H), 6.29 (1H, s, H-6), 4.93 (1H,
dd, Jˆ3.7, 2.2 Hz, H-2), 3.72 (1H, dq, 11.8, 7.4 Hz,
CH2CH3), 3.49 (1H, dq, 11.8, 7.0 Hz, CH2CH3), 3.08 (1H,
d, Jˆ13.8 Hz, CH2Ph), 2.95 (1H, d, Jˆ13.8 Hz, CH2Ph),
2.24 (1H, m, H-4), 2.04 (1H, m, H-4), 1.90±1.68 (3H,
complex, OH, H-3), 1.18 (3H, t, Jˆ7.4 Hz, CH3); 13C
NMR (75 MHz, CDCl3) dˆ141.7 (C-6), 133.35 (C0-1),
130.9, 128.5 and 127.6 (Ph±C), 125.9 (q, JC±Fˆ287.1 Hz,
CF3), 109.0 (C-5), 96.2 (C-2), 76.7 (q, JC±Fˆ28.3 Hz,
C±CF3), 63.7 (CH2CH3), 38.4 (CH2±Ph), 26.4 (C-3), 17.4
(C-4), 15.3 (CH2CH3); nmax (CH2Cl2, cm21) 3563 (OH),
1660 (CvC); LRMS (Scan AP1): m/zˆ299 (M12OH,
100%), 247 (M12CF3, 51); HRMS (CI1): (M11NH4)
found 334.1635, C16H19F3O3 requires 334.1630.
(2SR,20RS)-1,1,1-Tri¯uoro-2-(2-ethoxy-3,4-dihydro-2H-
5-pyranyl)-3-phenyl 2-propanol (10) was isolated as the
Experimental
General procedures are described elsewhere.1
2-(3,4-Dihydro-2H-5-pyranyl)-1,1,1-tri¯uoro-3-phenyl-
2-propanol (6). To a 100 ml round bottomed ¯ask (with an
addition funnel, magnetic stirrer bar and re¯ux condenser
carrying a calcium chloride tube), magnesium turnings
(0.54 g, 22.22 mmol), dry ether (4.0 ml) and a crystal of
iodine were added. A few drops of benzyl bromide
(3.80 g, 22.22 mmol) in dry ether (4.0 ml) were added drop-
wise, and the solution was stirred until the formation of the
Grignard reagent. The remainder of the benzyl bromide was
diluted with dry ether (8.0 ml) and the solution was added at
such a rate to maintain gentle re¯ux. After the complete
addition of the benzyl bromide, the reaction mixture was
re¯uxed with stirring on a warm water bath for 10 min. The
reaction mixture was cooled and a solution of the ketone (2)
(1.00 g, 5.55 mmol) in dry ether (4.0 ml) was added drop-
wise. The reaction mixture was stirred for 30 min, heated
1
major product as a low mp white solid (0.91 g, 65%); H
NMR (300 MHz, CDCl3) dˆ7.22 (3H, m, Ph±H), 7.12 (2H,
m, Ph±H), 6.29 (1H, d, Jˆ2.2 Hz, H-6), 4.90 (1H, t, Jˆ
2.9 Hz, H-2), 3.72 (1H, dq, 11.0, 7.0 Hz, CH2CH3), 3.48
(1H, dq, 11.0, 7.4 Hz, CH2CH3), 3.04 (2H, s, CH2Ph),
2.13 (1H, m, H-4), 1.97 (2H, complex, OH, H-4), 1.82
(1H, m, H-3), 1.61 (1H, m, H-3), 1.11 (3H, t, Jˆ7.4 Hz,
CH3); 13C NMR (75 MHz, CDCl3) dˆ141.0 (C-6), 133.8
(C0-1), 130.8, 128.5 and 127.5 (Ph±C), 109.2 (C-5), 95.9
(C-2), 76.9 (C±CF3), 63.6 (CH2CH3), 39.4 (CH2±Ph), 26.1
(C-3), 16.9 (C-4), 15.3 (CH3), nmax (®lm, cm21) 3500±3200
(OH), 1662 (CvC); LRMS (Scan AP1): m/zˆ299 (M12
OH, 20%), 247 (M12CF3, 37); HRMS (CI1): (M11NH4)

10062
S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
found 334.1625, C16H19F3O3 requires 334.1630. The
structure of alcohol (10) has been established by an X-ray
diffraction study (see Table 1). The reaction of the ethoxy
ketone (5) was repeated using benzyl magnesium bromide
(2 equiv.) to give the alcohol (9) (31%) and the alcohol (10)
(60%).
(300 MHz, CDCl3) dˆ7.21 (3H, m, Ph±H), 7.14 (2H, m,
Ph±H), 6.15 (1H, t, Jˆ2.0 Hz, H-2), 4.30 (2H, t, Jˆ9.6 Hz,
H-5), 3.06 (1H, d, Jˆ14.0 Hz, CH2±Ph), 2.96 (1H, d,
Jˆ14.0 Hz, CH2±Ph), 2.60 (2H, m, H-4), 2.11 (1H, s,
OH); 13C NMR (75 MHz, CDCl3) dˆ146.2 (C-2), 133.7
(C0-1), 130.8, 128.6 and 127.6 (Ph±C), 125.75 (q, JC±F
ˆ
287.1 Hz, CF3), 111.9 (C-3), 75.35 (C±CF3), 71.1 (C-5),
39.6 (CH2±Ph), 30.3 (C-4); nmax (CH2Cl2, cm21) 3566
(OH), 1654 (CvC); LRMS (Scan AP1): m/zˆ241 (M12
OH, 27%), 189 (M12CF3, 100); HRMS (CI1): (M11NH4)
found 276.1210, C13H13F3O2 requires 276.1211. Found C,
60.54; H, 4.92. C13H13F3O2 requires C, 60.46; H, 5.07%.
2,2,2-Tri¯uoro-1-(2-benzyltetrahydro-3-furanyl)-1-etha-
none (12) was isolated as a pale yellow oil (0.48 g, 31%) 1H
NMR (300 MHz, CDCl3) dˆ7.32±6.97 (5H, complex, Ph),
4.38 (1H, ddd, Jˆ9.0, 7.4, 4.4 Hz, H-2), 4.08 (1H, m, H-5),
3.72 (1H, dd, Jˆ16.2, 7.4 Hz, H-5), 3.58 (1H, q, Jˆ7.4 Hz,
H-3), 2.71 (1H, dd, Jˆ13.8, 8.8 Hz, CH2Ph), 2.58 (1H, dd,
Jˆ13.8, 4.4 Hz, CH2Ph), 2.19 (2H, m, H-4); 13C NMR
(75 MHz, CDCl3) dˆ191.7 (q, JC±Fˆ35.0 Hz, CvO),
137.7 (C0-1), 129.3, 128.7 and 126.9 (Ph±C), 115.5 (q,
JC±Fˆ292.2 Hz, CF3), 81.7 (C-2), 67.2 (C-5), 48.1 (C-3),
37.5(CH2Ph), 29.75 (C-4); nmax (CH2Cl2, cm21) 1755
(CvO); LRMS (Scan AP1): m/zˆ258 (M1, 5%), 257
(M121, 15), 189 (M12CF3, 71); HRMS (CI1): (M11
NH4) found 276.1224, C13H13F3O2 requires 276.1211. The
isomer 2,2,2-tri¯uoro-1-(2-benzyltetrahydro-3-furanyl)-
1-ethanone (13) was isolated as a pale yellow oil (0.46 g,
30%) 1H NMR (300 MHz, CDCl3) dˆ7.44±7.08 (5H,
complex, Ph), 4.46 (1H, dd, Jˆ12.5, 6.6 Hz, H-2), 4.02
(1H, m, H-5), 3.88 (1H, dd, Jˆ14.7, 7.4 Hz, H-5), 3.28
(1H, dt, Jˆ9.6, 6.6, 6.6 Hz, H-3), 3.03 (1H, dd, Jˆ14.0,
6.6 Hz, CH2Ph), 2.90 (1H, dd, Jˆ14.0, 5.9 Hz, CH2Ph),
2.28 (1H, m, H-4), 2.11 (1H, m, H-4); 13C NMR
(75 MHz, CDCl3) dˆ191.7 (q, JC±Fˆ35.0 Hz, CvO),
137.0 (C0-1), 129.5, 128.7 and 127.0 (5C, Ph), 115.6 (q,
JC±Fˆ292.2 Hz, CF3), 81.8 (C-2), 68.00 (C-5), 49.7 (C-3),
40.7 (CH2Ph), 30.85 (C-4); nmax (CH2Cl2, cm21) 1757
(CvO); LRMS (Scan AP1): m/zˆ258 (M1, 13%), 257
(M121, 57), 189 (M12CF3, 58); HRMS (CI1): (M11
NH4) found 276.1207, C13H13F3O2 requires 276.1211.
Reaction of benzyl magnesium bromide with 2,2,2-
tri¯uoro-1-(2-methoxy-3,4-dihydro-2H-5-pyranyl)-1-
ethanone (4). Following the above procedure the ketone (4)
(1.0 g, 4.76 mmol) was reacted with benzyl magnesium bro-
mide and the two isomeric products (7) and (8) were sepa-
rated by ¯ash column chromatography [silica gel, hexane/
ethyl acetate (95:5)] to give as the minor product
(2SR,20SR)-1,1,1-tri¯uoro-2-(2-methoxy-3,4-dihydro-2H-
5-pyranyl)-3-phenyl-2-propanol (7) as a white solid
(0.49 g, 34%), which was crystallised from petroleum
ether to give white crystals mp: 46±478C; 1H NMR
(300 MHz, CDCl3) dˆ7.22 (3H, m, Ph±H), 7.13 (2H, m,
Ph±H), 6.26 (1H, s, H-6), 4.82 (1H, t, Jˆ3.0 Hz, H-2), 3.35
(3H, s, CH3), 3.08 (1H, d, Jˆ14.0 Hz, CH2Ph), 2.93 (1H, d,
Jˆ14.0 Hz, CH2Ph), 2.19 (1H, m, H-4), 2.04 (1H, dt,
Jˆ16.2, 5.2, 5.2 Hz, H-4), 1.88±1.66 (3H, complex, OH,
H-3); 13C NMR (75 MHz, CDCl3) dˆ141.4 (C-6), 133.25
(C0-1), 131.0, 128.5 and 127.6(Ph±C), 125.9 (q, JC±F
ˆ
287.1 Hz, CF3), 109.25 (C-5), 97.3 (C-2), 55.6 (OCH3),
38.55 (CH2±Ph), 26.2 (C-3), 17.1 (C-4); nmax (®lm, cm21
)
3550±3250 (OH), 1664 (CvC); LRMS (Scan AP1):
m/zˆ285 (M12OH, 84%), 233 (M12CF3, 100); HRMS
(CI1): (M11NH4) found 320.1473, C15H17F3O3 requires
320.1473; Found C, 59.64; H, 5.79. C15H17F3O3 requires
C, 59.60; H, 5.67%. (2SR,20RS)-1,1,1-tri¯uoro-2-(2-meth-
oxy-3,4-dihydro-2H-5-pyranyl)-3-phenyl-2-propanol (8)
was isolated as the major product as a white solid (0.89 g,
61%) and was recrystallised from petroleum ether to give
1
white crystals mp 69±708C; H NMR (300 MHz, CDCl3)
dˆ7.32 (3H, m, Ph±H), 7.20 (2H, m, Ph±H), 6.36 (1H, d,
Jˆ2.2 Hz, H-6), 4.89 (1H, t, Jˆ2.9 Hz, H-2), 3.45 (3H, s,
OCH3), 3.13 (2H, s, CH2Ph), 2.30±2.11 (2H, complex, OH,
H-4), 2.06 (1H, m, H-4), 1.91 (1H, m, H-3), 1.66 (1H, m,
H-3); 13C NMR (75 MHz, CDCl3) dˆ140.8 (C-6), 133.9
(C0-1), 130.8, 128.5 and 127.5 (Ph±C), 125.8 (q, JC±F
ˆ
287.1 Hz, CF3), 109.4 (C-5), 97.2 (C-2), 77.1 (C±CF3),
55.7 (OCH3), 39.4 (CH2±Ph), 25.8 (C-3), 16.65 (C-4);
nmax (CH2Cl2, cm21) 3566 (OH), 1661 (CvC); LRMS
(Scan AP1): m/zˆ285 (M12OH, 56%), 233 (M12CF3,
100); HRMS (CI1): (M11NH4) found 320.1473,
C15H17F3O3 requires 320.1473. Found C, 59.65; H, 5.62.
C15H17F3O3 requires C, 59.60; H, 5.67%. The reaction of
the methoxy ketone (4) was repeated using benzyl mag-
nesium bromide (2 equiv.) to give the alcohol (7) (32%)
and the alcohol (8) (56%).
Spiro[2-benzylfuran-3][furo-(2,3-d)][2,6-ditri¯uoro-
methyl-2-hydroxy-3,4-dihydropyran] (14). The reaction
of ketone (3) with benzyl magnesium bromide was repeated
using benzyl magnesium bromide (1.2 equiv.) and gave the
alcohol (11) (6%), a further product the spiro compound
(14) (10%), the ketone (12) (7%) and the isomeric ketone
(13) (10%). The reaction was also repeated using benzyl
magnesium bromide (2 equiv.) and gave the alcohol (11)
(18%), the spiro compound (14) (5%), the ketone (12)
(18%) and the isomeric ketone (13) (26%). The title
compound (14) was isolated as a white solid (0.26 g,
10%) and was recrystallised from petroleum ether to give
white crystals mp 151±1528C; 1H NMR (300 MHz, CDCl3)
dˆ7.38±7.13 (5H, complex, Ph), 4.48 (1H, d, Jˆ2.2 Hz,
H00-2), 4.19 (1H, dt, Jˆ8.1, 8.1, 5.1 Hz, H00-5), 4.10 (1H,
t, Jˆ6.6 Hz, H-2), 3.95 (2H, m, H-5, H00-5), 3.62 (1H, m,
H-5), 3.12 (2H, d, Jˆ6.6 Hz, CH2Ph), 2.84 (2H, m, H00-4),
2.12 (1H, m, H-4), 1.97 (1H, m, H-4), 1.77 (1H, s, OH); 13C
NMR (75 MHz, CDCl3) dˆ140.0 (C0-1), 129.2, 128.4 and
126.3 (Ph±C), 122.8 (CF3), 82.3 (C-2), 73.9 (C00-2), 68.4
(C00-5), 65.2 (C-5), 35.2 (CH2±Ph), 28.1 (C00-4), 25.8 (C-4);
Reaction of 1-(4,5-dihydro-3-furanyl)-2,2,2-tri¯uoro-1-
ethanone (3) with benzyl magnesium bromide. Following
the above procedure the ketone (3) (1.00 g, 6.02 mmol) was
reacted with benzyl magnesium bromide and gave a brown
oil which was puri®ed by ¯ash column chromatography
[silica gel, hexane/ethyl acetate (90:10)] to give an alcohol
(11) and the two isomeric ketones (12) and (13). 2-(4,5-
Dihydro-3-furanyl)-1,1,1-tri¯uoro-3-phenyl-2-propanol
(11) was isolated as a white solid (0.53 g, 34%) and was
1
recrystallised from petroleum ether mp 95±968C H NMR

S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
10063
n
max (CH2Cl2, cm21) 3595, 3338 (OH); LRMS (Scan AP1):
(2) was reacted with p-methoxybenzyl chloride and after
chromatography gave ®rst the trans-ketone (18) as a white
solid (0.21 g, 14%) which was recrystallised from petro-
m/zˆ258 (M12(C6H5F3O2), 27%), 257 [(M121)
-
(C6H5F3O2), 48], 189 [M12(C6H5F3O21CF3), 58]; HRMS
(CI1): (M11NH4) found 442.1468, C19H18F6O4 requires
442.1453. The structure of alcohol (14) has been established
by X-ray diffraction (see Fig.1 and Table 1).
1
leum ether to give white crystals mp 41±428C H NMR
(300 MHz, CDCl3) dˆ7.12 (2H, d, Jˆ8.7 Hz, Ar±H),
6.82 (2H, d, Jˆ8.7 Hz, Ar±H), 3.99 (1H, m, H-6), 3.81
(4H, m, H-2, CH3), 3.38 (1H, m, H-6), 2.93 (1H, m, H-3),
2.68 (1H, d, Jˆ14.3 Hz, CH2±Ar), 2.59 (1H, d, Jˆ14.3 Hz,
CH2±Ar), 2.21 (1H, m, H-4), 1.73±1.58 (3H, complex, H-4,
H-5); 13C NMR (75 MHz, CDCl3) dˆ193.8 (CvO), 158.4
Reaction of 1-(4,5-dihydro-3-furanyl)-2,2,2-tri¯uoro-1-
ethanone (3) with benzyl lithium. To a mixture of toluene
(3.55 g, 38.58 mmol) and TMEDA (1.0 g, 8.61 mmol), a
solution of butyl lithium in hexanes (2.5 M/l) (4.35 ml,
10.88 mmol) was added dropwise under nitrogen. The reac-
tion mixture was heated under gentle re¯ux for about 30 min
(until all the gas evolution stopped) and the red solution
allowed to cool to room temperature. The benzyl lithium
was added dropwise via a syringe to a solution of the ketone
(3) (0.85 g, 5.0 mmol) in ether (12.5 ml) kept in a liquid
nitrogen bath. The reaction mixture was stirred for
30 min, allowed to warm to room temperature, diluted
with ether (25.0 ml) and poured into saturated ammonium
chloride solution (50 ml). The two phases were separated
and the aqueous phase extracted with ether (3£15 ml). The
combined organic phases were collected, washed with
water, dried over MgSO4 and the solvent evaporated in
vacuo to give the alcohol (11) (0.39 g, 30%), which is
described before.
(C0-4), 130.45 (Ar±C), 129.9 (C0-1), 115.5 (q, JC±F
ˆ
292.7 Hz, CF3), 113.8 (Ar±C), 78.65 (C-2), 68.0 (C-6),
55.3 (OCH3), 48.5 (C-3), 39.9 (CH2±Ar), 28.2 (C-4), 24.7
(C-5); nmax (CH2Cl2, cm21) 1754 (CvO); LRMS (Scan
AP1): m/zˆ303 [(M111), 12%], 302 (M1, 100);. Found
C, 59.76; H, 5.61. C15H17F3O3 requires C, 59.60; H,
5.67%. The cis-ketone (17) was isolated after chroma-
tography as a white solid (0.75 g, 50%) and was recrystal-
lised from petroleum ether to give white crystals mp 55±
568C 1H NMR (300 MHz, CDCl3) dˆ7.09 (2H, d,
Jˆ8.5 Hz, Ar±H), 6.85 (2H, d, Jˆ8.5 Hz, Ar±H), 4.08
(1H, m, H-6), 3.82±3.73 (4H, complex, CH3 and H-2),
3.48 (1H, dt, Jˆ11.0, 11.0, 2.9 Hz, H-6), 3.08 (1H, m,
H-3), 2.95 (1H, dd, Jˆ14.2, 8.3 Hz, CH2±Ar), 2.61 (1H,
d, Jˆ14.2, 6.0 Hz, CH2±Ar), 2.14 (1H, m, H-4), 1.91 (1H,
m, H-4), 1.73 (1H, m, H-5), 1.48 (1H, m, H-5); 13C NMR
(75 MHz, CDCl3) dˆ191.7 (CvO), 158.5 (C0-4), 129.7
(C0-1), 130.2 (Ar±C), 115.3 (q, JC±Fˆ293.9 Hz, CF3),
114.1 (Ar±C), 78.8 (C-2), 67.7 (C-6), 55.4 (OCH3), 43.3
(C-3), 38.0 (CH2±Ar), 25.05 (C-4), 21.6 (C-5); nmax
(CH2Cl2, cm21) 1753 (CvO); LRMS (Scan AP1):
m/zˆ303 [(M111), 13%], 302 (M1, 100), 285 (M12OH,
13), 232 [(M121)±CF3, 9]. Found C, 59.65; H, 5.47.
C15H17F3O3 requires C, 59.60; H, 5.67%. The structure of
ketone (17) has been established by X-ray diffraction (see
Table 1).
Reaction of benzyl magnesium bromide with 1-(3,4-dihy-
dro-2H-pyranyl)-2,2,2-tri¯uoro-1-ethanone (2) in tetra-
hydrofuran. Following the above general procedure for
preparation of alcohol (6), reaction of benzyl magnesium
bromide, in tetrahydrofuran, with ketone (2) (1.00 g,
5.55 mmol), in tetrahydrofuran, gave after chromatography
[silica gel, hexane/ethyl acetate (90:10)] ®rst the trans-
2,2,2-tri¯uoro-1-(2-benzyltetrahydro-2H-3-pyranyl)-1-etha-
none (16) as a colourless oil (0.11 g, 7%), which is
described below and then the cis-2,2,2-tri¯uoro-1-(2-
benzyltetrahydro-2H-3-pyranyl)-1-ethanone (15) as
colourless oil (0.56 g, 37%) which also is described below.
a
cis-2,2,2-Tri¯uoro-1-(2-benzyltetrahydro-2H-3-pyranyl)-
1-ethanone (15) and trans-2,2,2-tri¯uoro-1-(2-benzyl-
tetrahydro-2H-3-pyranyl)-1-ethanone (16). Following
the above procedure the ketone (2) was reacted with benzyl
bromide and after chromatography gave ®rst the trans-
Reaction of benzyl magnesium halides in tetrahydro-
furan-ether with 1-(3,4-dihydro-2H-pyranyl)-2,2,2-
tri¯uoro-1-ethanone (2). To magnesium turnings (0.33 g,
13.58 mmol) in dry ether (34.00 ml) benzyl halide
(10.0 mmol) dissolved in dry ether/tetrahydrofuran (1:1,
34 ml) was added dropwise at 08C under nitrogen. The
reaction mixture was stirred at room temperature for
1
ketone (16) as a colourless oil (0.24 g, 18%) H NMR
(300 MHz, CDCl3) dˆ7.38±7.13 (5H, complex, Ph±H),
4.0 (1H, m, H-6), 3.9 (1H, ddd, Jˆ10.0, 6.6, 5.2 Hz, H-2),
3.39 (1H, m, H-6), 3.0 (1H, m, H-3), 2.79 (1H, d, Jˆ
14.0 Hz, CH2Ph), 2.69 (1H, d, Jˆ14.0 Hz, CH2Ph), 2.23
(1H, m, H-4), 1.79±1.57 (3H, complex, H-4, H-5); 13C
NMR (75 MHz, CDCl3) dˆ193.7 (q, JC±Fˆ35.0 Hz,
CvO), 137.9 (C0-1), 129.5, 128.4 and 126.7 (Ph±C),
115.5 (q, JC±Fˆ292.7 Hz, CF3), 78.5 (C-2), 68.0 (C-6),
48.6 (C-3), 40.8 (CH2Ph), 28.2 (C-4), 24.65 (C-5); nmax
(®lm, cm21) 1753 (CvO); LRMS (Scan AP1): m/zˆ272
(M1, 28%), 271 [(M121), 74], 203 [(M12CF3), 61];
HRMS (CI1): (M111) found 273.1103, C14H15F3O2
requires 273.1102. The cis-ketone (15) was isolated as a
45 min and
a solution of the ketone (2) (0.90 g,
5.00 mmol) in dry tetrahydrofuran (10.0 ml) was added
dropwise at 08C. The reaction mixture was stirred at room
temperature for 1.5 h and was poured into saturated ammo-
nium chloride solution (100 ml). The two phases were
separated and the aqueous phase extracted with ether
(3£15 ml), the combined organic phases were collected,
washed with water, dried over MgSO4 and the solvent
evaporated in vacuo. The resulting oil was puri®ed by
¯ash column chromatography [silica gel, hexane/ethyl
acetate (90:10)] to give a mixture of two isomeric ketones.
1
colourless oil (0.63 g, 46%) H NMR (300 MHz, CDCl3)
dˆ7.40±7.10 (5H, complex, Ph±H), 4.08 (1H, m, H-6),
3.85 (1H, ddd, Jˆ8.1, 5.9, 3.0 Hz, H-2), 3.49 (1H, dt,
11.0, 11.0, 2.9 Hz, H-6), 3.08 (1H, m, H-3), 3.05 (1H, dd,
Jˆ14.0, 8.1 Hz, CH2Ph), 2.69 (1H, dd, Jˆ14.0, 5.9 Hz,
CH2Ph), 2.15 (1H, m, H-4), 1.90 (1H, m, H-4), 1.76 (1H,
m, H-5), 1.50 (1H, m, H-5); 13C NMR (75 MHz, CDCl3)
cis-2,2,2-Tri¯uoro-1-[2-(p-methoxybenzyl)tetrahydro-
2H-3-pyranyl)-1-ethanone (17) and trans-2,2,2-tri¯uoro-
1-[2-(p-methoxybenzyl)tetrahydro-2H-3-pyranyl)-1-
ethanone (18). Following the above procedure the ketone

10064
S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
dˆ191.6 (CvO), 137.7 (C0-1), 129.2, 128.7 and 126.8
(Ph±C), 115.3 (q, JC±Fˆ293.9 Hz, CF3), 78.6 (C-2), 67.7
(C-6), 43.35 (C-3), 38.9 (CH2Ph), 25.1 (C-4), 21.6 (C-5);
nmax (®lm, cm21) 1755 (CvO); LRMS (Scan AP1):
m/zˆ272 (M1, 7%), 271 [(M121), 23%], 255 (M12OH,
16), 203 [(M12CF3), 100]; HRMS (CI1): (M111) found
273.1091, C14H15F3O2 requires 273.1102.
chloride. To magnesium turnings (0.44 g, 18.1 mmol) in
dry ether (1.5 ml), cinnamyl chloride (0.03 g, 0.20 mmol)
was added and the reaction mixture was heated with
vigorous stirring to initiate the reaction. A solution of the
ketone (2) (1.00 g, 5.54 mmol) and the cinnamyl chloride
(0.99 g, 6.48 mmol) in dry ether (3.0 ml) was added drop-
wise to maintain re¯ux. The reaction mixture was heated
under re¯ux for 3 h, allowed to cool to room temperature
and poured into cold saturated aqueous ammonium chloride
(50 ml). The two phases were separated and the aqueous
phase extracted with ether (3£15 ml), the combined organic
phases were collected, washed with water, dried over
MgSO4 and the solvent evaporated in vacuo. The resulting
oil was puri®ed by ¯ash column chromatography [silica gel,
hexane/ethyl acetate (90:10)] to give two alcohols (21)
and (22). 2-(3,4-Dihydro-2H-5-pyranyl)-1,1,1-tri¯uoro-
3-phenyl-4-penten-2-ol (21) was ®rst isolated as a white
solid (0.51 g, 31%) and was recrystallised from petroleum
(1E)-1-Ethoxy-3-(tri¯uoromethyl)-1,5-hexadien-3-ol (19).
To magnesium turnings (1.0 g, 41.15 mmol) in dry ether
(75.0 ml), allyl bromide (2.41 g, 20.0 mmol) dissolved in
dry ether (75.0 ml) was added dropwise under nitrogen.
The reaction mixture was stirred at room temperature for
1 h and a solution of the ketone (1) (0.84 g, 5.00 mmol) in
tetrahydrofuran (60 ml) was added dropwise at 08C. The
reaction mixture was stirred at room temperature for 2 h,
poured into saturated ammonium chloride solution
(200 ml), the two phases were separated and the aqueous
phase extracted with ether (3£15 ml). The combined
organic phases were collected, washed with water, dried
over MgSO4 and the solvent evaporated in vacuo. The
resulting oil was puri®ed by ¯ash column chromatography
[silica gel, hexane/ethyl acetate (95:5)] to give the title
1
ether, mp 89±908C H NMR (300 MHz, CDCl3) dˆ7.43±
7.12 (5H, complex, Ph±H), 6.86 (1H, s, H-6), 6.20 (1H, ddd,
Jˆ16.9, 10.2, 10.0 Hz, CHvCH2), 5.12 (1H, d, Jˆ10.2 Hz,
CHvCH2), 5.07 (1H, d, Jˆ16.9 Hz, CHvCH2), 3.98 (2H,
m, H-2), 3.85 (1H, d, Jˆ10.0 Hz, CH±Ph), 2.4 (1H, s, OH),
2.07 (2H, m, H-4), 1.85 (2H, m, H-3); 13C NMR (75 MHz,
CDCl3) dˆ144.5 (C-6), 138.9 (C0 ±Ph), 135.9 (CHvCH2),
129.3, 128.9 and 127.65 (Ph±C), 117.1 (CHvCH2), 107.4
(C-5), 65.5 (C-2), 52.2 (CH±Ph), 22.0 (C-3), 20.3 (C-4);
nmax (CH2Cl2, cm21) 3564 (OH), 1651 and 1601 (CvC);
LRMS (Scan AP1): m/zˆ281 [(M12OH), 50%], 229
[(M12CF3), 60]; Found C, 64.31; H, 5.62. C16H17F3O2
requires C, 64.42; H, 5.74%. The structure of alcohol (21)
has been established by X-ray diffraction (see Table 1).
2-(3,4-Dihydro-2H-5-pyranyl)-1,1,1-tri¯uoro-3-phenyl-4-
penten-2-ol (22) was isolated as a colourless oil (0.96 g,
58%) 1H NMR (300 MHz, CDCl3) dˆ7.43±7.13 (5H,
complex, Ph±H), 6.48 (1H, s, H-6), 6.31 (1H, m,
CHvCH2), 5.29 (1H, d, Jˆ10.3,CHvCH2), 5.13 (1H, d,
Jˆ16.9 Hz, CHvCH2), 3.88 (1H, d, Jˆ8.1,CH±Ph), 3.72
(2H, m, H-2), 2.48 (1H, s, OH), 1.91 (2H, m, H-4), 1.68 (1H,
m, H-3), 1.38 (1H, m, H-3); 13C NMR (75 MHz, CDCl3)
dˆ144.5 (C-6), 138.8 (C0 ±Ph), 135.45 (CHvCH2), 129.4,
128.3 and 127.2 (Ph±C), 119.6 (CHvCH2), 108.2 (C-5),
65.3 (C-2), 52.95 (CH±Ph), 21.7 (C-3), 20.5 (C-4); nmax
(CH2Cl2, cm21) 3562 (OH), 1650 and 1600 (CvC);
LRMS (Scan AP1): m/zˆ299 [(M111), 9%), 281
[(M12OH), 81%], 229 [(M12CF3), 100]; HRMS (CI1):
(M111) found 299.1260, C16H17F3O2 requires 299.1259.
1
compound (19) as a colourless oil (0.85 g, 81%); H NMR
(300 MHz, CDCl3) dˆ6.68 (1H, d, Jˆ12.5 Hz, H-1), 5.79
(1H, m, H-5), 5.23 (2H, m, H-6), 4.78 (1H, d, Jˆ12.5 Hz,
H-2), 3.78 (2H, q, Jˆ7.0 Hz, CH2CH3), 2.52 (2H, m, H-4),
2.18 (1H, s, OH), 1.28 (3H, t, Jˆ7.0 Hz, CH3); 13C NMR
(75 MHz, CDCl3) dˆ151.0 (C-1), 130.9 (C-5), 125.5 (q,
JC±Fˆ284.8 Hz, CF3), 121.25 (C-6), 100.2 (C-2), 74.1 (q,
JC±Fˆ57.6 Hz, C±CF3), 65.5 (CH2CH3), 40.2 (C-4), 14.7
(CH2CH3); nmax (®lm, cm21): 3443±3350 (OH), 1656
(CvC); LRMS (Scan AP1): m/zˆ211 [(M111), 36%),
193 [(M12OH), 53%], 141 [(M12CF3), 100];
HRMS(CI1): (M111) found 211.0946, C9H13F3O2 requires
211.0946.
2-(3,4-Dihydro-2H-5-pyranyl)-1,1,1-tri¯uoro-4-penten-
2-ol (20). Following the above procedure the ketone (2)
(0.9 g, 5.0 mmol) was reacted with allyl magnesium
bromide to give the title compound (20) as a colourless oil
1
(0.91 g, 82%) H NMR (300 MHz, CDCl3) dˆ6.71 (1H, s,
H-6), 5.72 (1H, m, CHvCH2), 5.25 (2H, m, CHvCH2),
3.96 (2H, m, H-2), 2.65 (1H, dd, Jˆ14.7, 6.6 Hz,
CH±CH2), 2.50 (1H, dd, Jˆ14.7, 7.5 Hz, CH±CH2), 2.3
(1H, d, Jˆ4.4 Hz, OH), 2.08 (2H, m, H-4), 1.85 (2H, m,
H-3); 13C NMR (75 MHz, CDCl3) dˆ144.7 (C-6), 130.75
(CHvCH2), 125.7 (q, JC±Fˆ287.1 Hz, CF3), 121.2
(CHvCH2), 108.1 (C-5), 75.6 (q, JC±Fˆ28.3 Hz, C±CF3),
65.5 (C-2), 37.8 (CH2), 22.0 (C-3), 20.45 (C-4); nmax ®lm,
cm21) 3550±3400 (OH), 1659 (CvC); LRMS (Scan AP1):
m/zˆ205 [(M12OH), 100%], 153 [(M12CF3), 93]; HRMS
(CI1): (M11NH4) found 240.1216, C10H13F3O2 requires
240.1211.
Reaction of ketone (2) with crotyl magnesium bromide.
Following the method for the reaction of ketone (1) in
preparation of alcohol (19) using allyl bromide, the ketone
(2) (0.9 g, 5.0 mmol) was reacted with crotyl bromide
(2.7 g, 20.0 mmol) and gave after chromatography [silica
gel, hexane/ethyl acetate (95:5)] a mixture of the two
isomeric alcohols 2-(3,4-dihydro-2H-5-pyranyl)-1,1,1-
tri¯uoro-3-methyl-4-penten-2-ol (23) as a colourless oil
(1.12 g, 95%) (obtained as a 38:62% ratio); 1H NMR
(300 MHz, CDCl3) dˆ6.76 (1H, s, H-6), 6.69 (1H, s,
H-6), 5.99 (1H, m, CHvCH2), 5.81 (1H, m, CHvCH2),
5.22 (2H, m, CHvCH2), 5.11 (2H, m, CHvCH2), 3.98
(4H, m, H-2), 2.78 (2H, m, CHCH3), 2.32±1.72 (8H,
complex, H-4, H-3), 1.13 (3H, d, Jˆ6, CH3), 1.01 (3H, d,
Jˆ7, CH3); 13C NMR (75 MHz, CDCl3) dˆ143.9 (C-6),
Reaction of ketone (2) (1.0 g, 5.55 mmol) with allyl mag-
nesium bromide (4 equiv.) in ether following the general
procedure as described above for reaction of benzyl mag-
nesium bromide with ketone (2) afforded after ¯ash column
chromatography [silica gel, hexane/ethyl acetate (95:5)] the
title compound (20) in 67% yield.
Reaction of ketone (2) with cinnamyl magnesium

S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
10065
138.0 and 137.4 (CHvCH2), 125.5 (CF3), 117.8 and 116.5
(CHvCH2), 107.8 (C-5), 65.5 (C-2), 40.9 and 39.15 (CH±
CH3), 22.1, 20.45 and 20.2 (C-3, C-4), 14.0 and 13.5 (CH3);
nmax (®lm, cm21) 3500±3200 (OH), 1658 (CvC); LRMS
(Scan AP1): m/zˆ237 [(M111), 8%], 219 [(M12OH),
100], 167 [(M12CF3), 99]. HRMS (CI1) (M111) found
237.1095, C11H15F3O2 requires 237.1102.
leum ether/ethyl acetate (90:10)] to afford as a colourless oil
(0.28 g, 45%) 2-(4,5-dihydro-3-furanyl)-1,1,1-tri¯uoro-4-
penten-2-ol (26) 1H NMR (300 MHz, CDCl3) dˆ6.39 (1H,
t, Jˆ2.2 Hz, H-2), 5.70 (1H, m, CHvCH2), 5.18 (2H, m,
CHvCH2), 4.35 (2H, t, Jˆ9.6 Hz, H-5), 2.65 (2H, m, H-4),
2.50 (2H, d, Jˆ7.4 Hz, CH±CH2) 2.35 (1H, s, OH) 13C
NMR (75 MHz, CDCl3) dˆ146.1 (C-2), 130.6
(CHvCH2), 125.45 (q, JC±Fˆ286.0 Hz, CF3), 121.2
(CHvCH2), 111.7 (C-3), 74.1 (q, JC±Fˆ29.4 Hz, C±CF3),
71.1 (C-5), 38.3 (CH-CH2), 29.8 (C-4); nmax (®lm, cm21)ˆ
3500±3200 (OH), 1662 (CvC); LRMS (Scan AP1):
m/zˆ209 [(M111), 18%], 191 [(M12OH), 98], 139
[(M12CF3), 100]; HRMS (CI1): (M11NH4) found
226.1058, C9H11F3O2 requires 226.1055.
Reaction of ketone (1) with cinnamyl magnesium
chloride. Following the above procedure for the preparation
of alcohols (21) and (22), the ketone (1) (0.93 g, 5.54 mmol)
was reacted with cinnamyl magnesium chloride and gave
after chromatography [silica gel, hexane/ethyl acetate
(90:10)] a mixture of two isomeric alcohols (24) (0.95 g,
60%) (obtained as a 42:58% ratio), from which the more
polar isomer was separated as a white solid. One isomer of
(1E)-1-Ethoxy-4-phenyl-3-(tri¯uoromethyl)-1,5-hexadien-
3-ol (24) was isolated as a white solid and was recrystallised
Acknowledgements
1
from petroleum ether mp 65±668C, H NMR (300 MHz,
We thank the Egyptian Government for a research student-
ship (A. H. El-S.) and EPSRC for X-ray facilities.
CDCl3) dˆ7.43±7.18 (5H, complex, Ph), 6.62 (1H, d, Jˆ
12.5 Hz, H-1), 6.27 (1H, m, H-5), 5.28 (2H, m, H-6), 4.85
(1H, d, Jˆ12.5 Hz, H-2), 3.77 (3H, m, H-4, CH2CH3), 2.29
(1H, d, Jˆ1.5 Hz, OH), 1.29 (3H, m, CH3); 13C NMR
(75 MHz, CDCl3) dˆ151.1 (C-1), 138.35 (C0 ±Ph), 135.6
(C-5), 129.5, 128.4 and 127.4 (Ph±C), 120.0 (C-6), 98.75
(C-2), 65.6 (CH2CH3), 55.8 (C-4), 14.75 (CH3); nmax (®lm,
cm21) 3600±3200(OH); LRMS (Scan AP1): m/zˆ287
[(M111), 5%), 269 [(M12OH), 100], 217 [(M12CF3),
100]; HRMS (CI1): (M111) found 287.1266, C15H17F3O2
requires 287.1259; Found C, 62.65; H, 5.77. C15H17F3O2
requires C, 62.93; H, 5.99%.
References
1. Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7261.
2. Mellor, J. M.; Reid, G.; El-Sagheer, A. H.; El-Tamany, E. H.
Tetrahedron 2000, 56, 10039.
3. Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263.
4. Mellor, J. M.; El-Sagheer, A. H.; Metwally, R. N. Tetrahedron
2000, 56, 10067.
5. Mellor, J. M.; El-Sagheer, A. H.; Salem, E. M. Tetrahedron
Lett. 2000, 41, 7383.
Reaction of ketone (1) with crotyl magnesium bromide.
Following the method for the reaction of ketone (1) with
allyl bromide, the ketone (1) (0.84 g, 5.0 mmol) was reacted
with crotyl bromide (2.7 g, 20.0 mmol) and gave after chro-
matography [silica gel, hexane/ethyl acetate (90:10)] a
mixture of two isomeric alcohols (1E)-1-ethoxy-4-methyl-
3-(tri¯uoromethyl)-1,5-hexadien-3-ol (25) as a colourless
6. Yanovskaya, L. A.; Kryshtal, G. V.; Kul'ganek, V. V. Russ.
Chem. Rev. 1984, 53, 744.
7. Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
8. Kyriakakou, G.; Roux-Schmitt, M. C.; Seyden-Penne, J.
Tetrahedron 1975, 31, 1883.
9. Cossentini, M.; Deschamps, B.; Anh, N. T.; Seyden-Penne, J.
Tetrahedron 1977, 33, 409.
1
oil (1.11 g, 99%) (obtained as a 50:50% ratio). H NMR
10. Lefour, J-M.; Loupy, A. Tetrahedron 1978, 34, 2597.
11. Posner, G. H. Org. React. 1972, 19, 1.
(300 MHz, CDCl3) dˆ6.56 (2H, m, H-1), 5.70 (2H, m,
H-5), 5.05 (4H, m, H-6), 4.77 (2H, m, H-2), 3.70 (4H, m,
CH2CH3), 2.54 (2H, m, H-4), 2.17 (2H, s, OH), 1.19 (6H, m,
CH3), 0.97 (6H, m, CH3); 13C NMR (75 MHz, CDCl3)
dˆ151.2 and 150.8 (C-1), 138.05 and 137.9 (C-5), 125.8
(CF3), 118.5 and 117.3 (C-6), 98.5 and 98.0 (C-2), 65.7 and
65.5 (CH2CH3), 44.7 and 43.7 (C-4), 15.2, 14.75 and 14.3
(CH3); nmax (®lm, cm21)ˆ3500±3150 (OH), 1655 (CvC);
LRMS (Scan AP1): m/zˆ225 [(M111), 11%), 207
[(M12OH), 78], 178 [(M12C2H5OH), 9], 155 [(M12
CF3), 100]; HRMS (CI1): (M111) found 225.1103,
C10H15F3O2 requires 225.1102.
12. Marson, C. M.; Walker, A. J.; Pickering, J.; Hobson, A. D.;
Wrigglesworth, R.; Edge, S. J. J. Org. Chem. 1993, 58, 5944.
13. Hunig, S.; Wehner, G. Chem. Ber. 1980, 113, 302.
14. Cohen, T.; Abraham, W. D.; Myers, M. J. Am. Chem. Soc.
1987, 109, 7923.
15. Reich, H. J.; Sikorski, W. H. J. Org. Chem. 1999, 64, 14;
Strzalko, T.; Seyden-Penne, J.; Wartski, L.; Corset, J.; Castella-
Ventura, M.; Froment, F. J. Org. Chem. 1998, 63, 3295.
16. Gustafsson, B. Acta Chem. Scand. 1977, 31B, 382.
17. Pearson, A. J.; Babu, M. K. M. Organometallics 1994, 13,
2539.
18. Armstrong, A. In Comprehensive Organic Functional Group
Transformations, Roberts, S. M., Ed.; Pergamon: Oxford, 1995;
Vol. 1, p 293.
Reaction of the ketone (3) with allyl bromide and
indium. To
a mixture of the ketone (3) (0.5 g,
3.01 mmol), water (23 ml) and tetrahydrofuran (7.8 ml),
indium powder (0.5 g, 4.36 mmol) and allyl bromide
(0.84 g, 6.94 mmol) were added at room temperature. The
reaction mixture was stirred for 3 h, ®ltered through a pad of
alumina and washed with dichloromethane, extracted with
dichloromethane and dried over MgSO4. The solvent was
evaporated in vacuo to give a colourless oil, which was
puri®ed by ¯ash column chromatography [silica gel, petro-
19. House, H. O.; Tra®cante, D. D.; Evans, R. A. J. Org. Chem.
1963, 28, 348.
20. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.
21. Spassky-Pasteur, A.; Riviere, H. Bull. Soc. Chim. Fr. 1969,
811.
22. Nenaidenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ.
Chem. Rev. 1999, 68, 437.

10066
S. J. Coles et al. / Tetrahedron 56 (2000) 10057±10066
23. Oroshnik, W.; Karmas, G.; Mallory, R. A. J. Am. Chem. Soc.
1954, 76, 2325.
29. Masson, S.; Saquet, M.; Thuillier, A. Tetrahedron 1977, 33,
2949.
24. Gillespie, J. S.; Acharya, S. P.; Shamblee, D. A.; Davis, R. E.
Tetrahedron 1975, 31, 3.
30. Leger, L.; Saquet, M. Bull. Soc. Chim. Fr. B 1975, 657.
31. Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976,
98, 4054.
25. Holm, T. Acta Chem. Scand. 1983, 37B, 567.
26. Gallagher, M. J.; Harvey, S.; Raston, C. L.; Sue, R. E. J. Chem.
Soc. Chem. Commun. 1988, 289; Van Campen, M. G.; Meisner,
D. F.; Parmerter, S. M. J. Am. Chem. Soc. 1948, 70, 2296.
27. Danishefsky, S.; Migdalof, B. H. J. Chem. Soc. Chem.
Commun. 1969, 1107; Benkeser, R. A.; Snyder, D. C. J. Org.
Chem. 1982, 47, 1243; Bernardon, C.; Deberly, A., J. Org.
Chem. 1982, 47, 463.
32. Boga, C.; Forlani, L.; Todesco, P. F. Tetrahedron Lett. 1997,
38, 4845.
33. Terlinden, R.; Boland, W.; Jaenicke, L. Helv. Chim. Acta
1983, 66, 466.
34. Blessing, R. H. Acta Crystallogr. 1995, A51, 33; Blessing,
R. H. J. Appl. Crystallogr. 1997, 30, 421.
35. Sheldrick, G. M. shelxl 97. Program for crystal structure
28. El Idrissi, M.; Santelli, M. J. Org. Chem. 1988, 53, 1010; Zair,
T.; Santelli-Rouvier, C.; Santelli, M. J. Org. Chem. 1993, 58, 2686.
È
re®nement, University of Gottingen, 1997.