Flexible metathesis-based approaches to highly functionalised furans and pyrroles

Article abstract of DOI:10.1016/j.tet.2007.09.087

A range of differentially functionalised furans and pyrroles have been synthesised in short order by the judicious use of a ring-closing metathesis/aromatisation strategy. Two contrasting approaches are described exploiting a palladium-catalysed union of

Full text of DOI:10.1016/j.tet.2007.09.087

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 809e820
www.elsevier.com/locate/tet
Flexible metathesis-based approaches to highly functionalised
furans and pyrroles
a
a
Timothy J. Donohoe a, , Neil M. Kershaw , Allan J. Orr ,
Katherine M.P. Wheelhouse (nee Gosby) a, Lisa P. Fishlock a,
Adam R. Lacy a, Matilda Bingham b, Panayiotis A. Procopiou c
*
a Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
b Department of Medicinal Chemistry, Organon Laboratories Ltd, Newhouse, Lanarkshire ML1 5SH, Scotland, UK
c GlaxoSmithKline Research and Development Limited, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 18 July 2007; accepted 6 September 2007
Available online 24 October 2007
Abstract
A range of differentially functionalised furans and pyrroles have been synthesised in short order by the judicious use of a ring-closing
metathesis/aromatisation strategy. Two contrasting approaches are described exploiting a palladium-catalysed union of allylic alcohols and
sulfonamides in one case, and a titanium mediated methylenation of homoallylic esters in another. A number of groups that are difficult to install
via traditional methods were incorporated successfully.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Ring-closing metathesis; Furan; Pyrrole; Arenes; Catalysis
1. Introduction
MesN
Cl
NMes
Ph
MesN
Cl
NMes
PCy3
Ru
PCy3
Ru
Cl
Cl
Cl
Ru
Ru
In recent years, the metathesis reaction has become regarded
as one of the most important CeC bond forming processes and
has been utilised extensively in total synthesis.1 The advent of
well defined catalyst systems combining excellent activity and
broad functional group compatibility has been the major factor
in popularising this reaction.2 Ruthenium carbenoids 1e4
represent a selection of an increasing number of commercially
available metathesis catalysts, which are widely used because
of their relative insensitivity to oxygen, moisture and minor
impurities in reaction solvents (Fig. 1).
One of the most powerful tactics for the synthesis of carbo-
cyclic and heterocyclic frameworks is ring-closing metathesis
(RCM).3 However, in the context of aromatic and heteroaro-
matic ring formation, rationally designed RCM strategies
have only recently been highlighted in the literature.4 Indeed,
Cl
Cl
Cl
Ph
PCy3
PCy3
i
i
PrO
PrO
Grubbs 1st
generation
catalyst 1
Hoveyda-Grubbs
Grubbs 2nd
generation
catalyst 3
Hoveyda-Grubbs
1
st generation
2
nd generation
catalyst 2
catalyst 4
Figure 1. A selection of commercially available metathesis catalysts.
many early examples of the synthesis of aromatic compounds
by RCM were viewed as unwanted degradation reactions.5 As
heteroaromatic compounds are prevalent in biologically active
compounds, both as natural products and in medicinal chem-
istry, the development of a flexible, novel approach to aro-
matic compounds utilising RCM as a key step was undertaken.
In the first instance, it was decided to concentrate efforts on
the synthesis of five-membered heterocycles and furans in par-
ticular. Two plausible disconnections (A and B) utilising RCM
as a key bond forming process were considered (Scheme 1).
* Corresponding author. Tel.: þ44 1865 275 649; fax: þ44 1865 275 708.
E-mail address: timothy.donohoe@chem.ox.ac.uk (T.J. Donohoe).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.087

810
T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
ꢀ Disconnection A, in which a leaving group is present at
Treatment of mixed acetals 11 and 14 with 10 mol % of
Grubbs second generation catalyst 3 smoothly effected ring
closure to the corresponding dihydrofurans. Aromatisation to
the desired furans 12 and 15 on exposure to acid proceeded
in excellent overall yield. A problem frequently encountered
during the purification of metathesis reactions is contamina-
tion of the relatively nonpolar products with (nonpolar) phos-
phine residues from the catalyst. Although the RCM/
aromatisation could be performed in a single operation and
in high yield (e.g., 11/12; 90% for a one-pot protocol), it
was generally found to be advantageous to purify rapidly the
more polar dihydrofuran prior to the aromatisation step. This
circumvented any unwanted contamination of the less polar
furans with phosphine residues.
C-5, reveals allylic mixed acetal 7.
ꢀ Disconnection B, in which a leaving group is present at
C-3, reveals enol ether 9.
R2
R2
R1
R3
R4
R2
R3
R3
R4
aromatise
aromatise
RO
R1
4
5
3
2
R1
R4
O
6
O
5
O
8
B
A
OR
RCM
R2
RCM
R4
R3
R3 R1
O
O
R4 OR
R2 OR
9
R1
7
Having successfully generated monosubstituted furans, the
synthesis of a range of disubstituted furans was attempted. Ac-
cordingly, known BayliseHillman adducts 16aed13 were
readily transformed into mixed acetals 17aed using the previ-
ously described conditions; RCM and aromatisation furnished
2,3-disubstituted furans 18aed in moderate to excellent yield
(Scheme 3).
Scheme 1.
Acyclic dienes 7/9, bearing groups R1, R2, R3 and R4,
would be expected to form dihydrofurans 6/8 upon RCM.
Critically, 6 and 8 are at the correct oxidation level to furnish
the aromatic furan 5 upon elimination of the alcohol leaving
group.6 The possibility of achieving the RCM and subsequent
aromatisation in ‘one-pot’ made this a very attractive proposal.
It was anticipated that this approach would allow access to a
wide variety of differentially substituted furans and, by ana-
logy, pyrroles.
CO2Me
MeO2C
R1
MeO2C
R1
R1
i)
ii,iii)
OH
16a-d
O
17a-d
OMe
O
18a-d
Scheme 3. Reagents and conditions: (i) methoxyallene, 5% Pd(OAc)2, 5%
dppp, Et3N, MeCN, reflux; (ii) 10 mol % 3, CH2Cl2, reflux; (iii) 0.6 equiv
TFA, CH2Cl2, rt.
2. Results and discussion
In addition to the methyl ester at R2 (see 5, Scheme 1), both
alkyl and a range of substituted aryl groups were readily in-
stalled at R1 via this sequence and yields were generally
good (Table 1). Moreover, it seems feasible that additional
functionality could be introduced at R4 by exploiting the
reactivity of the furan nucleus in electrophilic substitution
reactions or through a-metallation followed by a range of
palladium-catalysed couplings or electrophilic quenches.
The successful synthesis of a range of furans and pyrroles
based on these two disconnections was recently communi-
cated.7,8 Herein, a full account of these studies is detailed,
contrasting the scope of the two strategies outlined in Scheme 1.
2.1. Mixed acetal route to furans and pyrroles
A robust method was required for the formation of O,O-
and N,O-acetals and it was noted that such transformations
had been achieved via the reaction of methoxyallene9 with
alcohols and sulfonamides under palladium(II) catalysis.5b,10
Initially, allylic alcohols 1011 and 1312 were synthesised, esta-
blishing functionality at R1 and R2, respectively, via single
step literature procedures. These were then converted to the
corresponding mixed acetals in good yield (Scheme 2).
Table 1
Yields for the sequence depicted in Scheme 3
Entry
R1
Yield (%)
(i)
(ii,iii)
1 (a)
2 (b)
3 (c)
4 (d)
Me
91
73
58
58
79
70
59
81
3-MeC6H4
3-CF3C6H4
4-NO2C6H4
Ar
i)
ii,iii)
Ar
74%
79%
OH
10
Ar
O
11
OMe
O
12
Encouraged by this initial success, attention was turned to
the synthesis of N-protected pyrroles. The required allylic sul-
fonamides 19 and 22 were prepared in short order from com-
mercially available starting materials and converted to the
corresponding N,O-acetals in an analogous fashion to that
described above. Then RCM and aromatisation proceeded
smoothly, forming the desired N-protected pyrroles 21 and
24 in good yield after purification (Scheme 4).
Ar = 4-MeOC6H4
Ph
Ph
Ph
i)
ii,iii)
70%
75%
OH
13
O
14
OMe
O
15
Scheme 2. Reagents and conditions: (i) methoxyallene, 5% Pd(OAc)2, 5%
dppp, Et3N, MeCN, reflux; (ii) 10 mol % 3, CH2Cl2, reflux; (iii) 0.6 equiv
TFA, CH2Cl2, rt.

T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
811
Ar
i)
ii,iii)
TsHN
TsHN
ArI
63%
Pd0Ln
78%
R
N
OMe
OMe
N
N
OMe
Ts
20
Ts
21
Ts
19
ii,iii)
61%
LnPdII
Ar
I
i)
63%
N
N
Ts
23
Ts
24
22
RNTs
PdIILnI
OMe
•
Scheme 4. Reagents and conditions: (i) methoxyallene, 5% Pd(OAc)2, 5%
dppp, Et3N, MeCN, reflux; (ii) 10 mol % 3, CH2Cl2, reflux; (iii) 0.6 equiv
TFA, CH2Cl2, rt.
K2CO3
Ar
OMe
RNHTs
Ph
Ph
Ph
i)
ii,iii)
74%
Although the preparation of functionalised allylic alcohols
and sulfonamides had been achieved, we were mindful that the
portion of the heterocycle derived from methoxyallene remained
unsubstituted. Metallation of alkoxyallenes adjacent to the alk-
oxy group followed by quenching with an appropriate electro-
phile had been reported in the literature.14 It was anticipated
that this reaction would allow access to more highly substituted
heterocycles without the need for further manipulation after
RCM and aromatisation. Unfortunately, although the functional-
ised methoxyallene derivative 25 could be prepared (albeit with-
out purification)15 the subsequent palladium coupling failed to
yield any of the desired N,O-acetal 26, with rearrangement and
hydrolysis of the allene being the major processes (Scheme 5).
TsHN
TsHN
71%
N
OMe
N
Ts
27
Ts
28
19
Ph
i)
70%
ii,iii)
54%
N
OMe
N
Ts
29
Ts
30
22
Ph
ii)
×
TsHN
i)
91%
Ph
OMe
Ph
N
Ts
32
31
Scheme 6. Reagents and conditions: (i) methoxyallene, 5% Pd(PPh3)2, PhI,
K2CO3, toluene, rt; (ii) 10 mol % 3, CH2Cl2, reflux; (iii) 0.6 equiv TFA,
CH2Cl2, rt.
ii)
×
19
i)
•
•
As an extension to this methodology, a range of biaryl sys-
tems were then targeted. Biaryl motifs are present in a range of
natural products such as roseophilin19 and are also of some im-
portance in material science.20 Accordingly, known pyrrole
3321 was converted to allylic acetal 34 in excellent yield.
RCM and aromatisation proceeded in good overall yield pro-
viding furan-pyrrole 35. In addition, the tandem cyclisation
of bis-allylic acetal 37, obtained from commercially available
diol 36, furnished bis-furan 38 in a pleasing 54% yield. The
expediency of this synthesis, facilitated by the tandem RCM,
provides many interesting opportunities for total synthesis
and for the generation of polyaromatic arrays (Scheme 7).
C5H11
OMe
N
TsHN
OMe
OMe
H11C5
Ts
25
26
Scheme 5. Reagents and conditions: (i) n-BuLi, THF, ꢁ40 ꢂC then n-pentyl
bromide; (ii) 5% Pd(OAc)2, 5% dppp, Et3N, MeCN, reflux.
Undeterred, functionalisation at the central carbon of the al-
lene was attempted via a palladium(0)-catalysed coupling of
an aryl halide, an allylic sulfonamide and methoxyallene.16
Presumably, the mechanism involves oxidative addition to
the aryl halide to form a palladium(II) species followed by car-
bopalladation of methoxyallene to yield a p-allyl system. Sub-
sequent attack by the sulfonamide at the most electron
deficient end of the p-allyl system would yield the N,O-acetal
and regenerate the palladium(0) catalyst (Scheme 6).16,17
To our delight, the three component coupling proceeded
smoothly furnishing N,O-acetals 27, 29 and 32 in excellent
yield. Subsequent RCM and aromatisation was high yielding
for the formation of monosubstituted pyrrole 28, thus install-
ing functionality at R3. The yield of pyrrole 30, with substitu-
ents at R1 and R3, was significantly lower although still very
efficient given the brevity of the overall sequence. This reduc-
tion in yield was attributed to the increased steric hindrance of
N,O-acetal 29 resulting in a less efficient ring closure. The in-
ability of N,O-acetal 32 to undergo RCM was disappointing,
although not surprising given this hypothesis. More powerful
catalysts, which are capable of forming tetrasubstituted double
bonds were recently described by Grubbs and co-workers.18
Reinvestigation of substrates 29 and 32 using these catalysts
would be expected to yield more fruitful results, thus enhanc-
ing the appeal of this approach.
i)
ii,iii)
N
N
O
88%
62%
O
OMe
Ts
OH
Ts
NTs
O
33
34
35
OH
i)
80%
ii,iii)
54%
O
OMe
MeO
O
O
OH
36
37
38
Scheme 7. Reagents and conditions: (i) methoxyallene, 5% Pd(OAc)2, 5%
dppp, Et3N, MeCN, reflux; (ii) 10 mol % 3, CH2Cl2, reflux; (iii) 0.6 equiv
TFA, CH2Cl2, rt.
In summary, monosubstituted furans with groups R1 and R2
at C-2 and C-3, respectively, as well as disubstituted examples
can be accessed using this strategy. The opportunity to introduce
additional functionality after aromatisation by a variety of
methods further enhances the appeal of this method. The toler-
ance of carbonyl, alkyl and a range of electron donating and

812
T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
withdrawing aryl groups is also significant. N-protected pyrroles
are also readily synthesised. Although metallation of methox-
yallene was ultimately unsuccessful in increasing substitution,
the use of a palladium(0)-catalysed three component coupling
protocol provided a straightforward route to disubstituted
pyrroles containing groups at either, or both, R1 and R3.
in this study. Pleasingly, on exposure to catalyst 3, followed
by treatment of the intermediate dihydrofuran with catalytic
acid in situ, furan 46 was isolated in a 69% yield over the
two steps (Scheme 9).
O
i)
82%
ii)
96%
OH
O
Ph
O
OMe
OMe
2.2. Enol ether route to furans
41
42
43
66% iii)
As part of our continuing interest in developing novel
syntheses of aromatic heterocycles via metathesis strategies,
disconnection B outlined in Scheme 1 was then investigated.
Clearly, this approach required a flexible synthesis of a range
of enol ethers 9; the enol ether moiety was to be installed by
methylenation of the corresponding ester 39, derived from
acylation of a homoallylic alcohol 40 (Scheme 8).
MeO
iv)
69%
O
Ph
Ph
Ph
O
46
O
45
OMe
44
Scheme 9. Reagents and conditions: (i) MeOH, 5% concd aq H2SO4, reflux;
(ii) PhCOCl, Et3N, CH2Cl2; (iii) TiCl4, TMEDA, Zn, PbCl2 (cat.), CH2Br2,
CH2Cl2, THF; (iv) 10 mol % 3, PhMe, 40 ꢂC then 0.6 equiv TFA.
R2
R2
R1
R3
R4
R3 R1
R3
Buoyed by this initial success, it was decided to investigate
the synthesis of 2,5-disubstituted furans. Araki and co-workers
had reported the addition of g-methoxyallylindium reagents to
aldehydes with complete regioselectivity at the g-position.32
With this in mind a synthetic scheme was devised allowing
elaboration of both R1 and R4. Accordingly, the formation of
a range of homoallylic alcohols 48aei was achieved from
the commercially available allyl ethyl ether 47 utilising this
procedure. These were then esterified by reaction with the ap-
propriate acid chloride or anhydride and methylenated in good
yields. RCM followed by aromatisation successfully generated
a range of 2,5-disubstituted furans 51aei (Scheme 10).
RO
R1
O
R4
R4
R2 OR
9
O
5
O
8
R3 R1
R3 R1
R2 OR
O
OH
O
R4
R2 OR
40
39
Scheme 8.
Schrock’s molybdenum catalyst had been reported to be an
effective catalyst for enol ether-olefin RCM reactions.22 How-
ever, poor activity was frequently observed when using
Grubbs’ first generation catalyst 1.22b,23 This has been attrib-
uted to the formation of Fisher-type carbenes,24 which have
been shown to be relatively inactive in the metathetic pro-
cesses required for RCM.25 Recently, several groups have re-
ported the use of the more active second generation catalyst 3
in enol ether-olefin RCM, generating cyclic enol ethers in
high yields in many cases.26 Encouraged by these results the
synthesis of a simple, monosubstituted furan was attempted.
Acid-catalysed ring opening of butadiene monoxide 41 with
methanol afforded the requisite homoallylic alcohol 42.27 Re-
action with benzoyl chloride then furnished ester 43 in excel-
lent overall yield. Initially, methylenation using the Petasis
reagent was attempted.28 Unfortunately, poor conversion was
R1
R1
O
i)
ii)
OH
O
R4
OEt
47
OEt
OEt
48a-i
49a-i
iii)
R1
O
iv)
R4
R1
R4
O
OEt
51a-i
50a-i
Scheme 10. Reagents and conditions: (i) s-BuLi, InCl3, R1CHO, THF, ꢁ78 ꢂC;
(ii) R4COCl or (R4CO)2O, Et3N, CH2Cl2; (iii) TiCl4, TMEDA, Zn, PbCl2 (cat.),
CH2Br2, CH2Cl2, THF; (iv) 10 mol % 3, PhMe, 60 ꢂC then 0.6 equiv TFA.
The results of this study are summarised in Table 2 and dem-
onstrate that the R1 substituent tolerated a range of aliphatic
(Table 2, entry 3), aromatic (Table 2, entry 1, 4e7), heteroaro-
matic (Table 2, entry 2) and fluorinated (Table 2, entry 9)
groups. Whilst aromatic (Table 2, entry 1, 2), primary aliphatic
(Table 2, entry 4) and secondary aliphatic (Table 2, entry 3, 5
and 9) groups were tolerated at R4, the tertiary aliphatic deriv-
ative failed to undergo methylenation, presumably due to steric
constraints (Table 2, entry 7). This difficulty was overcome by
introducing the tert-butyl group at R1, although the yields for
methylenation and the RCM/aromatisation were lower than
for the other examples (Table 2, entry 8). The RCM of trifluor-
omethyl enol ether successfully generated the corresponding
1
observed, as judged by H NMR analysis, even after long re-
action times or by increasing the amount of Petasis reagent.
An additional problem was that enol ether 44 was unstable
to flash column chromatography on silica gel (triethylamine
doped) and neutral or basic alumina. Eventually, it was dis-
covered that the TakaieUtimoto protocol29 effected complete
conversion to enol ether 44, which was sufficiently pure to be
used without further purification. It had been reported that
ring closure of enol ethers with appropriately placed pendant
alkenes could occur in situ using the TakaieUtimoto proce-
dure and the related Tebbe reagent.30,31 However, this was
not observed in any of the methylenation reactions performed

T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
813
Table 2
Yields for the sequence depicted in Scheme 10
undergo RCM under a variety of conditions, returning only
starting material in each case. It was thought that the catalyst
was unable to initiate on the 1,1-disubstituted alkene due to an
increased steric bulk (Scheme 11).
Entry
R1
R4
Yield (%)
(i)
(ii)
(iii)
(iv)
1 (a)
2 (b)
3 (c)
4 (d)
5 (e)
6 (f)
7 (g)
8 (h)
9 (i)
a
4-BrC6H4
2-Furyl
Cyclopropyl
Ph
Ph
Ph
70
75
91
90
90
90
90
65
83
93
82
99
95
86
77
70
84
80
72
71
79
82
79
62
0
58
50a
54
Ph
OH
Ph
O
i)
ii)
O
Ph
i-Pr
Me
i-Pr
CF3
t-Bu
Ph
86%
86%
n
O Bu
n
n
O Bu
O Bu
51
52
52
53
54
Ph
Ph
80% iii)
0
Ph
t-Bu
d
Ph
O
O Bu
55
50
63
41b
64c
iv)
×
C6F5
i-Pr
Ph
Ph
Ph
O
n
Furan 51b was unstable, and decomposition was observed within hours
56
after purification by column chromatography.
b
Contaminated with ca. 5% phosphine ligand that could not be removed by
column chromatography.
Scheme 11. Reagents and conditions: (i) s-BuLi, InCl3, PhCHO, THF, ꢁ78 ꢂC;
(ii) PhCOCl, Et3N, CH2Cl2; (iii) TiCl4, TMEDA, Zn, PbCl2 (cat.), CH2Br2,
CH2Cl2, THF; (iv) 10 mol % 3, PhMe, reflux then 0.6 equiv TFA.
c
Aromatisation carried out by heating the metathesis reaction mixture at
60 ꢂC with 1 equiv of PPTS until TLC analysis showed complete consumption
of starting material.
In order to circumvent this problem, the extra substituent
was moved to R2 and a similar sequence was repeated using
allyl ether 57. Addition of the g-alkoxyallylindium reagent to
benzaldehyde furnished homoallylic alcohol 58 in moderate
yield. Esterification and methylenation then proceeded in
excellent overall yield. The RCM/aromatisation sequence
afforded trisubstituted furan 61 in a 38% yield. Interestingly,
homoallylic alcohol 58 was also isolated in a 56% yield, pre-
sumably from hydrolysis of enol ether 60, meaning the yield
based on recovered starting material was 86%. It is likely
that this deleterious side reaction is a result of hydrolysis of
unreacted enol ether 60 during the aromatisation as a result
of the slower RCM reaction. Unfortunately, increasing catalyst
loading and/or reaction time did not lead to an increase in the
yield. Catalyst 4 was also successful in the RCM but did not
lead to any enhancement of the yield. It seems likely that the
steric hindrance is not too severe to prevent RCM completely
but may result in some unwanted initiation on the enol ether
to give a Fisher-type carbene, which is unreactive to RCM,
thus effectively sequestering the catalyst (Scheme 12).
dihydrofuran, however, aromatisation could not be achieved
under standard conditions (Table 2, entry 6). Even heating at re-
flux was unsuccessful, with eventual decomposition of the dihy-
drofuran being the only observable process. This was attributed
to the electron withdrawing effect of the trifluoromethyl group
destabilising the cation formed during an E1 elimination of eth-
anol. As a result, the aromatisation was attempted under basic
conditions using DBU but unfortunately, no reaction was ob-
served. Recently, phosphine free catalyst 4, developed by Hov-
eyda and co-workers,2b became commercially available.
Although rarely used in enol ether-olefin RCM33 it was decided
to attempt the cyclisation using this catalyst. Gratifyingly,
yields were comparable to those using catalyst 3 and in the
case of aliphatic enol ethers much higher yields were obtained.
In addition, shorter reaction times were frequently observed.
Although similar increases in yield were not observed for the
aromatic enol ethers, purification was simplified due to the ab-
sence of phosphine ligands in the reaction (Table 3).
A novel strategy for promoting RCM of unreactive sub-
strates was recently communicated by Hoye and co-workers
and referred to as relay ring-closing metathesis (RRCM).1f,34
A sacrificial tether containing a sterically unencumbered
Table 3
Yields for the RCM/aromatisation sequence of aliphatic enol ethers using
catalyst 4
Entry
R1
R4
Yield (%)
1 (c)
2 (d)
3 (e)
4 (i)
a
Cyclopropyl
Ph
i-Pr
Me
i-Pr
i-Pr
60
56
72
75a
Ph
Ph
O
ii)
i)
54%
Ph
C6F5
OH
O
92%
n
O Bu
n
n
O Bu
O Bu
57
58
59
Aromatisation carried out by heating the metathesis reaction mixture at
60 ꢂC with 1 equiv of PPTS until TLC analysis showed complete consumption
of starting material.
90% iii)
Ph
O
iv)
Ph
In order to synthesise trisubstituted furans, an additional
substituent was required on the allyl ether starting material.
Accordingly, allyl ether 52, bearing a methyl group at R3,
was metallated and then reacted with benzaldehyde using
the previously described indium methodology. Esterification,
followed by methylenation furnished the metathesis precursor
55 in good overall yield. Unfortunately, this substrate failed to
38%
O
61
n
O Bu
60
86% based on
recovered starting
material
Scheme 12. Reagents and conditions: (i) s-BuLi, InCl3, PhCHO, THF, ꢁ78 ꢂC;
(ii) i-PrCOCl, Et3N, CH2Cl2; (iii) TiCl4, TMEDA, Zn, PbCl2 (cat.), CH2Br2,
CH2Cl2, THF; (iv) 10 mol % 3, PhMe, reflux then 0.6 equiv TFA.

814
T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
alkene on which the catalyst can initiate delivers the ruthe-
nium carbene onto a sterically hindered or electron poor posi-
tion by intramolecular cyclisation and extrusion of
cyclopentene. It seemed feasible that this method could be
used to improve the yield for trisubstituted furans and allow
access to tetrasubstituted furans. A route to the requisite
RRCM precursor 62 (Scheme 13) was devised and relied on
a Wittig olefination to install the diene moiety. Whilst the Mu-
kaiyama aldol35 and acylation of methoxyacetophenone 63
proceeded uneventfully, subsequent Wittig reaction of 65
with hex-5-enyltriphenylphosphonium iodide failed to yield
any of the expected diene 62. Instead, elimination occurred,
furnishing enone 67 in 81% yield. Wittig reaction of alcohol
64 using 2 equiv of ylide, perhaps unsurprisingly, simply pro-
moted retro aldol followed by olefination. Reaction of alcohol
64 and ester 65 under TakaieUtimoto conditions using 1,1-di-
bromohex-5-ene were also unsuccessful. Finally, Wittig reac-
tion of 68 was followed by reaction with benzaldehyde
under the g-alkoxyallylindium metallation conditions de-
scribed previously. Although this route was successful in pro-
ducing 70, unfortunately, the reaction was low yielding.
Subsequent esterification and methylenation were also too
low yielding to allow significant quantities of material to be
produced in order to complete the synthesis (Scheme 13).
addition a number of groups that are difficult to install by con-
ventional methods (e.g., cyclopropyl, i-Pr, t-Bu) were readily
incorporated. Trisubstituted furans were also accessible via
this methodology, albeit in slightly lower yield. These studies
demonstrate the usefulness of the currently available catalysts
in RCM but also highlight limitations such as intolerance to
sterically encumbered substrates. Recent developments in
this respect by Grubbs and co-workers18 are expected to fur-
ther enhance the synthetic utility of this approach by facilitat-
ing the synthesis of tri- and tetrasubstituted furans.
3. Conclusions
Two contrasting strategies have been developed, which
allow access to a wide variety of functionalised furans and pyr-
roles. The functional group tolerance and access to otherwise
difficult substitution patterns is particularly significant. It
seems likely that as novel metathesis catalysts are developed
with increased activity, wider functional group tolerance and
decreased sensitivity to steric constraints,18 substrates such
as 60 or 55, which are currently less reactive or even unreac-
tive will become viable. This will undoubtedly increase the
usefulness of this methodology and provides excellent oppor-
tunity for future investigations. Thus, the scope of the RCM
reaction has been expanded from the formation of isolated
alkenes to allow the rapid synthesis of intermediates at the
correct oxidation level to prepare fully aromatic arrays. The
further development of this concept and applications to total
synthesis are currently underway in our laboratories and will
be reported in due course.
Ph
O
Ph
O
Ph
OMe
RRCM precursor 62
O
O
Ph
OH
O
Ph
O
i,ii)
iii)
4. Experimental
Ph
Ph
Ph
Ph
O
Ph
76, 73%
73%
OMe
63
OMe
OMe
64
65
4.1. General procedures and methods
55% iv)
81% iv)
O
Unless otherwise specified, all reactions were carried out
under an atmosphere of argon. Tetrahydrofuran (THF) was pu-
rified by filtration through two columns of activated alumina
(grade DD-2) as supplied by Alcoa, employing the method
of Grubbs.36 Acetonitrile, dichloromethane and toluene were
dried by passing through activated alumina columns (activated
basic aluminium oxide, Brockmann I, standard grade, w150
Ph
Ph
OMe
OMe
66
67
O
Ph
iv)
v)
29%
OH
˚
mesh, 58 A) as supplied by Aldrich. Methanol was purified
by distillation over calcium hydride, and stored over molecular
89%
OMe
68
OMe
OMe
69
70
˚
sieves (4 A). Other solvents were used as supplied without
Scheme 13. Reagents and conditions: (i) TMSCl, Et3N, NaI, MeCN; (ii)
PhCHO, TiCl4, CH2Cl2; (iii) PhCOCl, Et3N, pyridine, CH2Cl2; (iv) hex-5-
enyltriphenylphosphonium iodide, KHMDS, THF; (v) s-BuLi, InCl3, PhCHO,
THF, ꢁ78 ꢂC.
further purification. Reactions were monitored by thin-layer
chromatography (TLC) carried out on aluminium plates pre-
coated with Merck silica gel 60 F254. Flash column chroma-
tography was performed using Merck silica gel 60 (4.3e
6.3 mm). Melting points were recorded using a Leica VMTG
heated-stage microscope and are uncorrected. Infrared spectra
were recorded on a Bruker Tensor 27 Fourier Transform spec-
trometer, as a thin film between NaCl plates or as a KBr disc.
Proton (1H) and carbon (13C) NMR were recorded using a
Bruker AV400 (400 MHz and 100 MHz). Mass spectra (m/z)
and accurate mass (HRMS) were recorded on an Agilent
In spite of the difficulties encountered during the attempted
synthesis of the RRCM precursor the general strategy had
been highly successful in the synthesis of monosubstituted
and 2,5-disubstituted furans. It is particularly noteworthy
that the aldehyde and carboxylic acid equivalents used in the
synthesis of the 2,5-disubstituted furans are ultimately mani-
fested as groups R1 and R4, thus allowing great flexibility. In

T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
815
6890 Series GC system for chemical ionisation (CI) and on
a Fisons Platform II for electrospray ionisation (ESI).
for a further 30 min before addition of the corresponding alde-
hyde (1.0 equiv). After 1 h, the reaction mixture was allowed to
warm to room temperature before addition of 1.0 M aqueous
hydrochloric acid solution (5 mL/mmol). The aqueous layer
was extracted with diethyl ether (3ꢃ10 mL/mmol) and the com-
bined organic layers were washed with water (10 mL/mmol)
and saturated aqueous sodium chloride solution (10 mL/
mmol) then dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by flash column chromatogra-
phy to give the corresponding alcohol as an inconsequential
mixture of diastereoisomers, which were not separated.
4.1.1. Procedure A: oxy- and amidopalladation of
methoxyallene
Triethylamine (1.5 equiv), Pd(OAc)2 (5 mol %), dppp
(5 mol %) and methoxyallene (3 equiv) were added to a solu-
tion of the appropriate sulfonamide or alcohol in acetonitrile
(0.3 M). The reaction mixture was heated at reflux for 16 h
then cooled to room temperature. Triethylamine (1 mL/
mmol) was added and the reaction was quenched with water
(10 mL/mmol). The product was extracted with diethyl ether
(3ꢃ10 mL/mmol). The combined organic phases were dried
over Na2SO4 and concentrated in vacuo. The resulting crude
products were purified by flash column chromatography as
indicated.
4.1.6. Procedure F: ester formation
The appropriate acid chloride or anhydride (1.2 equiv) was
added dropwise to a stirred solution of the corresponding alco-
hol (1.0 equiv) and triethylamine (1.2 equiv) in CH2Cl2 (5 mL/
mmol) at room temperature. The reaction mixture was stirred
at room temperature until TLC analysis indicated complete
consumption of starting material. The reaction mixture was di-
luted with diethyl ether (10 mL/mmol), washed with 1.0 M
aqueous hydrochloric acid solution (5 mL/mmol) and 32%
aqueous ammonia solution (5 mL/mmol), then dried over
MgSO4. The solvent was removed in vacuo and the crude prod-
uct was purified by flash column chromatography as indicated.
4.1.2. Procedure B: amidopalladation of methoxyallene
with in situ trapping of iodobenzene
Iodobenzene (1 equiv), Pd(PPh3)4 (5 mol %), K2CO3
(2 equiv) and methoxyallene (3 equiv) were added to a solution
of the appropriate sulfonamide in toluene (0.3 M). The reaction
mixture was heated at reflux for 16 h then cooled to room
temperature. Triethylamine (1 mL/mmol) was added and the
reaction was quenched with water (10 mL/mmol). The product
was extracted with diethyl ether (3ꢃ10 mL/mmol). The com-
bined organic phases were dried over Na2SO4 and concentrated
in vacuo. The resultant crude products were purified by flash
column chromatography as indicated.
4.1.7. Procedure G: TakaieUtimoto olefination
TiCl4 (1.0 M solution in CH2Cl2, 8.5 equiv) and TMEDA
(16.5 equiv) were slowly added to THF (5 mL/mmol) with
stirring at 0 ꢂC. After stirring at this temperature for 20 min,
Zn dust (18.5 equiv) and PbCl2 (0.1 equiv) were added to
the solution. The resulting slurry was warmed to room temper-
ature and stirred for 30 min. A solution of the appropriate ester
(1.0 equiv) and dibromomethane (4.7 equiv) in THF (5 mL/
mmol) was added at room temperature and the slurry was
stirred for 16 h. The mixture was cooled to 0 ꢂC and saturated
aqueous K2CO3 solution (5 mL/mmol) was added. The reac-
tion mixture was passed through a thin pad of basic aluminium
oxide and washed with a solution of triethylamine in ether
(ether/triethylamine; 200:1, 250 mL). The mixture was con-
centrated in vacuo; if a white solid appeared at this point the
filtration was repeated until the solid was removed, and the
product was used without further purification.
4.1.3. Procedure C: ring-closing metathesis
The acyclic diene starting materials were dissolved in deox-
ygenated (sparged with argon for 30 min) dichloromethane or
toluene (ca. 0.01e0.02 M). The mixture was heated at reflux
for the indicated time then cooled to room temperature. The
resulting cyclised product could either be isolated by concen-
trating in vacuo and purifying by flash column chromatogra-
phy or subjected directly to general method D.
4.1.4. Procedure D: aromatisation
Trifluoroacetic acid (0.6 equiv) was added to a solution of
RCM product in dichloromethane or toluene (ca. 0.01e
0.02 M) and the reaction mixture was stirred at room temper-
ature until TLC indicated complete consumption of starting
material. Diethyl ether (10 mL/mmol) was then added. The
reaction mixture was washed with saturated aqueous NaHCO3
(10 mL/mmol) and the organic layer was separated, dried over
MgSO4, and concentrated in vacuo. The resulting aromatic
products were then purified by flash column chromatography
as indicated.
4.1.8. Procedure H: Wittig olefination
KHMDS (0.5 M in toluene, 2.2 equiv) was added dropwise
to a stirred solution of hex-5-enyltriphenylphosphonium iodide
(2.2 equiv) (which was dried under vacuum at 60 ꢂC for 12 h
prior to use) in THF (0.1 M) at ꢁ78 ꢂC. The orange slurry was
allowed to warm to room temperature and stirred at room tem-
perature for 90 min. The reaction mixture was cooled to
ꢁ78 ꢂC and a solution of the appropriate ketone (1 equiv) in
THF (0.1 M) was then added dropwise. The reaction mixture
was stirred at room temperature until TLC indicated complete
consumption of starting material, then concentrated in vacuo
onto silica gel and purified by flash column chromatography.
4.1.5. Procedure E: formation of alcohols via allyl indium
reagents
s-Butyl lithium (1.0 M solution in hexanes, 3.0 equiv) was
added to a solution of allyl ethyl ether (3.0 equiv) in THF
(0.1 M) at ꢁ78 ꢂC. After stirring for 1 h, a solution of InCl3
(1.0 equiv) in THF (0.2 M) was added. Stirring was continued

816
T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
4.2. Methods
51.2, 22.7, 22.0; m/z (ESI) 259 (35%, ([MþMeCNþNH4]þ),
223 (100, [MþNa]þ); HRMS (ESI) C10H16O4Na ([MþNa]þ)
The experimental details for compounds 12,7 15,37 18a,38
18d,7 19,39 21,22,40,41 24,42 28,7 31,43 35,7 38,7 46,44 48e
51aeg,i,8 52e61,8 6445 and 6746 have been published
previously.
requires 223.0937, found 223.0946.
4.2.4. 2-((1-Methoxyallyloxy)-m-tolylmethyl)acrylic acid
methyl ester (17b)
Allylic alcohol 16b (800 mg, 3.88 mmol) was subjected to
general procedure A. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 8:2þ1% Et3N) yielded 17b as
a pale yellow oil (812 mg, 70%) and as a 1:1 mixture of diaste-
reomers; nmax (film)/cmꢁ1 1725, 1632, 1622, 1588, 1261, 1147,
1034; dH (400 MHz; C6D6) 7.39e7.33 (2H, m, 2ꢃArH ), 7.13e
7.06 (1H, m, ArH ), 6.89 (1H, t, J 8.0, ArH ), 6.35 and 6.32 (1H,
2ꢃapparent dd, J 1.5, 1.1, C]CHH), 6.12 and 6.01 (1H,
2ꢃapparent t, J 1.5, C]CHH), 5.99 and 5.88 (1H, 2ꢃbr s,
CHAr), 5.83 and 5.78 (1H, 2ꢃddd, J 17.4, 10.6, 4.8, and 17.4,
10.6, 4.8, HC]CH2), 5.35 and 5.31 (1H, 2ꢃapparent dt, J
17.4, 1.5, trans-HC]CHH), 5.07 and 5.04 (1H, 2ꢃapparent
dt, J 10.4, 1.5, cis-HC]CHH), 4.99 and 4.97 (1H, 2ꢃdt, J
4.7, 1.2, CH(OCH3)), 3.20 (3H, 2ꢃs, OCH3), 3.14 and 3.07
(3H, 2ꢃs, OCH3), 2.06 and 2.04 (3H, 2ꢃs, CH3); dC
(100 MHz; C6D6) 166.0, 165.9, 142.7, 142.2, 140.7, 140.0,
138.1, 138.0, 135.5, 135.4, 129.2, 129.0, 128.9, 128.8, 128.6,
128.5, 125.7, 125.4, 124.4, 124.3, 118.4, 118.3, 101.5, 99.5,
75.6, 74.6, 52.0, 51.3, 51.2, 21.4, 21.3; m/z (ESI) 299 (100%,
[MþNa]þ); HRMS (ESI) C16H20O4Na ([MþNa]þ) requires
299.1259, found 299.1256.
4.2.1. 1-Methoxy-4-(1-(1-methoxyallyloxy)allyl)benzene (11)
Allylic alcohol 10 (750 mg, 4.60 mmol) was subjected to
general procedure A. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 9:1þ1% Et3N) yielded 11 as
a yellow oil (799 mg, 74%) and as a 1:1 mixture of diastereo-
mers, which were not separated; nmax (film)/cmꢁ1 3080, 2834,
1641, 1611; dH (400 MHz; C6D6) 7.45e7.42 (1H, m, ArH ),
7.37e7.34 (1H, m, ArH ), 6.93e6.85 (2H, m, 2ꢃArH ), 6.22e
6.14 (0.5H, m, CH2]CHCHAr), 6.04e5.92 (1.5H, m,
CH2]CHCHAr, CH2]CHCHOCH3), 5.56e5.43 (2H, m,
CH2]CHCHAr), 5.40e5.13 (3.5H, m, CH2]CHCHOCH3,
CHAr, CHOCH3), 5.08e5.06 (0.5H, m, CHOCH3), 3.41, 3.39
(3H, 2ꢃs, ArOCH3), 3.28, 3.25 (3H, 2ꢃs, OCH3); dC
(100 MHz; C6D6) 160.0, 159.8, 140.2, 139.3, 136.1, 136.0,
134.0, 133.2, 129.2, 128.7, 128.5, 118.3, 116.2, 114.8, 114.4,
114.3, 100.1, 99.5, 78.2, 77.8, 54.93, 54.91, 51.5, 51.2; m/z
(ESI) 257 (10%, [MþNa]þ), 163 (7), 147 (100); HRMS (ESI)
C14H18O3Na ([MþNa]þ) requires 257.1154, found 257.1158.
4.2.2. (1-(1-Methoxyallyloxymethyl)vinyl)benzene (14)
Allylic alcohol 13 (314 mg, 2.30 mmol) was subjected to
general procedure A. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 95:5þ1% Et3N) yielded 14 as
a colourless oil (350 mg, 75%); nmax (film)/cmꢁ1 3083, 2829,
1632; dH (400 MHz; C6D6) 7.50e7.42 (2H, m, 2ꢃArH ),
7.26e7.17 (3H, m, 3ꢃArH ), 5.96e5.87 (1H, m, CH]CH2),
5.55e5.51 (2H, m, CH]CH2), 5.50e5.49 (1H, m,
PhC]CHH), 5.47e5.45 (1H, m, PhC]CHH ), 5.03e5.00
(1H, m, CHOCH3), 4.58 (1H, d, JAB 13.1, one of OCH2), 4.44
(1H, d, JAB 13.1, one of OCH2), 3.24 (3H, s, OCH3); dC
(100 MHz; C6D6) 145.2, 139.6, 135.7, 128.7, 128.0, 126.6,
118.6, 113.8, 101.6, 67.1, 52.3; m/z (CI) 205 (4%, [MþH]þ),
174 (20), 134 (35); HRMS (CI) C13H17O2 ([MþH]þ) requires
205.1229, found 205.1226.
4.2.5. 2-((1-Methoxyallyloxy)-3-trifluoromethylphenyl
methyl)acrylic acid methyl ester (17c)
Allylic alcohol 16c (500 mg, 1.92 mmol) was subjected to
general procedure A. Flash chromatography (SiO2; petroleum
ether/ethyl acetate 96:4þ1% Et3N) yielded 17c as a pale yel-
low oil (366 mg, 58%) and as a 1:1 mixture of diastereomers;
nmax (film)/cmꢁ1 1724, 1662, 1632, 1602, 1529, 1330, 1265,
1176, 1129, 1079; dH (400 MHz; C6D6) 7.94 and 7.90 (1H,
2ꢃs, ArH ), 7.50 and 7.46 (1H, 2ꢃd, J 7.6, ArH ), 7.24 (1H, t,
J 7.4, ArH ), 6.95e6.88 (1H, m, ArH ), 6.25 and 6.22 (1H,
2ꢃs, C]CHH), 5.96 and 5.84 (1H, 2ꢃd, J 1.0, C]CHH),
5.86 and 5.79 (1H, 2ꢃs, CHAr), 5.70 (1H, ddd, J 17.4, 10.5,
4.6, HC]CHH), 5.28 and 5.23 (1H, 2ꢃdd, J 17.4, 1.1, trans-
HC]CHH), 5.03 and 5.00 (1H, 2ꢃdd, J 10.5, 1.1, cis-
HC]CHH), 4.87 and 4.77 (1H, 2ꢃd, J 4.7 and 4.6, CH(OCH3)),
3.17 (3H, 2ꢃs, OCH3), 3.01 and 2.95 (3H, 2ꢃs, OCH3); dC
(100 MHz; C6D6) 165.6, 165.5, 142.4, 142.3, 141.9, 141.4,
135.1, 135.0, 131.6, 131.3, 129.2, 129.1, 129.0, 128.5, 125.3,
125.1, 125.0, 124.9, 124.8, 124.7, 124.6, 124.5, 118.7, 118.6,
101.6, 100.3, 74.7, 73.9, 52.1, 51.9, 51.4, 51.3; m/z (ESI) 394
(100%, [MþMeCNþNa]þ) 353 (60, [MþNa]þ); HRMS (ESI)
C18H17NO4F3Na requires 394.1242, found 394.1231.
4.2.3. 2-(1-(1-Methoxyallyloxy)ethyl)acrylic acid methyl
ester (17a)
Allylic alcohol 16a (500 mg, 3.80 mmol) was subjected to
general procedure A. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 9:1þ1% Et3N) yielded 17a as
a pale yellow oil (691 mg, 91%) and as a 1:1 mixture of dia-
stereomers; nmax (film)/cmꢁ1 3071, 2954, 2800, 1720, 1631,
1439, 1349; dH (400 MHz; C6D6) 6.36e6.33 (1H, m,
CHH]CCO2Me), 6.05e6.04 (0.5H, m, CHH]CCO2Me),
5.95e5.86 (1.5H, m, CHH]CCO2Me), 5.46e5.44, 5.42e
5.40 (2H, m, CH2]CH), 5.05 (0.5H, q, J 6.4, CHCH3),
4.97e4.91 (1.5H, m, CHCH3, CHOCH3), 3.45, 3.44 (3H, s,
OCH3), 3.23, 3.21 (3H, s, OCH3), 1.53, 1.43 (3H, d, J 6.4,
CH3); dC (100 MHz; C6D6) 166.4, 144.3, 143.6, 136.1, 135.9,
128.5, 124.3, 118.3, 101.7, 100.9, 70.4, 69.6, 52.7, 51.4,
4.2.6. 2-((1-Methoxyallyloxy)4-nitrophenylmethyl) acrylic
acid methyl ester (17d)
Allylic alcohol 16d (500 mg, 2.1 mmol) was subjected to
general procedure A. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 75:25þ1% Et3N) yielded 17d
as a yellow oil (370 mg, 58%) and as a 1:1 mixture of

T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
817
diastereomers, which were not separated; nmax (film)/cmꢁ1
3081, 2832, 1721, 1632, 1608, 1523, 1349; dH (400 MHz;
CDCl3) 8.21e8.17 (2H, m, 2ꢃArH ), 7.61e7.56 (2H, m,
2ꢃArH ), 6.44, 6.42 (1H, s, CHH]C), 6.18, 6.10 (1H, s,
CHH]C), 5.84e5.75 (1H, m, CH]CH2), 5.70, 5.67 (1H, s,
CHAr), 5.47e5.42 (1H, m, CHH]CH), 5.38e5.30 (1H, m,
CHH]CH), 4.96, 4.83 (1H, d, J 5.0, 4.7, CHOCH3), 3.70,
3.69 (3H, s, CO2CH3), 3.24, 3.19 (3H, s, OCH3); dC
(100 MHz; CDCl3) 134.1, 128.6, 128.2, 126.4, 126.1, 123.53,
123.51, 119.4, 119.3, 101.5, 101.4, 74.1, 73.1, 52.4, 52.3,
51.99, 51.95; m/z (CI) 308 (5%, [MþH]þ); HRMS (CI)
C15H18NO6 ([MþH]þ) requires 308.1132, found 308.1134.
m, CHCH3), 3.34, 3.28 (3H, s, OCH3), 2.00 (3H, s, ArCH3),
1.65, 1.49 (3H, d, J 6.8, CHCH3); dC (100 MHz; C6D6)
142.74, 142.71, 141.4, 141.8, 139.9, 135.63, 135.60, 129.6,
129.5, 128.7, 128.4, 118.3, 118.1, 116.0, 115.3, 89.4, 89.0,
55.8, 55.7, 54.6, 21.3, 21.2, 20.2; m/z (ESI) 318 (10%,
[MþNa]þ), 354 (100, [MþMeCNþNH4]þ); HRMS (ESI)
C15H21NO3NaS ([MþNa]þ) requires 318.1140, found
318.1151.
4.2.10. N-Allyl-N-(1-methoxy-2-phenylallyl)-4-methyl
benzenesulfonamide (27)
Allylic sulfonamide 19 (500 mg, 2.40 mmol) was subjected
to general procedure B. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 9:1þ1% Et3N) yielded 27 as an
off white solid (643 mg, 71%); mp 69e71 ꢂC; nmax (KBr disc)/
cmꢁ1 3087, 2834, 1630, 1597, 1496, 1340, 1332, 1163, 1075,
1026; dH (400 MHz; C6D6) 7.42e7.29 (7H, m, 5ꢃPhH,
2ꢃArH ), 7.06 (2H, d, J 8.2, 2ꢃArH ), 6.15 (1H, s, CHOCH3),
5.58 (1H, s, CHH]CPh), 5.56 (1H, s, CHH]CPh), 5.54e
5.46 (1H, m, CH]CH2), 4.92 (1H, dd, J 17.1, 1.3, trans-CHH]
CH2), 4.86 (1H, dd, J 10.1, 1.3, cis-CHH]CH), 3.72e3.60 (2H,
m, CH2CH]CH2), 3.50 (3H, s, OCH3), 2.05 (3H, s, ArCH3); dC
(100 MHz; C6D6) 144.1, 143.1, 138.7, 137.0, 134.8, 129.1,
128.5, 128.0, 127.8, 127.2, 117.0, 116.8, 87.9, 56.1, 45.0, 21.5;
m/z (CI) 358 (100%, [MþH]þ); HRMS (CI) C20H24NO3S
([MþH]þ) requires 358.1477, found 358.1480.
4.2.7. 2-m-Tolylfuran-3-carboxylic acid methyl ester (18b)
Mixed acetal 17b (211 mg, 0.85 mmol) was subjected to
general procedure C for 16 h in dichloromethane, then general
procedure D. Flash column chromatography (SiO2; petroleum
ether/ethyl acetate; 97:3) yielded 18b as a colourless oil
(129 mg, 70%); nmax (film)/cmꢁ1 1723, 1610, 1573, 1515,
1487, 1439, 1297, 1254, 1196, 1149, 1068; dH (400 MHz;
CDCl3) 7.79e7.77 (2H, m, 2ꢃArH ), 7.42 (1H, d, J 1.9,
C(5)H ), 7.35e7.31 (1H, m, ArH ), 7.22 (1H, d, J 7.5, ArH ),
6.83 (1H, d, J 1.9, C(4)H ), 3.83 (3H, s, CO2CH3), 2.42 (3H, s,
CH3); dC (100 MHz; CDCl3) 164.0, 157.8, 141.1, 137.7,
130.2, 129.6, 128.8, 128.0, 125.6, 113.4, 112.9, 51.6, 21.5; m/
z (CI) 234 (20%, [MþNH4]þ), 217 (100, [MþH]þ), 216 (40,
[M]þ); HRMS (CI) C13H13O3 ([MþH]þ) requires 217.0865,
found 217.0863.
4.2.11. N-(1-Methoxy-2-phenylallyl)-N-(1-methylallyl)-4-
methylbenzenesulfonamide (29)
4.2.8. 2-(3-Trifluoromethylphenyl)furan-3-carboxylic acid
methyl ester (18c)
Allylic sulfonamide 22 (400 mg, 2.40 mmol) was subjected
to general procedure B. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 9:1þ1% Et3N) yielded 29 as
a yellow oil (464 mg, 70%) and as a 1:1 mixture of diastereoiso-
mers; nmax (film)/cmꢁ1 3064, 2984, 2934, 1639, 1598, 1495,
1445, 1380, 1336, 1196, 1159, 1094, 1074; dH (400 MHz;
C6D6) 7.63e6.69 (9H, m, 5ꢃPhH, 4ꢃArH ), 6.44 (1H, br s,
CHOCH3), 6.37 (0.5H, ddd, J 17.3, 10.4, 6.1, CH]CH2),
5.91 (0.5H, ddd, J 17.3, 10.4, 6.1, CH]CH2), 5.74e5.71 (1H,
m, CHH]CPh), 5.45e5.43 (1H, m, CHH]CPh), 5.07, 4.96
(1H, apparent dt, J 17.4, 1.5, trans-CHH]CH), 5.01, 4.82
(1H, apparent dt, J 10.4, 1.5, cis-CHH]CH), 4.49e4.40 (1H,
m, CHCH3), 3.54, 3.47 (3H, s, OCH3), 1.96 (3H, s, ArCH3),
1.68, 1.33 (3H, dd, J 6.9, 7.1, CHCH3); dC (100 MHz; C6D6)
145.8, 145.4, 142.44, 143.28, 141.1, 140.3, 140.1, 139.9,
139.5, 139.4, 137.7, 130.3, 129.1, 129.0, 128.62, 128.59,
126.8, 126.6, 117.6, 117.4, 114.83, 114.8, 89.8, 89.6, 56.4,
56.3, 53.8, 53.7, 21.1, 20.1, 19.4, 17.5; m/z (ESI) 394 (5%,
[MþNa]þ) 430 (100, [MþMeCNþNH4]þ); HRMS (ESI)
C21H25NO3SNa ([MþNa]þ) requires 394.1447, found
394.1449.
Mixed acetal 17c (127 mg, 0.42 mmol) was subjected to
general procedure C for 2 days in dichloromethane, then gen-
eral procedure D. Flash column chromatography (SiO2; petro-
leum ether/ethyl acetate; 98:2) yielded 18c as a colourless oil
(67 mg, 59%); nmax (film)/cmꢁ1 1724, 1604, 1578, 1516,
1479, 1440, 1331, 1298, 1201, 1127, 1103, 1083; dH
(400 MHz; CDCl3) 8.30 (1H, s, ArH ), 8.23 (1H, d, J 7.7,
ArH ), 7.65 (1H, d, J 7.6, ArH ), 7.56 (1H, t, J 7.8, ArH ), 7.48
(1H, d, J 1.9, C(5)H ), 6.87 (1H, d, J 1.9, C(4)H ), 3.85 (3H, s,
CO2CH3); dC (100 MHz; CDCl3) 163.7, 155.6, 141.8, 131.4,
131.0, 130.3, 128.6, 125.8, 125.2, 122.6, 114.7, 113.2, 51.8;
m/z (CI) 270 (100%, [M]þ); HRMS (CI) C13H9F3O3 ([M]þ)
requires 270.0504, found 270.0497.
4.2.9. N-(1-Methoxyallyl)-N-(1-methylallyl)-4-methyl
benzenesulfonamide (23)
Allylic sulfonamide 22 (305 mg, 1.40 mmol) was subjected
to general procedure A. Flash column chromatography (SiO2;
petroleum ether/ethyl acetate; 95:5þ1% Et3N) yielded 23 as
a colourless oil (259 mg, 63%) and as a 1:1 mixture of diastereo-
isomers; nmax (film)/cmꢁ1 2936, 2785, 1598, 1495, 1450, 1160;
dH (400 MHz; C6D6) 7.87e7.84 (2H, m, 2ꢃArH ) 6.88e6.86
(2H, m, 2ꢃArH ), 6.50e6.41, 6.27e6.18 (1H, m, CH(CH3)CH]
CH2), 5.81e5.69 (1H, m, CH2]CHCH(OCH3)), 5.55e5.52,
5.50e5.48, 5.46e5.44 (2H, m, CH2]CHCH(OCH3)), 5.13e
4.98 (3H, m, CH2]CHCH(CH3), CHOCH3) 4.27e4.20 (1H,
4.2.12. 1-(4-Methylbenzenesulfonyl)-2-methyl-4-phenyl-1H-
pyrrole (30)
Mixed acetal 29 (200 mg, 0.54 mmol) was subjected to gen-
eral procedure C for 24 h in toluene, then general procedure D.
Flash column chromatography (SiO2; petroleum ether/ethyl ac-
etate; 85:15) yielded 30 as a viscous yellow oil (93 mg, 54%);

818
T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
nmax (film)/cmꢁ1 3142, 3061, 2927, 1596, 1533, 1447, 1363,
1305, 1264, 1174, 1153, 1100, 1045, 990, 919; dH (400 MHz;
CDCl3) 7.72 (2H, d, J 8.4, 2ꢃArH ), 7.58 (1H, d, J 2.0,
C(5)H ), 7.51e7.23 (7H, m, 2ꢃArH, 5ꢃPhH ), 6.30 (1H, s,
C(3)H ), 2.42 (3H, s, ArCH3), 2.35 (3H, s, pyrrole-CH3); dC
(100 MHz; CDCl3) 144.9, 136.1, 133.6, 131.8, 130.0, 128.8,
126.9, 126.82, 126.78, 125.4, 117.5, 111.8, 21.6, 13.7; m/z
(CI) 312 (100%, [MþH]þ); HRMS (CI) C18H18NO2S
([MþH]þ) requires 312.1058, found 312.1064.
4.2.15. 3,4-Bis-(1-methoxyallyloxy)hexa-1,5-diene (37)
Diol36(1.0 g, 8.80 mmol)wassubjectedtogeneralprocedure
A. Flash column chromatography (SiO2; petroleum ether/ethyl
acetate; 95:5þ1% Et3N) yielded 37 as a colourless oil (1.79 g,
80%) and as a mixture of diastereoisomers; nmax (film)/cmꢁ1
3080, 2830, 1645; dH (400 MHz; CDCl3) 5.94e5.68 (4H, m,
4ꢃCH]CH2), 5.45e5.23 (8H, m, 4ꢃCH2]CH), 5.04e4.93
(2H, m, 2ꢃCHOCH3), 4.26e4.08 (2H, m, 2ꢃCHOCHOCH3)
3.34e3.28 (6H, m, 2ꢃOCH3); dC (100 MHz; CDCl3) 135.6,
135.3, 135.2, 135.0, 134.94, 134.91, 134.8, 134.75, 134.5,
134.4, 134.3, 119.4, 119.2, 119.1, 118.9, 118.6, 118.53, 118.50,
118.4, 118.0, 117.8, 117.7, 117.6, 102.5, 102.4, 102.2, 102.0,
99.1, 99.0, 79.5, 79.1, 78.9, 78.8, 78.5, 78.45, 78.2, 52.97,
52.91, 52.83, 52.76, 51.21, 51.17, 51.1, 51.0; m/z (ESI) 227
(100%, [MþNa]þ), 272 (25, [MþNH4]þ); HRMS (ESI)
C14H22O4Na ([MþNa]þ) requires 277.1416, found 277.1415.
4.2.13. N-(1-Methoxy-2-phenylallyl)-N-(1-phenylallyl)-4-
methylbenzenesulfonamide (32)
Allylic sulfonamide 31 (300 mg, 1.00 mmol) was subjected
to general procedure B. Flash column chromatography (SiO2;
petroleumether/ethyl acetate; 4:1þ1% Et3N) yielded 32as a yel-
low solid (395 mg, 91%) and as a 1:1 mixture of diastereoiso-
mers; mp 90e92 ꢂC; nmax (KBr disc)/cmꢁ1 3083, 2832, 1630,
1598, 1493, 1346, 1330, 1162, 1073; dH (400 MHz; CDCl3)
7.42e7.37, 7.34e7.25, 7.19e7.06, 7.02e6.96, 6.95e6.89,
6.78e6.69 (14H, m, 10ꢃPhH, 4ꢃArH ), 6.80e6.67 (0.5H, m,
CH]CH2), 6.36 (0.5H, ddd, J 17.2, 10.3, 8.1, CH]CH2)
6.21, 6.14 (1H, s, one of CH2]CPh), 5.71, 5.65 (1H, s, one of
CH2]CPh), 5.61, 5.59 (1H, s, CHOCH3), 5.36 (0.5H, d, J 8.1,
CHPh) 5.31 (0.5H, d, J 8.6, CHPh), 5.27 (0.5H, dt, J 10.3, 1.1,
cis-CH2]CHCHPh) 5.17 (0.5H, dt, J 17.2, 1.1, trans-
CH2]CHPh), 5.12 (0.5H, dt, J 10.3, 1.1, cis-CHH]CH2)
4.84 (0.5H, dt, J 17.2, 1.1, trans-CHH]CH2) 3.51, 3.33 (3H,
s, OCH3), 2.35, 2.26 (3H, s, ArCH3); dC (100 MHz; CDCl3)
145.1, 143.0, 142.3, 142.0, 139.0, 138.8, 138.7, 138.5, 137.9,
136.5, 129.8, 129.0, 128.6, 128.4, 128.1, 128.0, 127.8, 127.5,
127.34, 127.29, 127.2, 127.0, 126.9, 126.8, 118.0, 117.9,
117.7, 117.2, 89.6, 89.2, 61.5, 60.9, 56.6, 21.4, 21.3; m/z (ESI)
456 (10%, [MþNa]þ) 451 (10, [MþNH4]þ); HRMS (ESI)
C26H31N2O3S ([MþNH4]þ) requires 451.2055, found 451.2066.
4.2.16. 2-Methoxybut-3-enyl benzoate (43)
Alcohol 42 (50 mg, 0.49 mmol) was subjected to general pro-
cedure F. Flash column chromatography (SiO2; petroleum ether/
diethylether; 10:1) yielded 43 as a colourless oil (84 mg, 90%);
nmax (film)/cmꢁ1 3071, 2985, 2940, 2825, 1723, 1602, 1585,
1452, 1315, 1275, 1177, 1111, 1027, 993, 935, 712; dH
(400 MHz, CDCl3) 8.08e8.04 (2H, m, 2ꢃPhH ), 7.59e7.54
(1H, m, PhH ), 7.47e7.41 (2H, m, 2ꢃPhH ), 5.78 (1H, ddd, J
17.5, 10.0, 7.0, C(3)H ), 5.41 (1H, d, J 17.5, C(4)H ), 5.35 (1H,
d, J 10.0, C(4)H ), 4.39 (1H, dd, J 11.5, 4.5, C(1)H ), 4.33 (1H,
dd, J 11.5, 6.5, C(1)H ), 4.02e3.96 (1H, m, C(2)H ), 3.39 (3H,
s, OCH3); dC (100 MHz, CDCl3) 166.4, 134.6, 133.0, 130.1,
129.7, 128.3, 119.3, 80.5, 66.5, 56.8; m/z (CI) 224 (100%,
[MþNH4]þ), 206 (20, [MþH]þ); HRMS (CI) C12H15O3
([MþH]þ) requires 207.1021, found 207.1020.
4.2.17. 1-(1-(2-Methoxybut-3-enyloxy)vinylbenzene (44)
Ester 43 (250 mg, 1.20 mmol) was subjected to general
procedure G to give 44 as a yellow oil (195 mg, 66%), which
was used without further purification; nmax (film)/cmꢁ1 2928,
1642, 1601, 1574, 1494, 1447, 1286, 1196, 1128, 929, 803,
771, 701; dH (400 MHz, CDCl3) 7.67e7.64 (2H, m, 2ꢃPhH ),
7.38e7.32 (3H, m, 3ꢃPhH ), 5.88 (1H, ddd, J 17.0, 10.0, 7.0,
CH]CH2), 5.44 (1H, ddd, J 17.0, 1.5, 1.0, one of CH]CH2),
5.37 (1H, ddd, J 10.0, 1.5, 1.0, one of CH]CH2), 4.70 (1H, d,
J 3.0, one of CH2]CPh), 4.23 (1H, d, J 3.0, one of
CH2]CPh), 4.09e4.03 (1H, m, CH2CH(OCH3)CH]CH2),
3.98 (1H, dd, J 10.0, 6.0, one of CH2CH(OCH3)), 3.90 (1H,
dd, J 10.0, 4.0, one of CH2CH(OCH3)), 3.44 (3H, s, OCH3);
dC (100 MHz, CDCl3) 159.8, 136.3, 135.4, 128.5, 128.1,
125.4, 118.8, 82.7, 80.9, 70.2, 56.9; m/z (ESI) 227 (100%,
[MþNa]þ); HRMS (ESI) C13H16NaO2 ([MþNa]þ) requires
227.1043, found 277.1040.
4.2.14. 2-(1-(1-Methoxyallyloxy)allyl)-1-(4-methyl
benzenesulfonamide)-1H-pyrrole (34)
Pyrrole 33 (250 mg, 0.90 mmol) was subjected to general
procedure A. Flash column chromatography (SiO2; petroleum
ether/ethyl acetate; 9:1þ1% Et3N) yielded 34 as a colourless
oil (276 mg, 88%) and as a 1:1 mixture of diastereomers; nmax
(film)/cmꢁ1 1647, 1603, 1597, 1498, 1485, 1370, 1216, 1176,
1129, 1088, 1029; dH (400 MHz; C6D6) 7.65 (2H, d, J 8.4,
2ꢃArH ), 7.32, 7.30 (1H, 2ꢃapparent dd, J 3.3, 1.8, C(5)H ),
6.62 (2H, d, J 8.4, 2ꢃArH ), 6.40, 6.35 (1H, 2ꢃdd, J 3.3, 1.7,
C(4)H ), 6.11, 5.91 (1H, 2ꢃddd, J 16.9, 10.2, 6.7, CH(pyrro-
lyl)CH]CH2), 6.09e6.00 (1H, m, CH(pyrrolyl)), 6.03e6.00
(1H, m, C(3)H ), 5.80e5.70 (1H, m, CH(OCH3)CH]CH2),
5.35e5.25 (2H, m, 2ꢃtrans-CH]CH2), 5.05e4.97 (2H, m,
2ꢃcis-CH]CH2), 5.02e4.85 (1H, m, CH(OCH3)), 3.10, 3.08
(3H, 2ꢃs, OCH3), 1.74 (3H, s, CH3); dC (100 MHz; C6D6)
144.6, 144.4, 138.3, 137.4, 137.3, 137.1, 135.9, 135.7, 135.5,
135.3, 129.9, 129.8, 127.2, 127.1, 123.5, 123.4, 118.3, 118.2,
116.9, 115.6, 114.4, 114.0, 112.4, 112.2, 100.5, 100.0, 70.9,
70.7, 52.24, 52.17, 21.1; m/z (ESI) 370 (100%, [MþNa]þ);
HRMS (ESI) C18H21NO4NaS ([MþNa]þ) requires 370.1089,
found 370.1086.
4.2.18. 4-Ethoxy-2,2-dimethylhex-5-en-3-ol (48h)
Freshly distilled trimethylacetaldehyde (327 mL, 3.00 mmol)
was subjected to general procedure E. Flash column chromato-
graphy (SiO2; petroleum ether/diethyl ether; 20:1) yielded 48h
as a colourless oil (336 mg, 65%) and a mixture of diastereo-
1
isomers (ca. 2:1 from H NMR), which were not separated.

T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
819
The 1H and 13C NMR data provided is for the major diastereo-
isomer; nmax (film)/cmꢁ1 3508, 3077, 2957, 2872, 1481, 1339,
1364, 1244, 1079, 996, 925; dH (400 MHz, CDCl3) 5.76e5.91
(1H, m, CH]CH2), 5.16e5.32 (2H, m, CH]CH2), 3.68e
3.72 (1H, m, CHCH]CH2), 3.50e3.62 (1H, m, one of
OCH2CH3), 3.44 (1H, d, J 4.0, CHOH), 3.24e3.33 (1H, m,
one of OCH2CH3), 3.09 (1H, br s, OH ), 1.13e1.21 (3H, m,
OCH2CH3), 0.93 (9H, s, C(CH3)3); dC (100 MHz, CDCl3)
137.5, 117.3, 80.5, 80.0, 63.4, 34.7, 26.6, 15.1; m/z (ESI) 195
(100%, [MþNa]þ); HRMS (ESI) C10H20NaO2 ([MþNa]þ)
requires 195.1356, found 195.1358.
phosphine ligand, which could not be removed by further pu-
rification; nmax (film)/cmꢁ1 2946, 1596, 1549, 1487, 1447,
1380, 1250, 1204, 1070, 1022, 957, 921; dH (400 MHz,
CDCl3) 7.66e7.63 (2H, m, 2ꢃPhH ), 7.39e7.34 (2H, m,
2ꢃPhH ), 7.25e7.20 (1H, m, PhH ), 6.54 (1H, d, J 3.5,
C(4)H ), 6.05 (1H, d, J 3.5, C(3)H ), 1.35 (9H, s, C(CH3)3);
dC (100 MHz, CDCl3) 164.0, 151.8, 131.3, 128.6, 126.7,
123.3, 105.3, 104.0, 32.8, 29.1; m/z (CI) 201 (100%,
[MþH]þ); HRMS (CI) C14H17O ([MþH]þ) requires
201.1279, found 201.1279.
4.2.22. 2-Methoxy-3-oxo-1,3-diphenylpropyl benzoate (65)
Alcohol 64 (942 mg, 3.70 mmol) was subjected to general
procedure F. Flash column chromatography (SiO2; petroleum
ether/diethyl ether; 3:1) yielded 65 as a viscous yellow oil
(967 mg, 73%) and as a mixture of diastereoisomers, which
were not separated. The 1H and 13C NMR data provided is for
the major diastereoisomer; nmax (film)/cmꢁ1 3430, 3064,
2598, 2340, 2251, 1969, 1817, 1714, 1694, 1682, 1598, 1583,
1495, 1453, 1109, 1001; dH (400 MHz, CDCl3) 8.14e8.03
(15H, m, 15ꢃPhH ), 6.38 (1H, d, J 6.5, CHOC(O)Ph), 5.02
(1H, d, J 6.5, CHOCH3),3.39 (3H, s, OCH3); dC (100 MHz,
CDCl3) 197.7, 165.4, 136.1, 136.0, 135.9, 133.6, 133.2, 129.7,
128.9, 128.8, 128.8, 128.7, 128.4, 128.4, 86.3, 76.0, 58.8; m/z
(ESI) 419 (100%, [MþMeCNþNH4]þ); HRMS (ESI)
C23H20NaO4 ([MþNa]þ) requires 383.1254, found 383.1254.
4.2.19. 4-Ethoxy-2,2-dimethylhex-5-en-3-yl benzoate (49h)
Alcohol 48h (259 mg, 1.51 mmol) was subjected to general
procedure F. Flash column chromatography (SiO2; petroleum
ether/diethyl ether; 25:1) yielded 49h as a colourless oil
(375 mg, 84%) and as a mixture of diastereoisomers (ca. 2:1
from H NMR), which were not separated. The H and 13C
NMR data provided is for the major diastereoisomer; nmax
(film)/cmꢁ1 2972, 2871, 1723, 1602, 1481, 1451, 1398,
1366, 1337, 1314, 1111, 994; dH (400 MHz, CDCl3) 8.14e
7.41 (5H, m, 5ꢃPhH ), 5.74 (1H, ddd, J 17.5, 10.5, 7.0,
CH]CH2), 5.28e5.15 (2H, m, CH]CH2), 4.97 (1H, d, J
3.5, CHOC(O)Ph), 4.01 (1H, dd, J 7.0, 3.5, CHCH]CH2),
3.61e3.50 (1H, m, one of OCH2CH3), 3.38e3.25 (1H, m,
one of OCH2CH3), 1.16 (3H, t, J 7.0, OCH2CH3), 1.09 (9H,
s, C(CH3)3); dC (100 MHz, CDCl3) 166.3, 136.2, 132.7,
130.6, 129.8, 128.3, 117.3, 81.2, 80.5, 64.2, 35.1, 27.2, 15.2;
m/z (ESI) 335 (100%, [MþMeCNþNH4]þ), 299 (80,
[MþNa]þ), 277 (20), 237 (10); HRMS (ESI) C17H24NaO3
([MþNa]þ) requires 299.1618, found 299.1612.
1
1
4.2.23. (E ) and (Z )-1-(1-Methoxyocta-2,7-dien-2-yl)
benzene (66)
Ketone 64 (190 mg, 0.74 mmol) was subjected to general
procedure H. Flash column chromatography (SiO2; petroleum
ether/diethyl ether; 40:1) yielded 66 as a yellow oil (88 mg,
1
4.2.20. 1-(1-(4-Ethoxy-2,2-dimethylhex-5-en-3-yloxy)-
vinyl)benzene (50h)
55%) and as a mixture of isomers (ca. 3:1 from H NMR),
which were not separated. The 1H and 13C NMR data provided
is for the major isomer; nmax (film)/cmꢁ1 3078, 2978, 2925,
1640, 1600, 1494, 1443, 1352, 1190, 1101, 993, 912, 762;
dH (400 MHz, CDCl3) 7.48e7.23 (5H, m, 5ꢃPhH ), 5.92e
5.72 (2H, m, PhC]CH and CH]CH2), 5.01e4.91 (2H, m,
CH]CH2), 4.15 (2H, s, CH2OCH3), 3.36 (3H, s, OCH3),
2.12e2.00 (4H, m, CH2CH]CPh and CH2CH]CH2),1.50
Ester 49h (200 mg, 0.72 mmol) was subjected to general pro-
cedure G to give the 50h as a yellow oil (99 mg, 50%) and a mix-
ture of diastereoisomers, which were not separated (ca. 2:1 from
1H NMR) and used without further purification. The 1H and 13
C
NMR data provided is for the major diastereoisomer; nmax (film)/
cmꢁ1 2961, 1446, 1365, 1283, 1120, 1032, 771, 701; dH
(400 MHz, CDCl3) 7.71e7.20 (5H, m, 5ꢃPhH ), 5.89 (1H,
ddd, J 17.5, 10.5, 7.5, CH]CH2), 5.22e5.13 (2H, m,
CH]CH2), 4.74 (1H, d, J 3.0, one of CH2]CPh), 4.28 (1H,
d, J 3.0, one of CH2]CPh), 4.01e3.98 (2H, m, CHCH]CH2
and CHOC(]CH2)Ph), 3.62e3.50 (1H, m, one of OCH2CH3),
3.37e3.25 (1H, m, one of OCH2CH3), 1.17 (3H, t, J 7.0,
OCH2CH3), 1.06 (9H, s, C(CH3)3); dC (100 MHz, CDCl3)
160.4, 137.4, 132.7, 128.2, 128.0, 125.4, 116.7, 83.1, 85.4,
81.6, 64.2, 36.2, 27.4, 15.3; m/z (ESI) 275 (10%, [MþH]þ),
261 (100), 260 (30), 259 (10); HRMS (ESI) C18H27O2
([MþH]þ) requires 275.2011, found 275.2020.
(2H, apparent quintet,
J 8.0, CH2CH2CH]CPh); dC
(100 MHz, CDCl3) 139.0, 138.6, 137.4, 133.7, 130.6, 128.1,
126.9, 114.5, 77.7, 57.7, 29.1, 33.3, 28.1; m/z (ESI) 239
(100%, [MþNa]þ); HRMS (ESI) C15H20NaO ([MþNa]þ) re-
quires 239.1406, found 239.1400.
4.2.24. (E ) and (Z )-8-Methoxy-7-methylocta-1,6-diene (69)
Methoxyacetone 68 (184 mL, 0.74 mmol) was subjected to
general procedure H. Flash column chromatography (SiO2; pe-
troleum ether) yielded 69 as a colourless oil (275 mg, 89%) and
a mixture of isomers (ca. 10:1, (Z )/(E ) from 1H NMR and 1H
NOE experiments). The 1H and 13C NMR data provided is for
the major (Z )-isomer; nmax (film)/cmꢁ1 3078, 2966, 1641,
1608, 1490, 1447, 1350, 1201, 952; dH (400 MHz, CDCl3)
5.81 (1H, ddt, J 17.0, 10.5, 6.5, CH]CH2), 5.38 (1H, t, J 6.5,
CH3C]CH ), 5.01 (1H, ddd, J 17.0, 2.0, 3.0, one of
CH]CH2), 4.98e4.94 (1H, m, one of CH]CH2), 3.92 (2H,
4.2.21. 2-tert-Butyl-5-phenylfuran (51h)
Enol ether 50h (40 mg, 146 mmol) was subjected to general
procedure C in toluene then general procedure D. Flash col-
umn chromatography (SiO2; petroleum ether) yielding 51h
as a colourless oil (11 mg, 41%) contaminated with ca. 5%

820
T.J. Donohoe et al. / Tetrahedron 64 (2008) 809e820
13. (a) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723e4725;
(b) Chengzhi, Y.; Bin, L.; Longqin, H. J. Org. Chem. 2001, 66, 5413e
5418.
s, CH2OCH3), 3.29 (3H, s, OCH3), 2.11e2.03 (4H, m,
CH2CH]CCH3 and CH2CH]CH2), 1.76e1.74 (3H, m, CH3),
1.70e1.40 (2H, m, CH2CH2CH]CCH3); dC (100 MHz,
CDCl3) 138.7, 132.1, 129.3, 114.5, 70.8, 57.6, 29.1, 33.3,
27.1, 21.5; m/z (CI) 172 (50%, [MþNH4]þ), 140 (10), 123
(100), 107 (20), 85 (20), 81 (20); HRMS (CI) C10H22NO
([MþNH4]þ) requires 172.1701, found 172.1699.
14. (a) Derguini, F.; Linstrumelle, G. Tetrahedron Lett. 1984, 25, 5763e5766;
(b) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1968,
87, 916e924.
15. Methoxyallene derivative 25 proved unstable to flash column chromato-
graphy using silica gel (triethylamine doped) or either neutral or basic
alumina. Distillation also failed to achieve satisfactory results.
16. Desurbre, E.; Merour, J.-Y. Tetrahedron Lett. 1996, 37, 43e46.
17. Larock, R. C.; Berrios-Peiia, N. G.; Fried, C. A. J. Org. Chem. 1991, 56,
2615e2617.
Acknowledgements
18. Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.;
Schrodi, Y. Org. Lett. 2007, 9, 1589e1592.
We would like to thank the ESPRC, GlaxoSmithKline and
Organon for funding this project. AstraZeneca, Merck, Novar-
tis and Pfizer are also thanked for support.
19. Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron Lett.
1992, 33, 2701e2704.
20. (a) Deits, W.; Cukor, P.; Rubner, M.; Jopson, H. J. Electron. Mater. 1981,
10, 683e702; (b) Joshi, M. V.; Hemler, C.; Cava, M. P.; Cain, J. L.; Bakker,
M. G.; Mckinley, A. J.; Metzger, R. M. J. Chem. Soc., Perkin Trans. 2 1993,
1081e1086; (c) Ferraris, J. P.; Skiles, G. D. Polymer 1987, 28, 179e182.
21. Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Org. Chem. 1998, 63,
8163e8169.
References and notes
1. (a) For reviews see: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4490e4527; (b) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1e3, p 1234;
22. (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029e
4031; (b) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123e126.
23. Hekking, K. F. W.; van Delft, F. L.; Rutjes, P. J. T. Tetrahedron 2003, 59,
6751e6758.
(c) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012e3043; (d) Grubbs,
¨
R. H.; Chang, S. Tetrahedron 1998, 54, 4413e4450; (e) Gradillas, A.;
Perez-Castells, Jr. Angew. Chem., Int. Ed. 2006, 45, 6086e6101; (f)
Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912e1915.
2. (a) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2002, 41, 4035e4037; (b) Garber, S. B.; Kingsbury, J. S.; Gray,
B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168e8179; (c)
Scholl, M.; Ding, S.; Choon, W. L.; Grubbs, R. H. Org. Lett. 1999, 1,
953e956; (d) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791e799; (e) Schwab,
P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2039e2041.
24. Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153e2164.
25. Wu, Z.; Nguyen, S. T.; Grubbs, R. H.; Zillers, J. W. J. Am. Chem. Soc.
1995, 117, 5503e5511.
26. (a) Aggarwal, V. K.; Daly, A. M. Chem. Commun. 2002, 2490e2491; (b)
Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron Lett. 2001, 42, 179e
181; (c) Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2001,
42, 8023e8027; (d) Arisawa, M.; Theeraladanon, C.; Nishida, A.; Naka-
gawa, M. Tetrahedron Lett. 2001, 42, 8029e8033.
27. Kenworthy, M. N.; Taylor, R. J. K. Org. Biomol. Chem. 2005, 3, 603e611.
28. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392e6394.
29. (a) Takai, K.; Kataoka, Y.; Kahiuchi, T.; Utimoto, K. J. Org. Chem. 1994,
59, 2668e2670; (b) Takai, K.; Okazoe, T.; Oshima, K.; Utimoto, K.
J. Org. Chem. 1987, 52, 4410e4412.
3. (a) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740e
5750; (b) Martin, S. F.; Deiters, A. Chem. Rev. 2004, 104, 2199e2238;
(c) Hanson, P. R.; McReynolds, M. D.; Dougherty, J. M. Chem. Rev.
2004, 104, 2239e2258.
30. (a) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.; Rainier,
J. D. Tetrahedron 2002, 58, 1997e2009; (b) Majunder, U.; Rainier, J. D.
Tetrahedron Lett. 2005, 46, 7209e7211.
4. Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed. 2006, 45,
2664e2670 and references cited therein.
31. (a) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem.
Soc. 1996, 118, 1565e1566; (b) Nicolaou, K. C.; Postema, M. H. D.;
Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335e10336.
32. Hirashita, T.; Kamei, T.; Horie, T.; Yamamura, H.; Kawai, M.; Araki, S.
J. Org. Chem. 1999, 64, 172e177.
5. (a) Bassindale, M. J.; Hamley, P.; Leitner, A.; Harrity, J. P. A. Tetrahedron
Lett. 1999, 40, 3247e3250; (b) Kinderman, S. S.; Doodeman, R.; van
Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.; Moha-
selzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.;
Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 736e748.
33. Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A. H.
J. Am. Chem. Soc. 2006, 128, 5153e5157.
34. Hoye, T. R.; Jeffery, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am.
Chem. Soc. 2004, 126, 10210e10211.
6. Similar tactics have been utilised in a number of recent reports of the for-
mation of aromatic compounds by RCM: (a) Chen, Y. Z.; Dias, H. V. R.;
Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379e1382; (b) Declerck, V.;
Ribiere, P.; Martinez, J.; Lamaty, F. J. Org. Chem. 2004, 69, 8372e
8381; (c) Huang, K. S.; Wang, E. C. Tetrahedron Lett. 2001, 42, 6155e
6157; (d) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.; Imamoto,
T. Chem. Asian J. 2006, 1, 611e613.
35. Mukaiyama, T. Pure Appl. Chem. 1983, 55, 1749e1758.
36. Pangbon, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers,
F. J. Organometallics 1996, 15, 1518e1520.
37. Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302e4314.
38. Padwa, A.; Zhi, L.; Fryxell, G. E. J. Org. Chem. 1991, 56, 1077e1083.
39. Bates, D. K.; Li, X.; Jog, P. V. J. Org. Chem. 2004, 69, 2750e2754.
40. Zonta, C.; Fabris, F.; De Lucchi, O. Org. Lett. 2005, 7, 1003e1006.
41. Lorne, R.; Julia, S. A. Bull. Soc. Chim. Fr. 1986, 317e324.
42. Lautens, M.; Fillian, E. J. Org. Chem. 1997, 62, 4418e4427.
43. Chopade, P. R.; Davis, T. A.; Prasad, E.; Flowers, R. A. Org. Lett. 2004, 6,
2685e2688.
7. Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J. Org. Chem.
2005, 1969e1971.
8. Donohoe, T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou, P. A. Org. Lett.
2007, 9, 953e956.
9. For review and preparation see: Zimmer, R. Synthesis 1993, 165e178.
10. (a) Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.; Schoemaker, H. E.
Synlett 1998, 192e194; (b) Kinderman, S. S.; de Gelder, R.; van Maar-
seveen, J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T.
J. Am. Chem. Soc. 2004, 126, 4100e4101.
44. Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47, 1590e1592.
45. Swiss, K. A.; Choi, W. B.; Liotta, D. C.; Abdel-Magid, A. F.; Maryanoff,
C. A. J. Org. Chem. 1991, 56, 5978e5980.
11. Murakami, A.; Toyota, K.; Ohura, S.; Koshimizu, K.; Ohigashi, H.
J. Agric. Food Chem. 2000, 48, 1518e1523.
46. Arnould, J. C.; Enger, A.; Feigenbaum, A.; Pete, J. P. Tetrahedron 1979,
35, 2501e2512.
12. Barluenga, J.; Fernandez-Simon, J. L.; Concellon, J. M.; Yus, M. J. Chem.
Soc., Perkin Trans. 1 1989, 77e80.