An expedient route to substituted furans via olefin cross-metathesis

Article abstract of DOI:10.1073/pnas.0913466107

The olefin cross-metathesis (CM) reaction is used extensively in organic chemistry and represents a powerful method for the selective synthesis of differentially substituted alkene products. Surprisingly, efforts to integrate this remarkable process into strategies for aromatic and heteroaromatic construction have not been reported. Such structures represent key elements of the majority of small molecule drug compounds; methods for the controlled preparation of highly substituted derivatives are essential to medicinal chemistry. Here we show that the olefin CM reaction, in combination with an acid cocatalyst or subsequent Heck arylation, provides a concise and flexible entry to 2,5-di- or 2,3,5-tri-substituted furans. These cascade processes portend further opportunities for the regiocontrolled preparation of other highly substituted aromatic and heteroaromatic classes.

Full text of DOI:10.1073/pnas.0913466107

An expedient route to substituted furans
via olefin cross-metathesis
Timothy J. Donohoe1 and John F. Bower
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA UK
Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved December 23, 2009 (received for review November 20, 2009)
The olefin cross-metathesis (CM) reaction is used extensively in or-
ganic chemistry and represents a powerful method for the selective
synthesis of differentially substituted alkene products. Surpris-
ingly, efforts to integrate this remarkable process into strategies
for aromatic and heteroaromatic construction have not been re-
ported. Such structures represent key elements of the majority
of small molecule drug compounds; methods for the controlled pre-
paration of highly substituted derivatives are essential to medicinal
chemistry. Here we show that the olefin CM reaction, in combina-
tion with an acid cocatalyst or subsequent Heck arylation, provides
a concise and flexible entry to 2,5-di- or 2,3,5-tri-substituted furans.
These cascade processes portend further opportunities for the re-
giocontrolled preparation of other highly substituted aromatic and
heteroaromatic classes.
catalysis ∣ cembranolide ∣ Heck reaction
uthenium catalyzed olefin metathesis has become a remark-
R
ably powerful tool for organic chemistry (1–5). In recent
years, the potential of ring-closing olefin metathesis (RCM) as
a key step for the preparation of aromatic and heteroaromatic
compounds has begun to be realized (6–8). Studies from our
own laboratory have delineated versatile RCM-based protocols
for the regiodefined synthesis of pyridines, pyridazines, furans,
and pyrroles (9–15). Despite the evident potential of these meth-
ods it is notable that any RCM-based approach is reliant upon the
a priori construction of a suitable precursor, which necessarily
detracts from synthetic convergency and flexibility. A related ap-
proach involves the use of olefin cross-metathesis (CM) as a key
step. Here both fragment coupling and strategic C=C bond for-
mation are unified and, as such, potentially greater efficiencies
are afforded. Despite this potential, and presumably due to per-
ceived problems associated with double bond geometry, olefin
CM-based methodologies for aromatic and heteroaromatic con-
struction have not, to the best of our knowledge, been disclosed.
Herein we report the successful implementation of this concept in
terms of a versatile and direct entry to disubstituted and
trisubstituted furans. It is likely that these studies will set the stage
for the development of general olefin CM-based entries to other
aromatic and heteroaromatic classes of varying ring sizes
(Scheme 1, top).
Scheme 1 Cross-metathesis as an approach to di- and trisubstituted furans.
serve as highly versatile surrogates for 1,4-dicarbonyl com-
pounds, especially as the final furan substitution pattern is pro-
grammed by the oxidation level of the allylic alcohol and enone
components. The net result is an exceptionally concise and con-
trolled approach to this class of heteroaromatic compounds.
Results and Discussion
In our initial studies, we focused upon the formation of furan 8a
by the olefin CM of allylic alcohol 6a with methyl vinyl ketone 7a.
Here we found that, using the Grubbs–Hoveyda second genera-
tion catalyst (G-H II), the synthesis of the trans-hydroxyenone
intermediate was straightforward. Subsequent addition of a vari-
ety of Brønsted or Lewis acids to the reaction medium was then
evaluated to promote isomerization and condensation. From
these initial assays we established that catalytic quantities of
PPTS effected efficient furan formation. Furan formation pre-
sumably occurs via initial isomerization of the trans-hydroxye-
none metathesis product to either the corresponding 1,4-
dicarbonyl compound or the cis-hydroxyenone. We have not,
Substituted furans are prevalent in natural products and phar-
maceuticals and also represent useful intermediates in synthesis.
Convergent de novo approaches to furans that embody high levels
offlexibilityandpredictableregiocontrolareofparticularvalueyet
are relatively uncommon (16–22). Specifically, methods that
employ simple starting materials, enable facile substituent intro-
duction, andareconcisearelikelytobeofsignificancetobothmed-
icinal chemistry and total synthesis. Our approach to furans relies
upon the intermediacy of trans-γ-hydroxyenones 3 that are acces-
sible via the established olefin CM of readily available allylic alco-
hols 1 and enones 2 (Scheme 1, Bottom) (23). Here we show that a
tandem olefin CM-acid catalysed isomerization cascade provides a
direct entry to differentially 2,5-disubstituted furans 4. Addition-
ally, Heck reaction of the olefin CM products enables a tandem
arylation-furan formation cascade to afford 2,3,5-trisubstituted
furans 5 directly. As such, the trans-γ-hydroxyenone intermediates
Author contributions: T.J.D. and J.F.B. designed research; J.F.B. performed research, T.J.D.
and J.F.B. analyzed data, and T.J.D. and J.F.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
See Commentary on page 3279.
1To whom correspondence should be addressed. E-mail: timothy.donohoe@chem.ox.ac.uk.
This article contains supporting information online at www.pnas.org/cgi/content/full/
0913466107/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.0913466107
PNAS ∣ February 23, 2010 ∣ vol. 107 ∣ no. 8 ∣ 3373–3376

Table 2. Tandem CM-furan formation: scope of the allylic alcohol
component
as of yet, been able to unambiguously distinguish these pathways.
However, our preliminary investigations suggest that furan for-
mation from trans-hydroxyenones is faster than from analogous
1,4-dicarbonyl compounds. This would implicate a trans- to cis-
isomerization pathway (24).
At this stage, and given the known compatibility of Grubbs’
type catalyst systems and acids (25), we considered whether both
the ruthenium and acid catalysts could be employed from the out-
set. Gratifyingly, this proved to be the case and, under optimized
conditions, allylic alcohol 6a was converted to furan 8a in 82%
yield. Notably, increased overall efficiencies were observed using
this tandem approach compared to the stepwise alternative.
These conditions are generally applicable to a range of enone
components and enable the introduction of aryl, heteroaryl, cy-
clopropyl, and diverse alkyl substituents in good to excellent yield
(Table 1).
Examination of the scope of the allylic alcohol component re-
vealed a greater degree of substrate sensitivity, presumably as this
is the site of cross-metathesis initiation (Table 2). Under opti-
mized conditions, alkyl, aryl, and heteroaryl substituents could
all be introduced onto the furan core via the corresponding allylic
alcohol (6b-g) in moderate to excellent yield. The catalyst system
is, however, sensitive to the steric bulk of this component, and the
introduction of a t-butyl substituent was achieved in only 36%
yield (Entry 6) with the remainder of the mass balance consisting
largely of starting material. This defines a current limitation but
also portends further increases in scope as more efficient metath-
esis catalysts become available.
It is pertinent to consider the role of the allylic alcohol hydro-
xyl group in promoting the efficient CM reactions described here.
Recent work has highlighted the enhanced metathesis efficiency
of allylic alcohols compared to their corresponding ethers (26,
27), and our own preliminary observations are consistent with
O
G-H II (5 mol%)
PPTS (2.5 mol%)
OH
O
R
Me
Me
R
CH2Cl2 (0.25 M)
40 oC, 24h
6b-g
7a
8g-l
(100 mol%)
(500 mol%)
Entry
Allylic Alcohol
Product
Yield, %
76
OH
1
O
Me
Ph
Ph
6b
8g
2*
OH
61
53
65
Br
O
Me
Me
N
N
6c
8h
Br
Br
3†
4
OH
Br
O
6d
8i
OH
O
Me
6e
8j
OH
O
5
51
36
Me
BnO
BnO
6f
8k
O
6‡
OH
Ph
t-Bu
t-Bu
6g
8l
*The reaction was run at 70 °C.
†The reaction was run at 0.17 M.
‡Phenyl vinyl ketone was employed as the enone component and the
reaction was run at 60 °C.
Table 1. Tandem CM-furan formation: Scope of the enone
component
these findings. As evidenced by Hoveyda, it is possible that hy-
drogen bonding between the allylic alcohol derived carbene
and a ruthenium chloride ligand is crucial in expediting subse-
quent CM to the electron deficient enone (27).
O
G-H II (5 mol%)
PPTS (2.5 mol%)
OH
O
Ph(CH2)2
R
R
Ph(CH2)2
6a
CH2Cl2 (0.25 M)
40 oC, 24h
Given our ongoing interest in cembranolide natural products
such as deoxypukalide 15 (28), we were interested in assessing
whether this furan synthesis could be employed in an intramole-
cular setting to provide an entry to the macrocyclic furan core
present in many compounds of this class (Scheme 2). Such an
approach would unite the direct nature of the methodology pre-
sented herein with the established utility of olefin metathesis for
macrocycle formation (29). Wadsworth–Emmons olefination of
undecenal using the modified phosphonate reagent 9 afforded
acrylamide 10 in 90% yield. This species underwent efficient con-
jugate addition with the Gilman cuprate derived from n-BuLi to
generate 11. This route demonstrates the feasibility of installing
the C-1 substitution present in the cembranolide natural pro-
ducts. Note that organocuprate 1,4-additions onto Weinreb acry-
lamides have not previously been reported; we have found that
careful control of reaction temperature and time are essential in
preventing the known ene-type degradation of the intermediate
silyl ketene aminal (30). Oxidative cleavage of the terminal olefin
yielded 12, and this was subjected to double addition of vinyl
Grignard to set-up the tethered allylic alcohol-enone metathesis
precursor 13. Exposure of this species to our previously described
conditions but under higher dilution, afforded the 13-ring macro-
cyclic furan system 14 in excellent yield. Here prolonged reaction
times were required to effect (a) complete metathesis and (b)
complete conversion of the intermediate hydroxyenone to the
corresponding furan.
7a-f
(250 mol%)
8a-f
(100 mol%)
Entry
Enone
Product
Yield, %
82
O
O
1
2
3
Ph(CH2)2
Me
Et
Me
8a
7a
O
71
54
O
Ph(CH2)2
Et
7b
8b
O
O
Ph(CH2)2
cHex
7c
8c
O
O
4
5
76
56
Ph(CH2)2
Ph
Ph
8d
7d
O
TsN
Ts
N
O
Ph(CH2)2
7e
8e
O
6
63
O
Ph(CH2)2
Ph
Ph
8f
7f
3374
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www.pnas.org/cgi/doi/10.1073/pnas.0913466107
Donohoe and Bower

Scheme 2 RCM-furanization approach to the cembranolide macrocycle.
The formation of trisubstituted furans is potentially enabled by
this methodology. However, the use of allylic alcohols or enones
possessing 1,1-disubstitution affords only traces of the corre-
sponding trisubstituted furan under the conditions reported in
Tables 1 and 2. This is due to inefficiencies associated with the
metathesis step. Undeterred, we decided to examine Heck aryla-
tion of the trans-hydroxyenone CM products, and after some ex-
perimentation we found that exposure of hydroxyenone 16a and
bromotoluene to the mild Heck protocol reported by Fu (31) re-
sulted in the formation of furan 17a in 80% yield (Scheme 3).
Under these conditions, only traces of furan 8a (<10%) resulting
from cyclisation of hydroxyenone 16a in advance of Heck aryla-
tion were observed. This sequence is amenable to the introduc-
tion of diverse aryl substituents at C-3 and generally excellent
overall yields of the furan products 17a-f are achieved. Variation
of the hydroxyenone component adds further flexibility and facil-
itates regiodefined switching of the substituents at the 2- or 5-po-
sitions of the furan ring (c.f. 16b→18 and 16c→20). In the case of
furan 18, traces of 1,4-dicarbonyl 19 were also isolated, presum-
ably formed via either base or Pd-H mediated isomerization of
the starting enone 16b; notably this component did not cyclize
to the corresponding furan under the reaction conditions. This
sequence can also be used in an intramolecular setting. Accord-
ingly, enone 16d underwent efficient Heck cyclization to afford
tricyclic furan 21 along with significant quantities of 1,4-dicarbo-
nyl derivative 22. Again, this component did not cyclize under the
reaction conditions, even upon extended reaction times, and pre-
sumably arises via isomerization after the Heck reaction.
The use of a Heck reaction to trigger aromatization is of inter-
est. Our current understanding of this process finds precedence in
the known stereochemical outcome of Heck reactions onto trans-
acrylates under the conditions employed here (Scheme 4) (31).
Syn-carbopalladation of the enone I mandates σ-bond rotation
of II in advance of β-hydride elimination to deliver intermediate
III; this scenario assumes that β-hydride elimination occurs faster
than epimerization of the σ-Pd bond via an η-3 oxy-π-allyl palla-
dium species (32). Cis-hydroxyenones such as III are known to
exist in equilibrium with their corresponding hemiketals IV
(33) and have been observed to undergo spontaneous furan for-
mation (to V) by loss of water (34). To corroborate this mechan-
ism, trans-enone 23 was subjected to the Heck conditions and
found to deliver arylated product 24 where the substituents pre-
sent in the starting material now reside in a cis-arrangement, as
Scheme 3 CM-Heck approach to trisubstituted furans. Asterisks indicate con-
tamination with ca. 5% of non-arylated furan.
evidenced by diagnostic NOE enhancements (see SI Text). At
higher conversions, the ratio of 24 to isomeric products decreases.
Although this result establishes the feasibility of trans- to cis-iso-
merization during the Heck process, the concomitant formation
of isomeric products (as an inseparable mixture and character-
ized by mass spectrometry only) prevents definitive confirmation
that β-hydride elimination generates the cis-product directly.
Note that general Heck protocols involving β-alkylated enones
have not been reported, presumably due to facile secondary
isomerization of the initial adducts (35, 36). Furan formation
via the intermediacy of the corresponding 1,4-dicarbonyl (which
could potentially arise after Heck arylation) is discounted as 25
did not afford furan 18 when exposed to the Heck conditions.
Additional evidence discounting this pathway lies in our inability
so far to convert 1,4-dicarbonyl 22 to furan 21, even under forcing
conditions (see Scheme 3).
Conclusions
In summary, unique examples of the use of olefin CM as a means
of accessing heteroaromatic compounds have been described.
The present work illustrates the power of this approach in terms
of highly direct and controlled entries to di- and trisubstituted
furans. The synthesis of the latter relies upon the strategic em-
ployment of a Heck arylation to effect C-C bond formation with
concomitant aromatisation. The chemistry described here, which
capitalizes upon readily available components, is both direct and
regiocontrolled. As such, widespread application is anticipated.
Donohoe and Bower
PNAS
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∣
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General Procedure for the Synthesis of 2,5-Disubstituted Furans. A resealable
reaction tube, fitted with a magnetic follower, was charged with Grubbs–Ho-
veyda second generation catalyst (5 mol%) and PPTS (2.5 mol%). The tube
was then sealed with a rubber septum and purged with argon. Argon
sparged CH2Cl2 (0.25 M with respect to the allylic alcohol employed) was then
added via syringe, and the tube was cooled to −78 °C prior to sequential ad-
dition of the requisite enone (250 mol% or 500 mol%) and allylic alcohol
(100 mol%). The rubber septum was then replaced with a screw cap and
the tube was heated at 40 °C (oil bath temperature) for 24 h. After cooling
to room temperature, the reaction mixture was concentrated in vacuo and
the residue was filtered through a short cartridge of SiO2 (eluting with 10∶1
petrol-EtOAc). The fractions containing the target furan were combined and
concentrated in vacuo. Purification of the residue by flash column chroma-
tography afforded the corresponding furan.
General Procedure for the Synthesis of 2,3,5-Trisubstituted Furans. (A) Olefin
CM step: An argon purged reaction flask, fitted with a magnetic follower,
was charged with Grubbs–Hoveyda second generation catalyst (2.5 mol%)
and argon sparged CH2Cl2 (0.25 M with respect to the allylic alcohol em-
ployed). The requisite enone (500 mol%) and allylic alcohol (100 mol%) were
then added sequentially via syringe. The mixture was stirred at room tem-
perature for 24 h and then concentrated in vacuo. Purification of the residue
by flash column chromatography afforded the corresponding trans-γ-hydro-
xyenone. (B) Heck step: A reaction tube, fitted with magnetic follower, was
charged with Pd2ðdbaÞ3 (5 mol%), Pt-Bu3HBF4 (20 mol%), and (if solid) the
corresponding aryl bromide (250 mol%). The tube was sealed with a septum
and purged with argon. The requisite trans-γ-hydroxyenone (100 mol%), the
corresponding aryl bromide (if liquid) (250 mol%), anhydrous p-dioxane
(0.1 M with respect to the enone component) and then Cy2NMe (250 mol
%) were added sequentially via syringe. The mixture was then heated at
either 70 °C or 85 °C for 16 h. The mixture was cooled to room temperature
and filtered through a short cartridge of SiO2 (eluting with 10∶1 petrol-
EtOAc). The fractions containing the target furan were combined and con-
centrated in vacuo. Purification of the residue by flash column chromatogra-
phy afforded the corresponding furan.
Scheme 4 Proposed mechanism for the tandem Heck-furan formation se-
quence and some preliminary mechanistic experiments.
Methods
Full experimental details and compound characterization data are included
ACKNOWLEDGMENTS. We thank the EPSRC for supporting this project. Merck
is thanked for unrestricted funding.
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Donohoe and Bower