An alkyne hydroacylation route to highly substituted furans

Article abstract of DOI:10.1002/anie.201105795

More rings for your rhodium: Rhodium-catalyzed intermolecular alkyne hydroacylations deliver γ-hydroxy-α,β-enones, which can be cyclized in situ to deliver di-and trisubstituted furans. Functionalization of the intermediates using Heck chemistry allows the formation of regioisomeric furans. The use of an alternative Rh^I catalyst delivers 1,4-dicarbonyl compounds and hence pyrroles, thiophenes, and pyridazines, all from the same two starting materials. Copyright

Full text of DOI:10.1002/anie.201105795

DOI: 10.1002/anie.201105795
Heterocycle Synthesis
An Alkyne Hydroacylation Route to Highly Substituted Furans**
Philip Lenden, David A. Entwistle, and Michael C. Willis*
Heterocyclic compounds, such as the bioactive natural
products pukalide and nakadomarin A, and the hugely
successful drug molecules ranitidine (Zantac) and atorvasta-
tin (Lipitor) are of great importance in pharmaceutical,
agrochemical, and other fine-chemical applications
(Scheme 1).[1] While there exists a range of methods for
catalyst systems, and generate no by-products because of their
100% atom-economy.[3–5] In addition, a broad range of
aldehydes can now be employed, and particularly in the
case of alkyne hydroacylation, significant substitution of the
unsaturated component can be tolerated, thus allowing for
the regioselective production of highly substituted complex
molecules in one catalytic intermolecular carbon–carbon
bond forming step. Herein, we demonstrate the utility of
intermolecular alkyne hydroacylation in the efficient syn-
thesis of di- and trisubstituted furans and related heterocycles.
g-Hydroxy-a,b-enones are known to undergo acid-cata-
lyzed dehydrative cyclization to form furans, and this trans-
formation has been exploited by several research groups,[6]
most notably in the recent work from Donohoe et al.[7] The
intermolecular hydroacylation of an aldehyde with readily
available propargylic alcohols would permit the synthesis of
g-hydroxy-a,b-enones with 100% atom efficiency; coupling
this carbon–carbon bond formation with an acid-catalyzed
dehydrative cyclization would allow for the regioselective
synthesis of di- or trisubstituted furans. The associated
disconnection is novel for this type of heterocycle (Scheme 2).
Our initial investigations to realize the above route to
furans focused on the combination of propargyl alcohol 1a
Scheme 1. Examples of significant heterocycle-containing natural prod-
ucts and pharmaceuticals.
transforming relatively complex starting materials into sub-
stituted heterocycles, and for the functionalization of existing
heterocycles, there is less precedent for methodology which
involves the direct, regiodefined synthesis of highly substi-
tuted heterocycles from simple starting materials.[2] As such,
new methods for the synthesis of substituted heterocycles (or
their precursors) are potentially of significant value. This is
particularly true if such methods do not suffer from the same
drawbacks as the traditional syntheses of 1,4-dicarbonyl
compounds, the classic substrates for the preparation of
furans, thiophenes, and pyrroles; these syntheses are often
either step- or atom-inefficient. The recent advances achieved
in intermolecular alkene and alkyne hydroacylation chemis-
try means that these transformations are now ideal methods
to exploit for the synthesis of heterocyclic molecules, because
they employ simple substrates and commercially available
Scheme 2. An alkyne hydroacylation route to furans.
and the S-chelating alkyl aldehyde 2a (Table 1). The hydro-
acylative union of these two substrates using a dppe-derived
Rh catalyst proceeded without incident. However, attempts
to achieve a dehydrative cyclization using TFA provided only
a small amount of the desired furan 3a (entry 1). Reducing
the time for the cyclization event to 1 hour, and then to
10 minutes, increased the yield of furan up to 50% (entries 2
and 3). After exploring the use of several alternative acids, it
was found that the use of p-TSA increased the yield to 66%
(entries 4–7). Given the known acid sensitivity of simple
alkyl-substituted furans we speculated that the purification of
the furan product by chromatography on silica gel might be
responsible for the moderate yields of the isolated products.[8]
Accordingly, although the use of neutral alumina offered no
advantage, purifications employing Florisil (magnesium sili-
cate) or triethylamine-doped silica allowed the furan to be
isolated in significantly increased yields (entries 8–10).
[*] P. Lenden, Dr. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk/MCW/Home.html
Dr. D. A. Entwistle
Research API, Pfizer Global Research and Development
Sandwich, Kent, CT13 9NJ (UK)
With the optimized conditions established, a short series
of 2,5-disubstituted furans was prepared (Scheme 3). Prop-
argylic aryl and heteroaryl substituents could be introduced
[**] This work was supported by the EPSRC and Pfizer.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105795.
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Table 1: Rhodium-catalyzed hydroacylation/acid-catalyzed cyclization for
the synthesis of furan 3a.[a]
Entry Acid
t
Purification
Yield [%][b]
1
2
3
4
5
TFA (excess)
TFA (excess)
TFA (excess)
PPTS (10 mol%)
HCl (10 mol%)
16 h
1 h
10 min silica
1 h
1 h
silica
silica
trace
29
50
0
silica
silica
8
6
7
8
9
p-TSA (10 mol%) 30 min silica
57
66
26
75
p-TSA (10 mol%) 2 h
p-TSA (10 mol%) 2 h
p-TSA (10 mol%) 2 h
p-TSA (10 mol%) 2 h
silica
neutral alumina
Florisil
10
NEt3-doped silica 85
[a] Reaction conditions: 1 (0.75 mmol), 2 (1.1 equiv), [Rh(nbd)2]BF4
(0.05 equiv), dppe (0.05 equiv), DCE, 658C, 1 h, followed by acid
(equivalents as stated) at the given conditions. [b] Yields of the isolated
product. DCE=dichloroethane, dppe=1,2-bis(diphenylphosphino)-
ethane, nbd=norbornadiene, PPTS=pyridinium para-toluenesulfonate,
p-TSA=para-toluenesulfonic acid, TFA=trifluoroacetic acid.
without incident, as could a and b branching on the aldehyde
component (furans 3b–e). We next looked to expand the
process to include internal alkyne substrates, thus allowing
the preparation of trisubstituted furans. The hydroacylation
step employing internal alkynes proceeded efficiently,
although longer reaction times were needed for the reactions
to reach completion (16 h versus 1 h). The cyclization
conditions that had proved to be optimal for the 2,5-
disubstituted furans (10 mol% of p-TSA) were unsuccessful
for the trisubstituted examples, with only partial conversion
into the desired furan being observed. However, the use of
anhydrous HCl, which produced only traces of furan in the
majority of the 2,5-disubstituted examples because of product
decomposition, proved to be proficient at rapidly and cleanly
converting the hydroacylation products in situ into the
desired trisubstituted furans in good to excellent yields.
These reaction conditions were applied to the synthesis of a
variety of trisubstituted furans from alkyl and aryl aldehydes,
and internal propargylic alcohols. Two regioisomeric trisub-
stituted furans (3 f and 3g) were produced by simply altering
the alkyne employed in the hydroacylation step. Pleasingly,
modest scaling up of the reaction was also possible, with furan
3g being obtained in an excellent 93% yield upon isolation,
from a 3.0 mmol scale reaction. A trialkyl variant (3h) could
be synthesized, but was isolated only in 42% yield; although
both the hydroacylation step and the acid-catalyzed dehy-
drative cyclization proceeded to completion without the
production of any by-products, the product degraded when
purified by column chromatography, despite the use of
thoroughly base-washed silica. An ester substitutent was
readily incorporated (3j). A cyclohexenyl aldehyde was
utilized to furnish furan 3k. Aromatic aldehydes could also
be readily employed, leading to furans 3l–o. Furan 3n
includes an aryl chloride substituent, thus demonstrating the
tolerance of the method towards incorporating halide sub-
stituents for potential derivatization of the products.
Scheme 3. Scope of the rhodium-catalyzed hydroacylation/acid-cata-
lyzed cyclization synthesis of di- and trisubstituted furans. Reaction
conditions: aldehyde (0.75 mmol), alkyne (1.1 equiv), [Rh(nbd)2]BF4
(0.05 equiv), dppe (0.05 equiv), DCE, 708C, 1 h, or 16 h followed by
acid. Yields are of the isolated products. [a] p-TSA (10 mol%), 2 h.
[b] HCl (4.0m in dioxane, 1.0 equiv). [c] 3.0 mmol scale. [d] No acid
needed for cyclization.
An inherent limitation with methodology that is based on
employing propargylic alcohols as one of the reaction
components is the inability to directly access furans bearing
a substituent at the position that originated from the
propargylic carbon atom (i.e., position 3 as shown in
Scheme 2). To rectify this we explored the possibility of
functionalizing the initially formed hydroacylation adducts
before cyclization to the heterocycle. Subjecting g-hydroxy-
a,b-enone 4 to Heck-coupling conditions, as described by
Donohoe et al.,[7,9] with a range of aryl bromides, provided
trisubstituted furans 3p–r in good yields (Scheme 4). The
furans were isolated directly from the reactions, without the
need for an additional acid-catalyzed cyclization. The utility
of this set of Heck reactions is that it allows access to
regioisomers not available from the initial hydroacylation/
cyclization methodology, for example, compare furans 3 f, 3g,
and 3p. Combined with the ability to employ aryl aldehydes
as substrates, the methodology enables the selective intro-
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Scheme 4. Functionalization of hydroacylation adducts using the Heck
reaction leading to regioisomeric trisubstituted furans. dba=dibenzyli-
deneacetone.
duction of aryl substituents to each of the four furan carbon
atoms.
Attempts to apply the Heck chemistry to the synthesis of
tetrasubstituted furans were unsuccessful. However, tetra-
substituted products could be accessed from the correspond-
ing trisubstituted furans using In-catalyzed Friedel–Crafts
chemistry. For example, treatment of furan 3g with acetic
anhydride in the presence of catalytic In(OTf)3 delivered the
fully substituted heterocycle in 89% yield (Scheme 5).[10] This
overall process provides a concise and efficient route to fully
substituted furans.
Scheme 6. Rhodium-catalyzed preparation of 1,4-dicarbonyl com-
pounds and their conversion into various heterocycles. DPEphos=
bis(2-diphenylphosphinophenyl)ether.
developed an atom-efficient synthesis of 1,4-dicarbonyl com-
pounds, from the same reaction components, and demon-
strated the transformation of these products into five- and six-
membered heterocycles.
Received: August 16, 2011
Published online: September 20, 2011
Scheme 5. Indium-catalyzed Friedel–Crafts synthesis of tetrasubsti-
tuted furan 3s. Tf=trifluoromethanesulfonyl.
Keywords: heterogeneous catalysis · hydroacylation ·
.
oxygen heterocycles · regioselectivity · rhodium
Finally, given the efficiency of the aldehyde/propargylic
alcohol hydroacylative coupling it was desirable to be able to
access alternative heterocycles from the same combination of
substrates. However, attempts to convert the g-hydroxy-a,b-
enone products directly into pyrroles or thiophenes were
unproductive. A solution to this issue was realized when an
alternative catalyst system was used for the hydroacylation
step: employing a DPEphos-derived catalyst for the union of
aromatic aldehyde 2b and propargylic alcohol 1b led not to
the expected g-hydroxy-a,b-enone, but to 1,4-dicarbonyl 5a
(Scheme 6). The 1,4-dicarbonyl is presumed to originate from
a Rh-catalyzed isomerization of the initially formed g-
hydroxy-a,b-enone.[11] The ability to access 1,4-dicarbonyl
systems directly opened up a host of possibilities for further
functionalization; Scheme 6 shows representative 1,4-dicar-
bonyl products (5b–d), together with their conversion into
pyrrole,[12] thiophene,[13] and pyridazine[14] heterocycles.
In summary, we have demonstrated the applicability of a
rhodium-catalyzed intermolecular hydroacylation to the syn-
thesis of di- and trisubstituted furans in a regiocontrolled
fashion; this reaction proceeds through a 100% atom-
economic carbon–carbon bond forming step followed by a
simple dehydrative cyclization. The Heck reaction has been
utilized to further increase the scope of the methodology to
access regioisomeric trisubstituted furans. An unprecedented
indium-catalyzed acylation procedure for the synthesis of
tetrasubstituted furans from the trisubstituted furans thus
produced, has also been disclosed. In addition, we have a
[1] A. F. Pozharskii, A. T. Soldatenkov, A. R. Katritzky, Hetero-
cycles in Life and Society, Wiley, Chichester, 1997.
[2] For representative examples for furans, see: a) A. S. K. Hashmi,
P. Sinha, Adv. Synth. Catal. 2004, 346, 432; b) C.-K. Jung, J.-C.
Wang, M. J. Krische, J. Am. Chem. Soc. 2004, 126, 4118; c) J. M.
Aurrecoechea, A. Durana, E. Prez, J. Org. Chem. 2008, 73, 3650;
d) L. K. Sydnes, B. Holmelid, M. Sengee, M. Hanstein, J. Org.
Chem. 2009, 74, 3430; e) X. Zhang, Z. Lu, C. Fu, S. Ma, J. Org.
Chem. 2010, 75, 2589; f) J. Dheur, M. Sauthier, Y. Castanet, A.
Mortreux, Adv. Synth. Catal. 2010, 352, 557; g) F. M. Istrate, F.
Gagosz, Beilstein J. Org. Chem. 2011, 7, 878; h) N. T. Patil, Y.
Yamamoto, Arkivoc 2007, x, 121.
[3] M. C. Willis, Chem. Rev. 2010, 110, 725.
[4] For recent intermolecular Rh-catalyzed examples, see: a) C.-H.
Jun, H. Lee, J.-B. Hong, B.-I. Kwon, Angew. Chem. 2002, 114,
2250; Angew. Chem. Int. Ed. 2002, 41, 2146; b) M. Imai, M.
Tanaka, K. Tanaka, Y. Yamamoto, N. Imai-Ogata, M. Shimo-
watari, S. Nagumo, N. Kawahara, H. Suemune, J. Org. Chem.
2004, 69, 1144; c) M. C. Willis, S. J. McNally, P. J. Beswick,
Angew. Chem. 2004, 116, 344; Angew. Chem. Int. Ed. 2004, 43,
340; d) M. C. Willis, H. E. Randell-Sly, R. L. Woodward, G. S.
Currie, Org. Lett. 2005, 7, 2249; e) M. C. Willis, H. E. Randell-
Sly, R. L. Woodward, S. J. McNally, G. S. Currie, J. Org. Chem.
2006, 71, 5291; f) G. L. Moxham, H. E. Randell-Sly, S. K. Bray-
shaw, R. L. Woodward, A. S. Weller, M. C. Willis, Angew. Chem.
2006, 118, 7780; Angew. Chem. Int. Ed. 2006, 45, 7618; g) Y.-T.
Hong, A. Barchuk, M. J. Krische, Angew. Chem. 2006, 118, 7039;
Angew. Chem. Int. Ed. 2006, 45, 6885; h) K. Tanaka, Y. Shibata,
T. Suda, Y. Hagiwara, M. Hirano, Org. Lett. 2007, 9, 1215; i) R. T.
Stemmler, C. Bolm, Adv. Synth. Catal. 2007, 349, 1185; j) A. H.
Angew. Chem. Int. Ed. 2011, 50, 10657 –10660
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 10659

Communications
Roy, C. P. Lenges, M. Brookhart, J. Am. Chem. Soc. 2007, 129,
[6] a) R. C. Larock, C. L. Liu, J. Org. Chem. 1983, 48, 2151; b) D. M.
Sammond, T. Sammakia, Tetrahedron Lett. 1996, 37, 6065; c) A.
Boto, D. Hernandez, R. Hernandez, Org. Lett. 2007, 9, 1721;
d) Y. Zhu, C. Zhai, L. Yang, W. Hu, Chem. Commun. 2010, 46,
2865.
[7] a) T. J. Donohoe, J. F. Bower, Proc. Natl. Acad. Sci. USA 2010,
107, 3373; b) T. J. Donohoe, J. F. Bower, J. A. Basutto, Nat.
Protoc. 2010, 5, 2005.
[8] S. J. Pridmore, P. A. Slatford, J. E. Taylor, M. K. Whittlesey,
J. M. J. Williams, Tetrahedron 2009, 65, 8981.
[9] A. F. Littke, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 6989.
[10] a) C. J. Chapman, C. G. Frost, J. P. Hartley, A. J. Whittle,
Tetrahedron Lett. 2001, 42, 773; b) K. K. Chauhan, C. G. Frost,
J. Chem. Soc. Perkin Trans. 1 2000, 3015.
[11] a) S. H. Bergens, B. Bosnich, J. Am. Chem. Soc. 1991, 113, 958;
b) K. Tanaka, G. C. Fu, J. Org. Chem. 2001, 66, 8177; c) K.
Tanaka, T. Shoji, M. Hirano, Eur. J. Org. Chem. 2007, 2687.
[12] G. E. Veitch, K. L. Bridgwood, K. Rands-Trevor, S. V. Ley,
Synlett 2008, 2597. Additional safety information Chem. Eng.
News 2009, 87(15), 2; Chem. Eng. News 2009, 87(23), 4.
[13] a) I. Thomsen, K. Clausen, S. Scheibye, S.-O. Lawesson, Org.
Synth. 1984, 62, 158; b) D. R. Shridhar, M. Jogibhukta, P. S. Rao,
V. K. Handa, Synthesis 1982, 1061.
2082; k) G. L. Moxham, H. E. Randell-Sly, S. K. Brayshaw, A. S.
Weller, M. C. Willis, Chem. Eur. J. 2008, 14, 8383; l) J. D.
Osborne, M. C. Willis, Chem. Commun. 2008, 5025; m) J. D.
Osborne, H. E. Randell-Sly, G. S. Currie, A. R. Cowley, M. C.
Willis, J. Am. Chem. Soc. 2008, 130, 17232; n) H. E. Randell-Sly,
J. D. Osborne, R. L. Woodward, G. S. Currie, M. C. Willis,
Tetrahedron 2009, 65, 5110; o) Y. Shibata, K. Tanaka, J. Am.
Chem. Soc. 2009, 131, 12552; p) R. J. Pawley, G. L. Moxham, R.
Dallanegra, A. B. Chaplin, S. K. Brayshaw, A. S. Weller, M. C.
Willis, Organometallics 2010, 29, 1717; q) C. Gonzꢀlez-Rodrꢁ-
guez, S. R. Parsons, A. L. Thompson, M. C. Willis, Chem. Eur. J.
2010, 16, 10950; r) M. C. Coulter, K. G. M. Kou, B. Galligan,
V. M. Dong, J. Am. Chem. Soc. 2010, 132, 16330; s) D. T. H.
Phan, K. G. M. Kou, V. M. Dong, J. Am. Chem. Soc. 2010, 132,
16354; t) S. R. Parsons, J. F. Hooper, M. C. Willis, Org. Lett.
2011, 13, 998; u) P. Lenden, P. M. Ylioja, C. Gonzꢀlez-Rodrꢁ-
guez, D. A. Entwistle, M. C. Willis, Green Chem. 2011, 13, 1980;
v) H.-J. Zhang, C. Bolm, Org. Lett. 2011, 13, 3900.
[5] For recent intermolecular Ru-catalyzed examples, see: a) S.
Omura, T. Fukuyama, J. Horiguchi, Y. Murakami, I. Ryu, J. Am.
Chem. Soc. 2008, 130, 14094; b) F. Shibahara, J. F. Bower, M. J.
Krische, J. Am. Chem. Soc. 2008, 130, 14120; c) V. M. Williams,
J. C. Leung, R. L. Patman, M. J. Krische, Tetrahedron 2009, 65,
5024.
[14] G. Minetto, L. R. Lampariello, M. Taddei, Synlett 2005, 2743.
10660 www.angewandte.org
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