A continuous-flow synthesis of annulated and polysubstituted furans from the reaction of ketones and α-haloketones

Article abstract of DOI:10.1016/j.tetlet.2011.09.083

A synthesis of di-, tri- and tetra-substituted furans from reaction of the corresponding ketones and α-haloketones with LiHMDS is reported. Reaction under continuous-flow conditions gave increased yields and removed the need for external cooling when comp

Full text of DOI:10.1016/j.tetlet.2011.09.083

Tetrahedron Letters 52 (2011) 6267–6270
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Tetrahedron Letters
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A continuous-flow synthesis of annulated and polysubstituted furans
from the reaction of ketones and a-haloketones
Mark York
CSIRO Materials Science and Engineering, Bag 10, Clayton South 3169, Australia
Cooperative Research Centre for Polymers, 8 Redwood Drive, Notting Hill 3168, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Revised 31 August 2011
Accepted 16 September 2011
Available online 22 September 2011
A synthesis of di-, tri- and tetra-substituted furans from reaction of the corresponding ketones and
a-
haloketones with LiHMDS is reported. Reaction under continuous-flow conditions gave increased yields
and removed the need for external cooling when compared to the unoptimised batch conditions.
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords:
Continuous flow
Furan
a-Haloketone
Annulated furan
The synthesis of substituted furans is an area of continuing
interest in organic chemistry due to the presence of the furan nu-
cleus in a wide variety of natural products, drugs and other mate-
rials of industrial and academic relevance.1–3
The performance of chemical transformations under continu-
ous-flow conditions (either on meso- or microscale) is an area of
intense current research. This interest can be explained, at least
in part, by a number of potential advantages that continuous-flow
processes have over traditional batch chemistry including the ease
of scaling, high reproducibility, rapid heat transfer and mixing and
inherently higher safety due to small reactor volumes and the con-
tainment of hazardous intermediates.4
the loss of water to give furan 5 (Scheme 2). A similar reaction se-
quence has been previously reported by Migita and co-workers,6
but this required the use of extended reaction times at elevated
temperatures and preformed tributyltin enolates, necessitating
the addition of a further reaction step and also the handling and
potentially problematic removal of toxic tin compounds.7 An elec-
trochemical method for the synthesis of 4-aryl-2-methyl furans,8 a
zinc-mediated method allowing the preparation of 2,4 symmetri-
cally substituted furan compounds,9 and a homo-coupling of
phenacyl bromides in the presence of sodium telluride,10 have also
been reported to proceed via a similar mechanism.
The results of the initial trial experiments on the reaction be-
During the course of our research into the synthesis and appli-
cation of photochromic dyes,5 we had reason to prepare a number
of polysubstituted furan compounds. For this purpose we investi-
tween phenacyl bromide and either
be seen in Table 1. When phenacyl bromide reacted with
a
-tetralone or acetone can
a-tetra-
lone at À78 °C the corresponding furan was isolated in 65% yield.
This was reduced to 46% when the cooling was removed (Table
1, entries 1 and 2). Similarly, the product derived from reaction
with acetone could also be isolated, albeit in very low yields for
both the cooled and room temperature reactions (Table 1, entries
3 and 4). No attempt to further optimise the batch reactions was
made.
In an attempt to increase the yields seen with the batch reac-
tions and avoid the need for external cooling, the process was at-
tempted under continuous-flow conditions using a commercially
available flow reactor (Vapourtec). In this way a 2 M solution of ke-
tone in toluene (from a vessel containing a stock solution) and a
commercially available 1 M solution of LiHMDS in THF were com-
bined at ambient temperature and the resulting reagent stream
passed through a 10 mL flow coil to enable complete formation
gated the reaction between ketones 1 and a-haloketones 2 in the
presence of lithium bis(trimethylsilyl)amide (LiHMDS) with the
object of isolating not the perhaps expected 1,4-diketone com-
pound 3, or the corresponding furan 4, but furan product 5
(Scheme 1). Such a route would give furans with complementary
functionality to that seen using the standard 1,4-diketone method.
The formation of 5 can be thought of as occurring through an
initial addition of the enolate 6 derived from ketone 1 with
a-
haloketone 2 to give alkoxy adduct 7. This can then cyclise with
the loss of lithium bromide to the corresponding epoxide 8 which
is ring-opened by an intramolecular reaction with the carbonyl
oxygen to furnish dihydrofuran 9. This can then aromatise with
E-mail address: mark.york@csiro.au
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.083

6268
M. York / Tetrahedron Letters 52 (2011) 6267–6270
Scheme 1. Synthetic route to polysubstituted furan compounds.
Scheme 2. Proposed mechanism of formation for polysubstituted furan compounds.
Table 1
Batch mode synthesis of polysubstituted furan compounds
Entry
a-Haloketone
Ketone
Product
Yielda (%)
1
2
65b
46c
3
4
12b
6c
a
A solution of ketone (0.81 g, 5.53 mmol) in toluene (15 mL) was treated dropwise with a solution of LiHMDS (1 M in THF, 5.53 mL, 5.53 mmol) and stirred for 15 min.
Phenacyl bromide (1.00 g, 5.02 mmol) in THF (20 mL) was then added dropwise and stirring continued for 30 min. The mixture was quenched by the addition of H2O (30 mL),
the organic phase separated, dried (MgSO4) and evaporated in vacuo, the residue being purified by column chromatography eluting with 0–5% v/v EtOAc/petroleum ether.
b
Reaction performed at À78 °C.
c
Reaction performed at 22 °C.
Scheme 3. Experimental set-up for the flow synthesis of furans.
of the desired enolate. The material exiting this coil was then com-
bined with a further reagent stream consisting of a 1.4 M solution
of a-haloketone in THF (from a vessel containing a stock solution,
injection time delayed so as to coincide with the enolate stream)
and the mixture passed through a further two 10 mL flow coils be-
fore quenching and purification of the products (Scheme 3).11 The
total residence time for the reagents was approximately nine min-
The results of the continuous-flow synthesis of a number of
polysubstituted furans can be seen in Table 2. Even when per-
formed at ambient temperature the flow reactions gave consider-
able improvements in yield when compared to the unoptimised
batch reactions which required cooling at À78 °C (Table 2, entries
1 and 2 vs Table 1, entries 2 and 4). The majority of products were
isolated in fair to good yields with purification by column chroma-
tography simplified by the fact that in all cases the product furan
was the least polar, highest running component of the mixture.
utes, reaction at this rate equating to an
of 1.4 mmol per minute.
a-haloketone throughput

M. York / Tetrahedron Letters 52 (2011) 6267–6270
6269
Table 2
Continuous-flow synthesis of polysubstituted furan compounds
Entry
1
a-Haloketone
Ketone
Product
Yield (%)
75
25
2
3
47
43
52
4
5
6
0
7
22a (9:1)
8
15
51
23
32
9
10
11
12
80
a
Reaction produced a 9:1 mixture of regioisomers. Major isomer shown.
Examination of the reaction mixtures by 1H NMR and TLC prior to
chromatographic purification showed the presence of unreacted
starting materials and decomposed baseline material in addition
this methodology by the use of either cyclic ketones (Table 2, en-
tries 1, 5, 9 and 12) or cyclic a-haloketones (Table 2, entry 4). An
aromatic halogen substituent was tolerated in the reaction giving
the desired furan, albeit in low yield (Table 2, entry 10).
In summary a synthesis of polysubstituted furan compounds
to the expected products. Although
in the reaction they gave significantly lower yields than the corre-
sponding -bromoketone (Table 2, entry 1 vs entry 8). An attempt
a-chloroketones could be used
a
from the reaction of a ketone and a-haloketone in the presence
to replace the ketone reaction partner with an aldehyde did not
give any isolable amounts of the corresponding furan (Table 2, en-
try 6). Annulated furans are often used as building blocks in natural
product synthesis,2 and such compounds can be readily made with
of LiHMDS has been developed. The performance of the reactions
under continuous-flow gave increased yields of the desired prod-
ucts compared to reactions performed in batch-mode and removed
the need for external cooling (although optimisation of the batch

6270
M. York / Tetrahedron Letters 52 (2011) 6267–6270
5. (a) Evans, R. A.; York, M. Tetrahedron Lett. 2010, 51, 2195–2197; (b) Ali, A.;
Campbell, J. A.; Evans, R. A.; Malic, N.; York, M. Macromolecules 2010, 43, 8488–
8501; (c) Evans, R. A.; Hanley, T. L.; Skidmore, M. A.; Davis, T. P.; Such, G. K.;
Yee, L. H.; Ball, G. E.; Lewis, D. A. Nat. Mater. 2005, 4, 249–253; (d) Evans, R. A.;
York, M. Synth. Commun. 2010, 40, 3618–3628.
reactions was not attempted). The reaction gives ready access to a
large number of furan products from the wide range of commer-
cially available ketone and a-haloketone building blocks.
6. Kosugi, M.; Takano, I.; Hoshino, I.; Migita, T. J. Chem. Soc., Chem. Commun. 1983,
989–990.
Acknowledgements
7. Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072–3082.
8. Barba, F.; de la Fuente, J. L. Tetrahedron Lett. 1992, 33, 3911–3914.
9. Li, L.; Cai, P.; Guo, Q.; Xue, S. J. Org. Chem. 2007, 72, 8131–8134.
10. Padmanabhan, S.; Ogawa, T.; Suzuki, H. Bull. Chem. Soc. Jpn. 1989, 62, 2114–
2116.
The author thanks the Co-operative Research Centre for Poly-
mers and CSIRO Materials Science and Engineering for their
support.
11. Experimental Procedure. A solution of acetone (2 M in toluene, 4.62 mL of a
25 mL stock solution, 9.24 mmol) pumped at a rate of 0.76 mL minÀ1 was
mixed at ambient temperature with a solution of LiHMDS (1 M in THF, 9.24 mL,
9.24 mmol) pumped at a rate of 1.54 mL minÀ1 via a T-piece and passed
through a 10 mL reactor coil (PFA tubing, 1 mm i.d.). The eluent stream was
then mixed with a solution of phenacyl bromide (1.4 M in THF, 6.00 mL of a
50 mL stock solution, 8.4 mmol) pumped at a rate of 1 mL minÀ1 via a T-piece
(injection time delayed so as to coincide with the enolate stream) and passed
through two 10 mL reactor coils (PFA tubing, 1 mm i.d.). The flow solvent was
toluene. The eluent stream was collected in a flask containing H2O (20 mL),
shaken and the organic phase separated, washed with H2O (20 mL), dried
(MgSO4) and evaporated in vacuo, The residue was then purified by column
chromatography eluting with 0–5% v/v EtOAc/petroleum ether to give 2-
methyl-4-phenylfuran as a white solid (0.33 g, 25%). The product gave a good
spectral comparison with the data previously reported.12
Supplementary data
Supplementary data (experimental procedures and data for all
new compounds) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.09.083.
References and notes
1. Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, third ed.; Chapman and
Hall, 1995. pp. 278–300.
2. Shipman, M. Contemp. Org. Synth. 1995, 2, 1–17.
3. Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H.
N. C. Tetrahedron 1998, 54, 1955–2020.
12. Pri-Bar, I.; Pearlman, P. S.; Stille, J. K. J. Org. Chem. 1983, 48, 4629–4634.
4. For recent reviews, see: (a) Yoshida, J.; Kim, H.; Nagaki, A. ChemSusChem 2011,
4, 331–340; (b) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680; (c)
Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47, 4583–4592.