A sulfone-based strategy for the preparation of 2,4-disubstituted furan derivatives

Article abstract of DOI:10.1021/jo201529s

2,4-Disubstituted furans are prepared by treating 2,3-dibromo-1- phenylsulfonyl-1-propene (DBP, 2) with 1,3-diketones under basic conditions. The furan-forming step involves a deacetylation, and the selectivity of this process depends upon the steric demand of the R group. The substituent in position 4 is elaborated by reaction of sulfonyl carbanions with alkyl halides, acyl halides, and aldehydes. Oxidative or reductive desulfonylation produces the 2,4-disubstituted furans in 60-92% yield. This strategy has been used to prepare rabdoketone A (12) and the naturally occurring nematotoxic furoic acid 13. (Figure presented)

Full text of DOI:10.1021/jo201529s

NOTE
pubs.acs.org/joc
A Sulfone-Based Strategy for the Preparation of 2,4-Disubstituted
Furan Derivatives
Nathan R. Haines, Aaron N. VanZanten, Anthony A. Cuneo, John R. Miller, William J. Andrews,
David A. Carlson, Ryan M. Harrington, Adam M. Kiefer, Jeremy D. Mason, Julie A. Pigza, and S. Shaun Murphree*
Department of Chemistry, Allegheny College, Meadville, Pennsylvania 16335, United States
S Supporting Information
b
ABSTRACT: 2,4-Disubstituted furans are prepared by treating 2,3-
dibromo-1-phenylsulfonyl-1-propene (DBP, 2) with 1,3-diketones
under basic conditions. The furan-forming step involves a deacetyla-
tion, and the selectivity of this process depends upon the steric
demand of the R group. The substituent in position 4 is elaborated
by reaction of sulfonyl carbanions with alkyl halides, acyl halides, and
aldehydes. Oxidative or reductive desulfonylation produces the
2,4-disubstituted furans in 60À92% yield. This strategy has been
used to prepare rabdoketone A (12) and the naturally occurring
nematotoxic furoic acid 13.
he furan moiety enjoys wide-ranging eminence in the realm
T
of organic synthesis.1 Furans serve as the basis for many
pharmacophores, and furan-containing natural products con-
tinue to captivate the imagination of synthetic chemists, as
demonstrated by two recently reported independent syntheses
of the marine alkaloid (À)-nakadomarin A.2,3 Furans also
serve as useful synthetic intermediates, finding utility as masked
α,β-unsaturated esters4 and precursors to hydroxypyranones5
and polyoxygenated natural products,6 as well as mono- and
oligosaccharides.7 The furan substructure is also an increasingly
important motif in materials chemistry, providing promising
plastics derived from renewable sources,8 self-healing macromo-
lecular materials,9 conducting polymers,10 and photovoltaics.11
Consequently, the synthesis of furans has received considerable
attention in the literature.12
Figure 1. Synthetic approaches to 2,4-disubstituted furans.
One continuing challenge among existing preparative meth-
ods is general access to the 2,4-disubstituted derivatives, which
are widely distributed in nature. Representatives of this class include
methanofuran, a cofactor found in methanogenic microbes,13
flufuran, an antifungal compound produced by Aspergillus flavus,14
proximicins AÀC, unusual DNA-binding oligomers isolated from a
marine actinomycete,15 several antiviral and anti-inflammatory
metabolites from soft coral,16 andelymniafuran, a scentcomponent
of the butterfly Elymnias thryallis.17
2-alkynylallyl alcohols (path g) promoted by gold(I) catalysts
bearing carbene ligands26 or as intermediates in the PdII-
mediated reaction between alkynes and alkynoates,27 the gold-
catalyzed dehydrative cyclization of 3-alkyne-1,2-diols (path
h),28 the phosphine-mediated reductive condensation of γ-
acyloxy butynoates (path i),29 and the cyclocondensation of γ-
hydroxy ynones (path j) in the presence of sodium chloride and
p-toluenesulfonic acid.30 The cine substitution of 2-nitrofuran
derivatives has also been used to access this architecture.31 While
these protocols represent stalwart advances in the preparation of
2,4-disubstituted furans, there are still opportunities to design
methods with more easily accessible precursors and with greater
Previous routes to the 2,4-disubstituted furans18 include the
isomerization of alkynyl oxiranes (Figure 1, path a) using potas-
sium tert-butoxide,19 silver(I),20 and gold(I)21 catalysts; the p-
toluenesulfonic acid mediated rearrangement of benzotriazolyl
vinyl epoxides (path b)18 or β-epoxyketones (path c),22 the acid-
catalyzed cyclization of hydroxyenals (path d),23 the cycloisome-
rizationof allenals (path e) using silver(I) or rhodium,;24 the gold-
catalyzed dimerization of allenones (path f),25 the cyclization of
Received: July 28, 2011
Published: August 20, 2011
r
2011 American Chemical Society
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NOTE
Scheme 1. Sulfone-Mediated Conversion of β-Diketone to
Furan
Table 1. Elaboration of the Furan 4-Substituent
amt of nBuLi
entry
electrophile
benzyl bromide
(equiv)
product yield (%)
1
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
2.05
2.05
2.05
6a
6b
6c
6d
6e
6f
81
54
67
64
70
75
71
46
53
56
54
79
90
58
2
allyl bromide
3
3-chloro-2-methylpropene
tert-butyl bromoacetate
bromoethane
4
5
6
1-bromo-2-methylpropane
2-(bromoethyl)benzene
2-bromopropane
flexibility in the range of substituents; thus, additional contribu-
tions are of general interest to the synthetic community.
In connection with investigations into the unique reactivity
of the crystalline, shelf-stable sulfone reagent 2,3-dibromo-
1-(phenylsulfonyl)-1-propene (DBP, 2),32 2,4-pentanedione (1)
was found to react with DBP under basic conditions to give the
diketone 3a via additionÀelimination (Scheme 1). Under non-
nucleophilic conditions, this adduct cyclizes to form a trisubsti-
tuted furan;33 however, when sodium methoxide is used as a base,
intermediate 3a undergoes a sequence of deacetylation, O-alky-
lative ring closure, and double-bond migration to provide the
2,4-disubstituted sulfonyl furan 5.34 Since the formation of furans
from β-diketones is unusual, we considered this novel result
worthy of further investigation to develop the method into a
general preparative route for 2,4-disubstituted furans.
7
6g
6h
6i
8
9
benzaldehyde
10
11
12
13
14
pivaldehyde
6j
trans-crotonaldehyde
trimethylacetyl chloride
benzoyl chloride
6k
6l
6m
6n
acetyl chloride
Scheme 2. Selectivity in Deacetylation of Initial Adduct 3
We first turned our attention to the elaboration of the sub-
stituent at the 4-position. Since the alkylation of sulfonyl carba-
nions is well-established, we explored the reactivity of the sulfone-
stabilized anion derived from furan 5. Indeed, treatment of 5 with a
slight excess of n-butyllithium at À78 °C led to smooth deproto-
nation, and the corresponding carbanion reacted with electro-
philes to produce furan derivatives in fair to very good yields
(Table 1). This procedure accommodates both alkyl halides
(entries 1À8) and aldehydes (entries 9À11). Acyl chlorides can
also be used (entries 12À14); however, it is necessary to generate
the dianion of furan 5 in these cases.
Generality at the furan 2-position is a somewhat more subtle
issue. Since this substituent is determined by the starting
β-diketone, architectural flexibility at this location involves
two key considerations: (a) access to the starting materials and
(b) selectivity in the deacylation step (i.e., 3a to 4). For furan 5,
both considerations are trivial: 2,4-pentanedione is readily avail-
able and its symmetry renders the issue of deacylation selectivity
moot. However, relying on symmetrical diketones is limiting at
best, as few routes to symmetrical β-diketones exist; moreover,
for complex substrates, discarding half of the hard-won substi-
tuent is inefficient. We therefore focused our efforts on non-
symmetrical diketones, specifically methyl β-diketones.
Access to methyl β-diketones can be achieved through a
variety of methods, including the monoalkylation of 2,4-
pentanedione,35 the acetylation of methyl ketones,36 and the
acylation and subsequent Krapcho decarboxylation of ethyl
acetoacetate.37 The question remained as to the ability of
methoxide to discriminate between the two carbonyls of the
adduct, although similar selectivity in the cleavage of methyl
β-diketones had been reported.38
We began with 2,4-hexanedione (7a), in which the symmetry
has been broken by substituting an ethyl group for a methyl
substituent. Encouragingly, treatment with DBP (2) under
standard reaction conditions led to a 3:1 mixture of furans 9
and 5, arising from intermediate loss of an acetyl group (via 8)
and a propionyl group (via 4), respectively (Scheme 2). Although
the selectivity in this example is somewhat modest, we consid-
ered such a level of discrimination promising in light of the
similarity between the two substituents.
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NOTE
Table 2. Generality at the Furan 2-Position
a Molar ratio determined from crude reaction mixture by 1H NMR (see the Experimental Section)
We thus examined a series of substrates to explore the
influence of substituent identity. We were gratified to observe
that as the complexity of the R group increased, so too did the
selectivity of deacylation, as shown in Table 2. Generally speak-
ing, longer chains give higher selectivity (9d vs 9a), although
terminal unsaturation tends to diminish this effect (e.g., 9b,c),
presumably by privileging chain-extended conformers and there-
by minimizing steric impact adjacent to the carbonyl. The most
dramatic results are achieved by introducing branching, with
a greater than 20:1 selectivity observed with a β-methyl group
(i.e., 9f) and an almost 40:1 ratio resulting from α-branching
(i.e., 9g). The procedure is tolerant to aromatic substituents, as
demonstrated by benzoylacetone (entry 8).
Scheme 3. Reductive Desulfonylation of Sulfonyl Furan
(entry 7) and the marked decrease in selectivity for the benzoyl
group (entry 8).
To further demonstrate the potential of this methodology, we
examined the desulfonylation of select substrates. For example,
the benzyl derivative 6a was reductively desulfonylated with
sodium metal in a mixed medium of ethanol and THF40 to provide
2-methyl-4-phenethylfuran (10) in excellent yield (Scheme 3).
With acylated furans, the sulfonyl group can be removed
conveniently using samarium(II) iodide.41 Thus, the combina-
tion of acetyl derivative 6n with 2.6 equiv of SmI2 in THF at
À78 °C resulted in rapid desulfonylation to give 2-methyl-
4-acetonylfuran (11) in 62% yield (Scheme 4).
Oxidative methods can also be used to advantage. For example,
the isobutyl derivative 6f was deprotonated with n-butyllithium
and treated with dimethoxyboron chloride.49 The resulting di-
methylboronate intermediate was oxidized with m-chloroperbenzoic
acid to give a labile α-hydroxysulfone, which rapidly decomposed
with the ejection of phenylsulfinate anion, thus converting the
sulfone moiety into a ketone.42 This methodology proceeded in
The origin of this regioselectivity has not been established, but
the results would indicate a steric bias in favor of nucleophilic
attack at the methyl ketone moiety. Another potential factor
could be the degree of enolization at each center. In similar AdN
reactions involving α-diketones, Gewald and co-workers39 in-
voked reaction at the less enolized ketone group. While this could
also be operative in the present system, the constrained environ-
ment about the diketone locus in adducts of type 3 would be
expected to inhibit the coplanarity required for enolization, an
assumption supported by the observation that 3a exhibits only
1
one methyl signal in the H NMR spectrum.34 The electronic
impact of the substituents may also come into play, modulating
the inherent electrophilicity of the ketone moieties. This might
contribute to the enhanced selectivity for isopropyl ketones
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NOTE
Scheme 4. Reductive Desulfonylation of α-Ketosulfonyl
Furan
2-Methyl-4-(2-phenyl-1-(phenylsulfonyl)ethyl)furan (6a). Prepared
on a 6.2 mmol scale. Recrystallization (diethyl ether) gave 6a (1.30 g,
64%) as a light yellow solid (mp 102À104 °C). Chromatography
(20% EtOAc in hexane) of the supernatant provided additional product
1
(335 mg, 17%), for a combined yield of 81%. H NMR (400 MHz,
CDCl3): δ 7.72 (d, J = 8.1 Hz, 2H), 7.60 (t, J = 7.0 Hz, 1H), 7.47 (t, J =
7.7 Hz, 2H), 7.10À7.22 (m, 3H), 7.02 (d, J = 7.3 Hz, 2H), 6.75 (s, 1H),
6.05 (s, 1H), 4.13 (dd, J = 11.7, 2.6 Hz, 1H), 3.68 (dd, J = 13.7, 2.6 Hz,
1H), 3.09 (dd, J = 13.4, 11.9 Hz, 1H), 2.21 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 153.1, 141.2, 137.2, 136.9, 133.8, 129.2, 129.1, 128.8, 128.5,
126.9, 117.4, 106.4, 64.8, 33.8, 13.7. Anal. Calcd for C19H18O3S: C, 69.9;
H, 5.6. Found: C, 69.9; H, 5.5.
Scheme 5. Oxidative Desulfonylation to Furoketone;
Synthesis of Rabdoketone A
2-Methyl-4-(1-(phenylsulfonyl)but-3-enyl)furan (6b). Prepared on a
0.92 mmol scale. Chromatography (30% EtOAc in hexane) provided 6b
(137 mg, 54%) as a viscous oil. 1H NMR (400 MHz, CDCl3):
δ 7.54À7.68 (m, 3H), 7.43 (t, J = 7.9 Hz, 2H), 6.89 (s, 1H), 5.94
(s, 1H), 5.57 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.04 (ddt, J = 17.1, 1.5,
1.5 Hz, 1H), 4.98 (ddt, J = 10.2, 1.5, 1.1 Hz, 1H), 3.98 (dd, J = 11.6,
3.7 Hz, 1H), 2.99 (dddt, J = 14.2, 7.0, 3.7, 1.1 Hz, 1H), 2.59 (dddt,
J = 14.2, 11.6, 7.0, 1.1 Hz, 1H), 2.20 (d, J = 0.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 153.1, 141.0, 137.0, 133.7, 133.1, 129.2, 128.8,
118.5, 117.5, 106.4, 62.8, 32.0, 13.6. HRMS: calcd for C15H16O3S
276.0820, found 276.0808.
Scheme 6. Oxidative Desulfonylation to Furoic Acid
2-Methyl-4-(3-methyl-1-(phenylsulfonyl)but-3-enyl)furan (6c). Pre-
pared on a 1.28 mmol scale. Chromatography (25% EtOAc in hexane)
provided 6c (250 mg, 67%) as a white solid (mp 53À56 °C). 1H NMR
(400 MHz, CDCl3): δ 7.53À7.67 (m, 3H), 7.42 (t, J = 7.9 Hz, 2H), 6.88
(s, 1H), 5.92 (s, 1H), 4.70 (dt, J = 1.5, 1.1 Hz, 1H), 4.61 (s, 1H),
4.11 (dd, J = 12.1, 3.3 Hz, 1H), 2.96 (d, J = 14.3 Hz, 1H), 2.55 (dd,
J = 14.3, 12.1 Hz, 1H), 2.18 (d, J = 0.7 Hz, 3H), 1.58 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 152.9, 141.0, 140.1, 137.0, 133.7, 129.2, 128.8,
117.6, 114.1, 106.4, 61.8, 35.4, 22.1, 13.6. Anal. Calcd for C16H18O3S: C,
66.2; H, 6.3. Found: C, 66.1; H, 6.3.
60% overall yield to provide access to rabdoketone A (12), a
component of Rabdosia eriocalyx extract used in traditional
Chinese medicine for its antiedemic properties43 (Scheme 5)
Finally, the unsubstituted phenylsulfonylmethyl group can be
converted to a carboxylic acid moiety using an unprecedented
aerobic oxidative desulfonylation technique. The method involves
formation of the dianion using 2 equiv of lithium hexamethyldi-
silazide, followed by sparging with dry oxygen or air. The initial
oxygen adduct spontaneously decomposes with the ejection of
phenylsulfinate ion to yield the carboxylic acid, which is separated
from the phenylsulfinate through pH-controlled extraction.44 In
this way, furan 5 was converted in 88% yield to the methylfuroic
acid 13, a natural product which has been shown to exhibit
nematotoxic activity in the vegetative hyphae of Coprinus comatus45
(Scheme 6)
tert-Butyl 3-(5-Methylfuran-3-yl)-3-(phenylsulfonyl)propanoate (6d).
Prepared on a 0.87 mmol scale. Chromatography (25% EtOAc in hexane)
1
provided 6d (195 mg, 64%) as a buff solid (mp 71À73 °C). H NMR
(400 MHz, CDCl3): δ 7.54À7.66 (m, 3H), 7.43 (t, J = 7.7 Hz, 2H), 6.93
(s, 1H), 5.93 (s, 1H), 4.45 (dd, J = 10.5, 4.4 Hz, 1H), 3.14 (dd, J = 15.8,
4.4 Hz, 1H), 2.68 (dd, J = 15.8, 10.5 Hz, 1H), 2.18 (d, J = 0.7 Hz, 3H), 1.29
(s, 9H). 13C NMR (100 MHz, CDCl3): δ 168.6, 153.1, 140.6, 136.5, 134.0,
129.3, 128.9, 117.6, 106.4, 81.8, 59.5, 34.7, 27.9, 13.6. Anal. Calcd for
C18H22O5S: C, 61.7; H, 6.3. Found: C, 61.3; H, 6.3.
2-Methyl-4-(1-(phenylsulfonyl)propyl)furan (6e). Prepared on a
0.84 mmol scale. Chromatography (20% EtOAc in hexane) provided
6e (155 mg, 70%) as a buff solid (mp 58À60 °C). 1H NMR (400 MHz,
CDCl3): δ 7.42À7.69 (m, 5H), 6.92 (s, 1H), 5.95 (s, 1H), 3.82 (dd, J =
11.5, 3.5 Hz, 1H), 2.30 (dqd, J = 13.5, 7.4, 3.5 Hz, 1H), 2.23 (d, J =
0.7 Hz, 3H), 1.85 (ddq, J = 13.5, 11.5, 7.4 Hz, 1H), 0.90 (t, J = 7.3 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 153.2, 141.0, 137.3, 133.6,
129.2, 128.7, 117.7, 106.2, 64.8, 21.0, 13.6, 11.6. Anal. Calcd for
C14H16O3S: C, 63.6; H, 6.1. Found: C, 63.3; H, 6.1.
In conclusion, we have developed a convenient methodology
for the synthesis of 2,4-disubstituted furans which utilizes easily
accessible alkane-2,4-diones as starting materials. The present
protocol is quite flexible and complementary to existing methods.
’ EXPERIMENTAL SECTION
2-Methyl-4-(3-methyl-1-(phenylsulfonyl)butyl)furan (6f). Prepared
on a 1.5 mmol scale. Chromatography (25% EtOAc in hexane) provided
6f (330 mg, 75%) as a light brown solid (mp 94À97 °C). 1H NMR (400
MHz, CDCl3): δ 7.66 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.51 Hz, 1H), 7.45
(d, J = 7.9 Hz, 2H), 7.25 (s, 1H), 6.89 (s, 1H), 3.98 (dd, J = 11.35,
4.03 Hz, 1H), 2.23 (s, 3H), 1.84À1.99 (m, 2H), 1.43À1.56 (m, 1H),
0.91 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 153.1, 140.8, 137.3, 133.5, 129.2, 128.7, 118.0, 106.3, 61.8,
35.7, 25.3, 23.6, 20.8, 13.6. Anal. Calcd for C16H20O3S: C, 65.7; H, 6.9.
Found: C, 65.8; H, 6.8.
Conversion of 5 to 6 (General Procedure). 2-Methyl-4-
[(phenylsulfonyl)methyl]furan (532) in THF (5.5 mL/mmol 5) was
cooled to À78 °C and treated with 2.35 M n-butyllithium in hexanes
(1.05 equiv). After the mixture was stirred for 15 min at À78 °C, the
electrophile (1.05 equiv) was added dropwise. The mixture was stirred
for 5 min at À78 °C, warmed to room temperature, and stirred another
12 h. Saturated aqueous ammonium chloride (3 mL) was added, and the
THF was removed in vacuo. The residue was dissolved in dichloro-
methane (50 mL) and washed with water (50 mL). The aqueous phase
was extracted with dichloromethane (2 Â 25 mL). The combined
organic portions were dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography, except
where noted otherwise.
2-Methyl-4-(3-phenyl-1-(phenylsulfonyl)propyl)furan (6g). Pre-
pared on a 0.89 mmol scale. Chromatography (20% EtOAc in
hexane) provided 6g (215 mg, 71%) as a light yellow viscous oil.
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NOTE
1H NMR (400 MHz, CDCl3): δ 7.53À7.66 (m, 3H), 7.42 (t, J = 7.9 Hz,
2H), 7.15À7.29 (m, 3H), 7.07 (d, J = 7.0 Hz, 2H), 6.96 (s, 1H), 6.00 (s,
1H), 3.92 (dd, J = 11.4, 3.3 Hz, 1H), 2.73 (ddd, J = 13.1, 8.3, 4.7 Hz, 1H),
2.59 (dtd, J = 13.1, 8.1, 3.3 Hz, 1H), 2.48 (dt, J = 13.2, 8.1 Hz, 1H), 2.26 (s,
3H), 2.19 (dddd, J = 13.2, 11.4, 8.3, 4.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 153.4, 141.2, 140.1, 137.2, 133.7, 129.2, 128.8, 128.7, 128.5,
126.4, 117.7, 106.3, 62.3, 32.5, 29.0, 13.7. Anal. Calcd for C20H20O3S: C,
70.6; H, 5.9. Found: C, 70.6; H, 6.0.
(33% EtOAc in hexane) provided 6l (239 mg, 79%) as a light yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.54À7.67 (m, 3H), 7.42 (t, J = 7.7 Hz,
2H), 6.97 (s, 1H), 5.93 (s, 1H), 5.50 (s, 1H), 2.19 (s, 3H), 1.09 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 206.0, 153.4, 141.5, 136.4, 134.0,
130.4, 128.3, 115.3, 106.9, 67.1, 46.0, 26.0, 13.6. Anal. Calcd for
C17H20O4S: C, 63.7; H, 6.3. Found: C, 63.5; H, 6.2.
2-(5-Methylfuran-3-yl)-1-phenyl-2-(phenylsulfonyl)ethanone (6m).
The dianion of 2-methyl-4-[(phenylsulfonyl)methyl]furan was added
to benzoyl chloride using the general procedure on a 2.1 mmol scale.
Chromatography (33% EtOAc in hexane) provided 6m (650 mg, 90%) as
a viscous oil. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 7.3 Hz, 2H),
7.69 (d, J = 7.3 Hz, 2H), 7.52À7.62 (m, 2H), 7.39À7.47 (m, 4H), 7.19
(s, 1H), 6.10 (s, 1H), 6.09 (s, 1H), 2.21 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 190.9, 153.2, 142.0, 136.3, 136.1, 134.2, 130.3, 129.1, 129.0,
128.9, 128.5, 114.7, 107.3, 68.0, 13.6. HRMS: calcd for C19H16O4S :
341.0848 (M + 1), found 341.0851.
2-Methyl-4-(2-methyl-1-(phenylsulfonyl)propyl)furan (6h). Prepared
on a 0.88 mmol scale. Chromatography (20% EtOAc in hexane) provided
1
6h (113 mg, 46%) as a viscous oil. H NMR (400 MHz, CDCl3):
δ 7.49À7.68 (m, 3H), 7.40 (t, J = 7.9 Hz, 2H), 6.94 (s, 1H), 6.05 (s, 1H),
3.77 (d, J = 5.1 Hz, 1H), 2.76 (septd, J = 6.8, 5.1 Hz, 1H), 2.21 (s, 3H),
1.10 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 152.6, 141.3, 138.9, 133.3, 128.7, 128.6, 116.2, 107.7, 68.5,
27.5, 22.1, 19.3, 13.6. Anal. Calcd for C15H18O3S: C, 64.7; H, 6.5. Found:
C, 64.9; H, 6.6.
1-(5-Methylfuran-3-yl)-1-(phenylsulfonyl)propan-2-one (6n). The
dianion of 2-methyl-4-[(phenylsulfonyl)methyl]furan was added to acetyl
chloride using the general procedure on a 1.5 mmol scale. Chromatog-
raphy (25% EtOAc in hexane) provided 6n (240 mg, 58%) as a buff solid
(mp 65À67 °C). 1H NMR (400 MHz, CDCl3): δ 7.57À7.65 (m, 3H),
7.45 (t, J = 8.1 Hz, 2H), 7.12 (s, 1H), 6.03 (s, 1H), 5.11 (s, 1H), 2.43
(s, 3H), 2.22 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 198.0, 153.2,
141.6, 136.1, 134.3, 129.8, 128.7, 113.9, 107.0, 73.2, 31.5, 13.5. Anal.
Calcd for C14H14O4S: C, 60.4; H, 5.1. Found: C, 60.0; H, 5.0.
General Procedure for Conversion of Alkane-2,4-diones
into 2,4-Disubstituted Furans (9). The 1,3-diketone (0.74 mmol)
was dissolved in anhydrous methanol (3.75 mL) and cooled to 0 °C. The
solution was treated dropwise with 0.5 M methanolic sodium methoxide
(1.76 mL, 0.88 mmol), warmed to room temperature, and stirred for
20 min. After the anion solution was cooled to 0 °C, (E)-2,3-dibromo-
1-(phenylsulfonyl)-1-propene (250 mg, 0.74 mmol) was added in
one portion. The reaction mixture was warmed to room temperature
and stirred until TLC indicated the disappearance of starting material
(4À7 h). The mixture was cooled to 0 °C and treated dropwise with
0.5 M methanolic sodium methoxide (2.06 mL, 1.03 mmol). After it
was warmed to room temperature, the mixture was stirred for 12 h
and quenched with saturated aqueous ammonium chloride (3 mL).
Methanol was removed in vacuo, and the residue was partitioned
between equal portions of water and dichloromethane (40 mL). The
aqueous phase was further extracted with dichloromethane (2 Â
15 mL). The combined organic layers were washed with water
(30 mL), dried over sodium sulfate, and concentrated in vacuo to
provide the crude product. Deacylation ratios were determined by
comparing the integrals of the methyl group in 5 (2.23 ppm) with the
corresponding protons in 9aÀg. For 9h, the furan proton at 6.56
ppm was compared to the furan proton for 5 at 5.92 ppm. The desired
product was separated from furan 5 using chromatography.
2-(5-Methylfuran-3-yl)-1-phenyl-2-(phenylsulfonyl)ethanol (6i). Pre-
pared on a 3.7 mmol scale to give 6i as a 2:1 mixture of diastereomers
(determined by integration of 1H NMR). Chromatography (33% EtOAc
in hexane) provided the pure major isomer (674 mg, 53%) as a light
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.42À7.72 (m, 5H),
7.15À7.24 (m, 5H), 6.62 (s, 1H), 5.77 (s, 1H), 5.49 (d, J = 9.5 Hz,
1H), 4.54 (br s, 1H), 4.31 (d, J = 9.5 Hz, 1H), 2.08 (d, 0.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 152.7, 141.1, 139.8, 137.5, 134.1, 129.1,
128.9, 128.3, 128.2, 127.3, 116.0, 106.5, 73.6, 69.4, 13.4. Anal. Calcd for
C19H18O4S: C, 66.7; H, 5.3. Found: C, 66.5; H, 5.3.
3,3-Dimethyl-1-(5-methylfuran-3-yl)-1-(phenylsulfonyl)butan-2-ol
(6j). Prepared on a 0.42 mmol scale to give 6j as a 4:1 mixture of
diastereomers (determined by integration of 1H NMR). Chromatogra-
phy (25% EtOAc in hexane) provided the pure major isomer (76 mg,
56%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 7.3 Hz,
2H), 7.55 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.11 (s, 1H), 5.95
(s, 1H), 4.38 (d, J = 1.1 Hz, 1H), 4.12 (d, J = 1.1 Hz, 1H), 2.93 (br s, 1H),
2.16 (s, 3H), 0.80 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 152.2, 142.0,
137.0, 133.8, 129.1, 128.8, 115.0, 108.6, 74.5, 64.6, 36.1, 26.7, 13.4. Anal.
Calcd for C17H22O4S: C, 63.3; H, 6.9. Found: C, 63.5; H, 6.7.
(E)-1-(5-Methylfuran-3-yl)-1-(phenylsulfonyl)pent-3-en-2-ol (6k). Pre-
pared on a 0.42 mmol scale to give 6k as a 4:1 mixture of diastereomers
(determined by integration of 1H NMR). Chromatography (25% EtOAc
in hexane) provided the pure major isomer (70 mg, 54%) as a viscous oil.
1H NMR (400 MHz, CDCl3): δ7.63 (d, J = 7.0 Hz, 2H), 7.58 (t, J = 7.3 Hz,
1H), 7.43 (t, J = 7.7 Hz, 2H), 6.84 (s, 1H), 5.83 (s, 1H), 5.73 (dqd, J = 15.0,
6.6, 1.1 Hz, 1H), 5.29 (ddq, J = 15.2, 6.6, 1.7 Hz, 1H), 4.89 (t, J = 7.7 Hz,
1H), 4.05 (d, J = 8.4 Hz, 1H), 3.94 (br s, 1H), 2.18 (s, 3H), 1.57 (d, J =
6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 153.0, 141.2, 137.4, 134.0,
129.7, 129.1, 129.0, 128.8, 115.9, 106.7, 70.8, 68.3, 17.8, 13.6. Anal. Calcd for
C16H18O4S: C, 62.7; H, 5.9. Found: C, 62.7; H, 6.0.
2-Ethyl-4-(phenylsulfonylmethyl)furan (9a). 2,4-Hexanedione46 was
converted on a 0.44 mmol scale. Chromatography was carried out twice
(30% EtOAc in hexane) to provide 9a (60 mg, 55%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 2H), 7.62 (t, J =
7.0 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.05 (s, 1H), 5.89 (s, 1H), 4.12
(s, 2H), 2.57 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 159.0, 141.0, 133.8, 129.1, 129.0, 128.7, 113.0,
106.1, 53.8, 21.4, 12.1. HRMS: calcd for C13H14O3S 250.0664, found
250.0658.
2-(But-3-enyl)-4-(phenylsulfonylmethyl)furan (9b). 7-Octene-2,4-
dione47 was converted as described in the general procedure. Chro-
matography (20% EtOAc in hexane) provided 9b (140 mg, 69%) as a
viscous yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.3 Hz,
2H), 7.62(t, J = 7.5Hz, 1H), 7.48 (t, J = 7.9Hz, 2H), 7.04 (s, 1H), 5.91 (s,
1H), 5.78 (ddt, J = 17.2, 10.3, 6.6 Hz, 1H), 5.02 (ddt, J = 17.2, 1.8, 1.5 Hz,
1H), 4.98 (ddt, J = 10.3, 1.5, 1.5 Hz, 1H), 4.12 (s, 2H), 2.64 (t, J = 7.5 Hz,
General Procedure for Reaction with Acyl Chlorides. A
solution of 2-methyl-4-[(phenylsulfonyl)methyl]furan (0.95 mmol) in
THF (7 mL) was cooled to À78 °C and treated dropwise with 2.26 M
n-butyllithium in hexanes (0.84 mL, 1.89 mmol). Stirring was continued
for 15 min at À78 °C, after which the acyl chloride (0.99 mmol) was
added dropwise. The mixture was stirred for 5 min at À78 °C, warmed to
room temperature, and stirred another 12 h. Saturated aqueous ammo-
nium chloride (3 mL) was added, and the THF was removed in vacuo.
The residue was taken up in dichloromethane (50 mL) and washed with
water (50 mL). The aqueous phase was extracted with dichloromethane
(2 Â 25 mL). The combined organic portions were dried over sodium
sulfate and concentrated in vacuo to provide the crude product, which
was purified by chromatography.
3,3-Dimethyl-1-(5-methylfuran-3-yl)-1-(phenylsulfonyl)butan-2-one
(6l). The dianion of 2-methyl-4-[(phenylsulfonyl)methyl]furan was added
to trimethylacetyl chloride using the general procedure. Chromatography
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The Journal of Organic Chemistry
NOTE
2H), 2.33 (q, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 156.7,
141.2, 137.2, 133.8, 129.0, 128.7, 115.5, 113.1, 107.2, 100.0, 53.7, 31.9,
27.5. HRMS: calcd for C15H16O3S 276.0820, found 276.0824.
was cooled to À20 °C and treated with sodium metal (368 mg, 16.0 mmol).
Stirring was continued at À20 °C until TLC indicated the consumption
of starting material (2.5 h). The reaction was quenched with a mixture of
methanol (2 mL) and saturated aqueous ammonium chloride (2 mL).
The mixture was diluted with diethyl ether (40 mL) and washed
sequentially with saturated aqueous ammonium chloride (20 mL) and
brine (20 mL). The organic phase was dried over sodium sulfate and
concentrated in vacuo to yield a crude oil, which was purified by
chromatography (dichloromethane) to give 10 (132 mg, 92%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 7.5 Hz, 2H),
7.20À7.27 (m, 3H), 7.08 (s, 1H), 5.90 (s, 1H), 2.88 (t, J = 8.0 Hz, 2H),
2.71 (t, J = 8.0 Hz, 2H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 152.3, 142.0, 137.2, 128.5, 128.4, 126.1, 125.6, 107.2, 36.5, 27.1, 13.7.
Anal. Calcd for C13H14O: C, 83.8; H, 7.6. Found: C, 84.0; H, 7.4.
1-(5-Methylfuran-3-yl)propan-2-one (11). To a 15 mL round-
bottom flask containing samarium(II) iodide in THF (0.1 M, 4.9 mL,
0.49 mmol) at À78 °C was added dropwise a solution of 1-(5-methylfuran-
3-yl)-1-(phenylsulfonyl)propan-2-one (53.5 mg, 0.19 mmol) in a mix-
ture of methanol (0.14 mL) and THF (0.42 mL). The combined
contents were stirred for 10 min at À78 °C, warmed to room
temperature, and stirred for a further 15 min. The reaction mixture
was partitioned between diethyl ether (40 mL) and saturated aqueous
potassium carbonate (40 mL). The aqueous phase was extracted with
diethyl ether (20 mL). The combined organic phases were washed with
brine, dried over sodium sulfate, concentrated in vacuo, and subjected to
chromatography (diethyl ether) to give 11 (16.4 mg, 62%) as a colorless
2-(3-Phenylpropyl)-4-(phenylsulfonylmethyl)furan (9c). 7-Phenyl-
heptane-2,4-dione38 was converted on a 0.93 mmol scale. Chromatog-
raphy (20% EtOAc in hexane) provided 9c (112 mg, 36%) as a viscous
oil. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.6 Hz, 2H), 7.61 (t, J =
7.5 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.13À7.22
(m, 3H), 7.06 (s, 1H), 5.92 (d, J = 0.7 Hz, 1H), 4.13 (s, 2H), 2.60 (t, J =
7.7 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.91 (t, J = 7.5 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 157.1, 141.8, 141.2, 138.0, 133.8, 129.0, 128.7,
128.5, 128.4, 126.0, 113.1, 107.1, 53.7, 35.1, 29.5, 27.4. Anal. Calcd for
C20H20O3S: C, 70.6; H, 5.9. Found: C, 70.2; H, 5.9.
2-Butyl-4-(phenylsulfonylmethyl)furan (9d). Octane-2,4-dione was
converted on a 0.88 mmol scale. Chromatography (20% EtOAc in
hexane) provided 9d (220 mg, 93%) as a light yellow oil. 1H NMR (400
MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.49
(t, J = 7.9 Hz, 2H), 7.04 (s, 1H), 5.88 (s, 1H), 4.12 (s, 2H), 2.54 (t, J =
7.5 Hz, 2H), 1.55 (quint, J = 7.4 Hz, 2H), 1.30 (sext, J = 7.3 Hz, 2H), 0.90
(t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.7, 141.0, 138.0,
133.8, 129.0, 128.7, 113.0, 106.8, 53.8, 30.0, 27.6, 22.2, 13.9. Anal. Calcd
for C15H18O3S: C, 64.7; H, 6.5. Found: C, 64.9; H, 6.5.
2-(Oct-7-enyl)-4-(phenylsulfonylmethyl)furan (9e). Dodec-11-ene-
2,4-dione38 was converted as described in the general procedure.
Chromatography (20% EtOAc in hexane) provided 9e (100 mg, 41%)
as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J =
8.2 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.04
(s, 1H), 5.88 (s, 1H), 5.80 (ddt, J = 17.2, 10.3, 6.6 Hz, 1H), 4.99 (ddt, J =
17.2, 2.2, 1.5 Hz, 1H), 4.93 (ddt, J = 10.3, 2.2, 1.1 Hz, 1H), 4.12 (s, 2H),
2.53 (t, J = 7.5 Hz, 2H), 2.03 (m, 2H), 1.56 (quint, J = 7.3 Hz, 2H),
1.22À1.42 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 157.7, 141.0,
139.1, 138.0, 133.8, 129.0, 128.7, 114.3, 113.0, 106.8, 100.0, 53.8, 33.8,
28.9, 28.8, 27.9, 27.8. Anal. Calcd for C19H24O3S: C, 68.6; H, 7.3.
Found: C, 68.8; H, 7.3.
2-Isobutyl-4-(phenylsulfonylmethyl)furan (9f). 6-Methylheptane-
2,4-dione was converted as described in the general procedure. Chro-
matography (25% EtOAc in hexane) provided 9f (180 mg, 88%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.7 Hz, 2H),
7.61 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.04 (s, 1H), 5.86
(s, 1H), 4.13 (s, 2H), 2.40 (d, J = 7.0 Hz, 2H), 1.89 (nont, J = 6.8 Hz,
1H), 0.87 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 156.8,
141.1, 137.9, 133.8, 129.0, 128.7, 113.1, 107.7, 53.8, 37.1, 27.9, 22.3.
Anal. Calcd for C15H18O3S: C, 64.7; H, 6.5. Found: C, 64.7; H, 6.5.
2-Isopropyl-4-(phenylsulfonylmethyl)furan (9g). 5-Methylhexane-
2,4-dione48 was converted as described in the general procedure.
Chromatography (25% EtOAc in hexane) provided 9g (185 mg, 95%)
as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.3 Hz,
2H), 7.62 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.06 (s, 1H), 5.84
(s, 1H), 4.12 (s, 2H), 2.85 (sept, J = 7.0 Hz, 1H), 1.17 (d, J = 7.0 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 162.9, 141.0, 138.1, 133.8, 129.0,
128.7, 112.8, 104.8, 53.8, 27.8, 21.0. Anal. Calcd for C14H16O3S: C, 63.6;
H, 6.1. Found: C, 63.8; H, 6.1.
1
oil. H NMR (400 MHz, CDCl3): δ 7.18 (s, 1H), 5.89 (s, 1H), 3.45
(s, 2H), 2.25 (s, 3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 206.4, 152.9, 138.7, 118.3, 107.5, 40.4, 29.2, 13.6. Anal. Calcd for
C8H10O2: C, 69.5; H, 7.3. Found: C, 69.5; H, 7.5.
3-Methyl-1-(5-methylfuran-3-yl)butan-1-one (Rabdoketone
A, 12). 2-Methyl-4-(3-methyl-1-(phenylsulfonyl)butyl)furan (146 mg,
0.50 mmol) was dissolved in THF (1.0 mL). The solution was cooled
to À78 °C and treated with a solution of n-butyllithium in hexane
(2.5 M, 0.22 mL, 0.55 mmol). The mixture was stirred for 5 min at
À78 °C, warmed to À20 °C, and treated with a solution of dimethox-
yboron chloride in hexanes49 (1.5 M, 0.42 mL, 0.63 mmol). Stirring was
continued at À20 °C for 15 min and then at room temperature for 2 h,
after which time the solvent was removed by rotary evaporation. The
residue was taken up in dichloromethane (1.25 mL) and added to a
mixture of m-chloroperbenzoic acid (75 wt %, 144 mg, 0.62 mmol) and
sodium bicarbonate (106 mg, 1.26 mmol) in dichloromethane
(3.75 mL) at À20 °C. The mixture was stirred for 1 h at À20 °C and
then partitioned between dichloromethane (40 mL) and a 1:1 mixture of
saturated sodium carbonate and brine (40 mL). The organic layer was
dried over sodium sulfate, concentrated in vacuo, and subjected to
chromatography (15% EtOAc in hexane) to give 12 (50 mg, 60%) as
a straw-colored oil with spectroscopic properties in agreement with
those reported in the literature.43 1H NMR (400 MHz, CDCl3): δ 7.84
(s, 1H), 6.33 (s, 1H), 2.54 (d, J = 7.0 Hz, 2H), 2.29 (s, 3H), 2.15À2.28
(m, 1H), 0.95 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 195.5, 154.2, 145.8, 129.3, 104.5, 49.3, 25.6, 22.8, 13.5.
2-Phenyl-4-(phenylsulfonylmethyl)furan (9h). Benzoylacetone was
converted on a 0.59 mmol scale. Chromatography (dichloromethane)
provided 9h (85 mg, 48%) as a white solid (mp 117À118 °C) with
spectroscopic properties in agreement with those reported in the
literature.34 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.3 Hz, 2H),
7.56À7.66 (m, 3H), 7.50 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.27
(t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 6.56 (s, 1H), 4.20 (s, 2H). 13C NMR
(100 MHz, CDCl3): δ 154.9, 142.1, 137.8, 134.0, 130.2, 129.1, 128.8,
128.7, 128.0, 124.0, 114.7, 106.6, 53.6.
5-Methylfuran-3-carboxylic Acid (13). An oven-dried 25 mL
round-bottom flask was charged with 2-methyl-4-(phenylsulfonylmethyl)-
furan32 (99 mg, 0.42 mmol), sealed, and flushed with nitrogen, after
which anhydrous THF (5 mL) was added. The resulting solution was
cooled to À78 °C and treated dropwise with 0.5 M potassium
hexamethyldisilazide in toluene (2.1 mL, 1.05 mmol, 2.5 equiv). After
stirring for 30 min, dry oxygen was sparged through the stirred mixture at
À78 °C via a 22 gauge needle until the disappearance of starting material
(30À60 min).
2-Methyl-4-(2-phenylethyl)furan (10). 2-Methyl-4-(2-phenyl-
1-(phenylsulfonyl)ethyl)furan (6a; 251 mg, 0.77 mmol) was dissolved
in THF (20 mL) and absolute ethanol (0.9 mL). The resulting solution
After warming to room temperature, the reaction mixture was
quenched with saturated aqueous sodium bicarbonate (5 mL) and
saturated aqueous sodium carbonate (5 mL). The contents were
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The Journal of Organic Chemistry
NOTE
transferred to a separatory funnel with deionized water. The aqueous
mixture was extracted with ethyl ether (2 Â 30 mL) to remove traces of
starting material and then carefully acidified with 1 M hydrochloric acid
(ca. 30 mL) to pH 1.2.
The acidic aqueous layer was extracted with diethyl ether (3 Â 20 mL),
and the combined organic extracts were washed successively with pH 2
bisulfate buffer (20 mL), 1 M sodium metabisulfite solution at pH 2 (2 Â
20 mL), and brine at pH 1 (20 mL). Drying over sodium sulfate and
removal of solvent in vacuo afforded 13 (47 mg, 88%) as a white solid
(mp 110À112 °C) with spectroscopic properties in agreement with
those reported in the literature.50 1H NMR (400 MHz, CDCl3): δ 7.94
(s, 1H), 6.33 (s, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 147.58, 119.76, 105.54, 154.01, 168.39, 13.33.
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’ ASSOCIATED CONTENT
S
Supporting Information. Text giving general experimen-
b
tal details and figures giving 1H and 13C NMR spectra for all com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
(28) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett.
2009, 11, 4624–4627.
(29) Jung, C.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 4118–4119.
Corresponding Author
*E-mail: smurphre@allegheny.edu.
(30) Karpov, A. S.; Merkul, E.; Oeser, T.; M€uller, T. J. J. Chem.
Commun. 2005, 2581–2583.
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’ ACKNOWLEDGMENT
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We gratefully acknowledge financial support by the donors of
the Petroleum Research Fund, administered by the American
Chemical Society (No. PRF 42382-B1), and the Shanbrom Fund
at Allegheny College. S.S.M. wishes to thank Edward Walsh and
Doug Taber for their helpful discussions.
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