Solvent-dependent oxidative coupling of 1-aryl-1,3-dicarbonyls and styrene

Article abstract of DOI:10.1016/j.tet.2009.06.118

This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas

Full text of DOI:10.1016/j.tet.2009.06.118

Tetrahedron 65 (2009) 10762–10768
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-dependent oxidative coupling of 1-aryl-1,3-dicarbonyls and styrene
*
Brian M. Casey, Cynthia A. Eakin, Jingliang Jiao, Dhandapani V. Sadasivam, Robert A. Flowers, II
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2009
Received in revised form 25 June 2009
Accepted 29 June 2009
Available online 3 July 2009
This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative
coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are ob-
tained when reactions are performed in methanol whereas a-tetralones can be selectively synthesized in
acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted
deprotonation of a radical cation intermediate playing an integral role in the selective formation of
products.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
obtained in methylene chloride (CH2Cl2). The basis for this solvent-
selective chemoselectivity is a result of solvent-assisted desilylation
In recent decades, the use of Ce(IV) reagents in single electron
transfer (SET) reactions has steadily increased.1 Ceric ammonium
nitrate (CAN) in particular has proven to be a cost-effective and
synthetically versatile single electron oxidant. CAN is capable of
generating radicals and radical cations that can further react gen-
erating carbon–carbon and carbon–heteroatom bonds.2,3 Although
traditionally restricted to aqueous or polar organic solvents, the
replacement of the ammonium counterions of CAN with tetra-n-
butylammonium yields ceric tetra-n-butylammonium nitrate
(CTAN) which is more lipophilic resulting in increased solubility in
less polar organic solvents.4 The single electron oxidative coupling
of enolizable carbonyl and 1,3-dicarbonyl substrates to activated
olefins has received a great deal of interest.5 Previous research from
our group reported the solvent-dependent oxidative coupling of
1,3-dicarbonyl substrates to allyltrimethylsilane (Scheme 1).6
When reactions were performed in acetonitrile (MeCN), allylated
products were obtained whereas dihydrofuran derivatives were
of the b-silyl cation intermediate in more polar solvents such as
MeCN leading to allylated products and inhibiting the cyclization
pathway which results in dihydrofuran derivatives. A similar sol-
vent-dependent chemoselectivity was observed for the oxidative
addition of b
-carbonyl imines to allyltrimethylsilane.7
The oxidative coupling of 1,3-dicarbonyls to allyltrimethylsilane
highlights the ability of solvent to have a significant impact on the
reaction pathways of some carbon-carbon bond-forming events.
Based on this precedent, the effect of solvent on the oxidative
coupling of 1-aryl-1,3-dicarbonyl substrates to styrene was in-
vestigated. While previous research has examined similar synthetic
systems, 1-aryl-1,3-dicarbonyl substrates were not used and re-
actions were performed only in polar solvents.8 The synthetic and
mechanistic details for the Ce(IV)-mediated oxidative coupling of
1-aryl-1,3-dicarbonyl compounds to styrene are presented herein.
2. Results and discussion
2.1. Scope of reaction
O
O
CTAN/MeCN
R1
R2
O
O
In an initial study, when an equivalent of 1-phenyl-1,3-butane-
dione (1) is treated with 2 equivalents of CAN in MeCN in the
presence of a slight excess of styrene, the a-tetralone derivative (1a)
was formed as the major product in an isolated yield of 76% (Table 1,
entry 1). Interestingly, when the same reaction was performed in
methanol (MeOH) with CAN, the dihydrofuran derivatives (1b) were
produced in a combined 78% yield. To examine the scope of this
solvent-dependent reaction, a variety of 1-aryl-1,3-dicarbonyl
compounds were examined as substrates. As shown in entries 1–3
in Table 1, the synthesis worked well for a 1-aryl-1,3-diketone (1),
SiMe3
+
R1
R2
O
R1
CTAN/CH2Cl2
R2
SiMe3
O
Scheme 1. Solvent-dependent synthesis of 2-allylated 1,3-dicarbonyl and dihy-
drofuran derivatives.
* Corresponding author.
E-mail address: rof2@lehigh.edu (R.A. Flowers, II).
a 1,3-diaryl-1,3-diketone (2), and 1-aryl-b-ketoesters (3–5). For the
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.118

B.M. Casey et al. / Tetrahedron 65 (2009) 10762–10768
10763
Table 1
Ce(IV)-mediated oxidative coupling of 1-aryl-1,3-dicarbonyls to styrene
Entry
Substrate
Conditionsa
Yieldb (%)
76
Ratio (a/b)
78:22
Productc
O
O
A
1a
O
O
Ph
1
Ph
Ph
1b (1.5:1)
O
O
1
Ph
B
A
B
78
59
84
20:80
60:40
10:90
O
O
Ph
O
O
Ph
2a
O
O
Ph
O
2
3
4
Ph
2
Ph
2b
O
Ph
O
O
OEt
A
B
A
B
74
78
30
74
77:23
16:84
33:67
11:89
3a
O
O
Ph
OEt
Ph
3
O
Ph
3b
O
OEt
O
O
OMe
4a
O
O
F
Ph
OMe
4
Ph
O
F
F
4b
O
OMe
O
O
MeO
MeO
OEt
5a
O
O
A
B
78
25
100:Trace
70:30
MeO
MeO
OEt
OMePh
5
5
Ph
5b
OEt
MeO
MeO
MeO
O
OMe
O
a
Condition A: 2 equiv CAN in MeCN, rt, 2 h; condition B: 2 equiv CAN in MeOH, rt, 2 h.
Isolated yield.
a
b
c
-Tetralones are mixture of diastereomers (syn/anti). 1a (1:2.5), 3a–5a (1:1). Ratios determined by 1H NMR by comparing the relative intensities of the proton signals from
5.6–6.0 ppm in the crude reaction mixture.
dihydrofuran syntheses using the 1-aryl-
were obtained as single isomers. In all cases the
ucts were obtained as mixtures of the syn and anti diastereomers.
These diastereomers proved to be inseparable by column chroma-
tography, but could be distinguished through the resonance for the
proton on the 2 position of the tetralone ring.
In order to establish which resonance corresponded to which
diastereomer, a series of computational and NMR experiments was
performed. Gaussian 03 at the B3LYP/6-31G{d,p} level was used for
DFT optimizations.9 When the structures for both diastereomers
were optimized, the protons in position 2 and 4 for the syn di-
astereomer of 1a were in close proximity, whereas they pointed
away from one another in the anti diastereomer (Supplementary
data). A 2D NOESY NMR experiment performed on 1a showed
a weak cross signal for the more downfield resonance from the
proton at position 2 to the overlapping signals from the proton at
position 4. As a result, this signal was attributed to the syn
b
-ketoesters, the products
-tetralone prod-
diasteromer. The conformations of the other a-tetralone products
were characterized by analogy. While the syn/anti ratio of di-
astereomers for 1a was 1:2.5, the ratios were 1:1 for the products
a
obtained from the b-ketoester substrates. While the calculations
suggest that the anti diastereomer of 1a is slightly more stable than
the syn, optimized syn and anti structures of 3a indicated negligible
energy differences between the two diastereomers.
In addition to varying the types of 1-aryl-1,3-dicarbonyl com-
pounds used, the effect of altering the electron density of the 1-aryl
ring was examined. As shown in entry 4, when an electron-with-
drawing fluorine was incorporated into the ring, the major product
for the reaction performed in MeCN was dihydrofuran 4b instead of
the expected
by the addition of three methoxy substituents, the selectivity was
significantly shifted towards the formation of -tetralone 5a in
a-tetralone 4a. Similarly, when the ring was activated
a
MeOH, producing 5b in only a 25% yield. In addition, when the
reaction was performed in MeCN, analysis of the crude reaction

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B.M. Casey et al. / Tetrahedron 65 (2009) 10762–10768
mixture by 1H NMR showed only trace amounts of dihydrofuran 5b.
These results suggested a strong electronic effect with electron rich
was performed. Preliminary studies were focused on the initial
oxidation of the 1-aryl-1,3-diketone or -ketoester in the absence of
b
aryl rings favoring
a
-tetralone formation and electron poor aryl
styrene to determine the impact of solvent on the mechanism of
oxidation and the stability of the radical cation intermediate. Ob-
served rate constants (kobs) for the oxidation of substrates 1 and 3
were obtained in all three solvents using either CAN or CTAN (k1
values, Table 3). These rate data were obtained by monitoring the
decay of the Ce(IV) absorbance at 380 nm with a stopped-flow
spectrophotometer. While the lmax of Ce(IV) is at 330 nm, the decay
of Ce(IV) was monitored at 380 nm since the absorbance of the
substrates overlapped at 330 nm. To assess the role of solvent, rate
studies were performed first in the absence of styrene under
pseudo-first order conditions keeping the substrate in excess with
respect to the oxidant. Based on the previous studies of 1,3-dicar-
bonyls, it was postulated that the first step of the reaction involved
the oxidation of the enol tautomer of the 1-aryl-1,3-dicarbonyl
species by Ce(IV) to generate a radical cation.13,14 This supposition is
also supported by the fact that many radical cations absorb in
the range of 400–500 nm.15 To obtain a better understanding of the
process, a time-resolved absorption spectrum was obtained for the
oxidation of 3. As shown in the inset of Figure 1, a clear isosbestic
point was observed at 420 nm. Since the substrates, Ce(IV) and
Ce(III) do not absorb above 400 nm, the absorption at 460 nm was
attributed to a radical cation intermediate. The rate of growth of the
absorption at 460 nm for substrates 1 and 3 were recorded in each
solvent and are included in Table 3. The growth of the radical cation
absorption k2 was equal to the decay of Ce(IV) at 380 nm k2 within
experimental error, a finding consistent with earlier studies on the
Ce(IV)-mediated oxidation of 1-alkyl-1,3-diketones.13
rings favoring the production of dihydrofurans. Furthermore, these
results indicated the possibility of the carbonyl and the phenyl
groups competing to trap the intermediate produced after addition
of the dicarbonyl to styrene during the course of the reaction.
The experiments described above show that both the solvent
polarity and the electron density of the 1-aryl ring play a role in
product distribution. Based on this observation, could the chemo-
selectivity be controlled by the use of an even less polar solvent? To
examine this hypothesis, the oxidative addition of substrates 1–4 to
styrenewas performed in CH2Cl2 using CTANas the oxidant (Table 2).
For all four substrates, the selective formation of a-tetralone de-
rivatives was improved when the reaction was performed in CH2Cl2
with CTAN when compared to MeCN and CAN. Whereas substrate 4
favored dihydrofuran formation in MeCN, the reaction in CH2Cl2
produced the desired
a-tetralone 4a in a 62% yield.
Table 2
a
Selective synthesis of a-tetralone derivatives in CH2Cl2
Entry
Substrate
Product
Ratio (a/b)
Yieldb (%)
1
2
3
4
1
2
3
4
1a
2a
3a
4a
88:12
85:15
82:18
66:34
81
79
80
62
a
2 equiv CTAN in CH2Cl2, rt, 2 h.
Isolated yield.
b
With a simple procedure and mild reaction conditions, the ox-
idative addition of 1-aryl-1,3-dicarbonyls to styrene presented
above provides an efficient approach to substituted -tetralones
a
and dihydrofurans selectively in good to very good yields. The
ability to produce these classes of compounds is synthetically of
interest since dihydrofuran and
a
-tetralone moieties are present in
-tetralones are syn-
a variety of natural products.10 In addition,
a
thetic precursors to biologically relevant molecules such as podo-
phyllotoxin and phyltetralin.11 WhileMn(III)-mediated synthetic
routes to a-tetralones have been developed previously, these ap-
proaches require prolonged reaction times, elevated temperatures
and proceeded through dihydrofuran intermediates which were
converted to the
a
-tetralones using SnCl4.12 In comparison, the
Ce(IV)-mediated methodology is a one-step reaction that can be
performed at room temperature in only 2 h.
2.2. Mechanistic studies
Figure 1. Time-resolved absorption spectrum observed from CTAN and ethyl-
benzoylacetate (3) in CH2Cl2 ([3]¼50 mM, [CTAN]¼1 mM) from 400–500 nm at 25 ꢃC.
Spectrum was obtained by taking 10 scans every 5 nm over a period of 50 ms.
In order to fully elucidate the solvent-dependent chemo-
selectivity exhibited in this system, a thorough mechanistic analysis
Table 3
Kinetic rate data for the Ce(IV)-mediated oxidation of 1-phenyl-1,3-butanedione and ethylbenzoylacetatea
Entry
Substrate
Intermediate
Oxidant
Solvent
Rate constant
Rate constant of radical cation
Rate constant of radical cation
of Ce(IV) decay
formation at 460 nm k2b (sꢀ1
)
decay at 460 nm k3b (sꢀ1
)
at 380 nm k1 (sꢀ1
)
b
MeOH
MeCN
MeCN
CH2Cl2
MeOH
MeCN
MeCN
CH2Cl2
5.8ꢁ0.6ꢂ102
8.3ꢁ0.2
6.0ꢁ0.2ꢂ102
8.7ꢁ0.1
4.1ꢁ0.1ꢂ10ꢀ2
5.8ꢁ0.2ꢂ10ꢀ3
5.1ꢁ0.5ꢂ10ꢀ3
1.7ꢁ0.1ꢂ10ꢀ3
3.2ꢁ0.1ꢂ10ꢀ1
9.0ꢁ0.3ꢂ10ꢀ2
8.8ꢁ0.2ꢂ10ꢀ2
1.5ꢁ0.1ꢂ10ꢀ2
OH
O
CAN
1
1
3
6.0ꢁ0.3
6.2ꢁ0.1
CTAN
CAN
3.4ꢁ0.3
3.4ꢁ0.1
3.5ꢁ0.3ꢂ102
6.2ꢁ0.1
3.7ꢁ0.2ꢂ102
6.3ꢁ0.1
OH
O
2
3.8ꢁ0.4
3.9ꢁ0.1
OEt
CTAN
1.4ꢁ0.1
1.6ꢁ0.1
a
[Ce(IV)]¼1 mM, [substrate]¼20 mM at 25 ꢃC.
b
Average of at least two runs.

B.M. Casey et al. / Tetrahedron 65 (2009) 10762–10768
10765
The rate data obtained indicated a clear trend based on the
polarity of the solvent. The rate of decay of Ce(IV) increased with
solvent polarity being fastest in MeOH and slowest in CH2Cl2.
radical cations derived from 1,3-diketones and related silyl enol
ethers are deprotonated by MeOH through solvent-assisted depro-
tonation whereas in CH2Cl2 and MeCN, the intermediates are
deprotonated through a unimolecular mechanism.13 Based on this
precedent, the rate order of styrene in MeOH was interpreted as
being consistent with deprotonation of the radical cation by solvent
prior to addition to styrene.
Furthermore, the rate of oxidation of diketone 1 and b-ketoester 3
is roughly 2 orders of magnitude faster in MeOH than in MeCN. The
impact of solvent polarity and the relative rate differences among
the solvents examined are consistent with earlier studies on 1-al-
kyl-1,3-diketones and related silylenol ethers.13
Next, the impact of solvent on the lifetime of the radical cation
was examined by monitoring its decayat 460 nm. Examination of the
observed rate constants of radical cation decay (k3) contained in
Table 3 shows a clear dependence on solvent polarity in the order of
MeOH>MeCN>CH2Cl2. The k3 value is 4–7 times greater in MeOH
than in MeCN whereas k3 is 3–6 times greater in MeCN than in
CH2Cl2. The general trend for the stability of radical cations in the
solvents examined is the same as in previous studies of 1,3-diketones
Table 5
Rate order of styrene for decay of radical cation at 460 nm
Entry
Oxidant
Solvent
Styrene rate
ordera,b
1
2
3
CAN
CAN
CTAN
MeOH
MeCN
CH2Cl2
0.28ꢁ0.01
0.97ꢁ0.05
1.02ꢁ0.06
a
Average of at least 2 runs.
Determined from the slope for the plot of ln kobs versus ln[styrene].
and b
-silyl enol ethers.13 However, the difference in the rates of
b
radical cation decay of 1 and 3 among the solvents examined is less.
Previous studies on radical cations derived from 1-alkyl-1,3-dike-
tones showed a large difference among the solvents with decays in
MeOH on the order of 15–100 times faster than in MeCN.15 It is likely
that the presence of the 1-phenyl group stabilizes the radical cation
intermediate thereby tempering the impact of solvent.
To further probe the role of solvent, 2,2-dideuterio-1-phenyl-
1,3-butanedione was prepared and the rate of decay of its radical
cation was measured under conditions identical to those described
previously. The data are displayed in Table 4. The kH/kDvalues for
both MeCN and CH2Cl2 were greater than 2 (entries 2 and 3, Table
4), a finding consistent with studies reported by Schmittel for the
deprotonation of the anisyldimesitylethenol radical cation.16 The
kH/kD value for MeOH (entry 1, Table 4) was 1.5. The lower value in
MeOH is likely due to exchange between solvent and deuterium in
the substrate.
Taken together, these studies indicated several key details about
the mechanism of the Ce(IV)-mediated oxidative coupling of 1-
aryl-1,3-dicarbonyls to styrene. First, the rates of oxidation of
substrates by Ce(IV), the rates of radical cation formation and the
rates of decay of the radical cations were solvent-dependent
(MeOH>MeCN>CH2Cl2). Second, styrene was first order in both
MeCN and CH2Cl2. Finally, a fractional rate order of styrene for the
decay of the radical cation in MeOH indicated solvent-assisted
deprotonation of the radical cation to a radical species prior to
addition to styrene.
From the experimental results and points described above,
the mechanism provided in Scheme 2 is proposed to explain the
solvent-dependent chemoselectivity of the oxidative coupling of
1-aryl-1,3-dicarbonyls to styrene. Initial oxidation of the enol tau-
tomer (60) by Ce(IV) produces radical cation 7. In MeOH, solvent-
assisted deprotonation of the radical cation yields radical
intermediate 8. After the addition to styrene to form 9, rotation
around one of the carbonyl–CH bonds and another single electron
oxidation by Ce(IV) produces cation 10. Cyclization and deproto-
nation of 10 result in dihydrofuran derivative 11. Conversely in less
polar solvents such as MeCN and CH2Cl2, radical cation 7 adds di-
rectly to styrene producing intermediate 12. This intermediate has
restricted rotation since the proton is shared by the two carbonyl
groups, thus placing the intermediate in close proximity to the
phenyl ring. Oxidation to cation 13 followed by addition to the
phenyl ring and subsequent deprotonation provides a pathway to
Table 4
Observed rate constants for the decay of the radical cation of 2,2-dideuterio-1-
a
phenyl-1,3-butanedione in MeOH, MeCN, and CH2Cl2
Entry
Oxidant/solvent
kDb (sꢀ1
)
kH/kD
1
2
3
CAN/MeOH
CAN/MeCN
CTAN/CH2Cl2
2.7ꢁ0.1ꢂ10ꢀ2
2.7ꢁ0.1ꢂ10ꢀ3
7.3ꢁ0.1ꢂ10ꢀ4
1.5ꢁ0.1
2.2ꢁ0.1
2.4ꢁ0.1
a
[Ce(IV)]¼1 mM, [substrate]¼20 mM at 25 ꢃC.
b
Average of at least two runs.
Both the observation that the radical cations of 1-aryl-1,3-
diketones and 1-aryl- -ketoesters decay faster in more polar sol-
a-tetralone 14. A variation on this mechanism can be envisioned
b
through intramolecular radical addition in 12 followed by a second
single electron oxidation and deprotonation to provide 14 as well.
Observations from reactions involving substrates 4 and 5 in-
dicate an electronic effect consistent with the proposed mecha-
nism. Based on the mechanism shown in Scheme 2, lower
nucleophilicity of the aryl ring should promote dihydrofuran for-
mation whereas an electron rich ring should lead to a higher yield
vents and the results from the deuterium isotope study agree with
the known solvent-assisted mechanism of O–H bond cleavage17,18
and are consistent with previous mechanistic studies on the role of
solvent in the decay of radical cations derived from 1-alkyl-1,3-
diketones.13
The studies described to this point support solvent playing an
important role in the oxidation of substrate and in the stability of
the initial radical cation intermediate. In the absence of styrene, the
decay of the radical cation was a result of deprotonation. Next,
a series of experiments was performed to determine the mecha-
nistic role of styrene in the reaction. In these studies, the decay of
the radical cation of 1-phenyl-1,3-butanedione (1) was monitored
in the presence of increasing concentrations of styrene in all three
solvents under pseudo-first order conditions with respect to the
oxidant. The data for these experiments are contained in Table 5.
These experiments clearly showed that the rate order of styrene
was 1 in MeCN and CH2Cl2 whereas it was significantly less than
unity (0.28) in MeOH. These results indicated that reaction of radical
cation with styrene was the rate-limiting step of the reaction in
MeCN and CH2Cl2. Previous studies from our group have shown that
of
showing that the electron rich aryl ring in substrate 5 produces
-tetralone 5a predominantly whereas substrate4 containing an
a-tetralone. This supposition is borne out by synthetic studies
a
electron deficient ring favors dihydrofuran formation.
The key feature of the above mechanism is that direct addition
of the radical cation to styrene before deprotonation provides
a conformationally restricted intermediate that directs C–C bond
formation leading to a-tetralone rather than C–O bond formation
producing dihydrofuran. If this hypothesis is correct, addition of
a basic solvent to the reaction performed in CH2Cl2 (or MeCN)
should provide the dihydrofuran as the major product. To test this
supposition, the reaction of substrate 2 with styrene employing
CTAN as the oxidant was conducted in CH2Cl2 containing 5 equiv of
MeOH. Dihydrofuran 2b was obtained in 80% yield.

10766
B.M. Casey et al. / Tetrahedron 65 (2009) 10762–10768
H
OH
O
O
O
O
O
Ce(IV)
R
R
R
6
6'
7
H
H
MeCN
or
Ph
Ce(IV)
O
O
O
O
O
O
O
O
O
CH2Cl2
Ce(IV)
MeOH
-(H+)
Ph
R
R
R
R
Ph
O
R
8
Ph
13
Ph
9
Ph
12
10
-(H+)
Ph
O
O
O
R
O
R
Ph
14
11
Scheme 2. Proposed mechanism for the solvent-dependent chemoselective oxidative addition of 1-aryl-1,3-dicarbonyls to styrene.
3. Conclusions
Innovative Technology, Inc. Methanol (MeOH) was dried with ac-
tivated 3 Å molecular sieves prior to use. All 1-aryl-1,3-dicarbonyl
substrates were purchased commercially and used without further
purification. Styrene was filtered through a plug of neutral alumina
to remove stabilizers. CAN was purchased commercially and used
without further purification. CTAN was synthesized using a pre-
viously reported procedure.4 Products were separated using pre-
packed silica gel columns with a gradient elution of either
ethylacetate/hexanes or ether/hexanes.
For the mechanistic studies the Ce(IV) oxidants and substrates
were prepared separately in the appropriate solvent in a glovebox,
transported in airtight syringes, and injected into the stopped-flow
spectrophotometer. The cellblock and the drive syringes of the
stopped-flow spectrophotometer were flushed at least three times
with dry, degassed solvent to make the system anaerobic. Tem-
perature in the stopped-flow spectrophotometer was maintained
at 25 ꢃC using a NESLAB RTE-111. The geometries of the syn and anti
structures of 1a were optimized using Gaussian at the B3LYP/6-
31G{d,p} level of theory.
A solvent-dependent chemoselective method for the Ce(IV)-me-
diated oxidative coupling of 1-aryl-1,3-dicarbonyls to styrene pro-
ducing substituted dihydrofuran and
been developed. Reactions performed in MeOH yielded pre-
dominantly dihydrofuran derivatives whereas reactions in MeCN or
CH2Cl2 favored the formation of a-tetralones. The reaction is general,
working for a variety of 1-aryl-1,3-dicarbonyls and generating the
desired products in good to very good yields. The reaction conditions
are straightforward with short reaction times at room temperature. A
thorough mechanistic analysis was consistent with the rate of sol-
vent-assisted deprotonation of an initial radical cation intermediate
playing an integral role in the selective formation of products. To the
best of our knowledge, this approach is the first reported inwhich the
reaction pathway is controlled by the lifetime of a radical cation in-
termediate. Further studies of other solvent-dependent reaction
systems involving radical cations are currently underway.
a-tetralone derivatives has
4. Experimental
4.3. General procedures
4.1. Instrumentation
4.3.1. Synthesis of a-tetralone derivatives
Mechanistic rate data and time-resolved spectra were obtained
using a computer-controlled stopped-flow reaction spectrophotom-
eter from Applied Photophysics Limited. 1H, 13C and NOESY NMR
spectra were recorded on a Bruker 500 MHz spectrometer. Mass
spectra were obtained using a HP 5890 series GC–MS instrument.
Column chromatography was performed using the automated
CombiFlashÒ Rf system from Teledyne Isco, Inc. A Satellite FTIR from
Thermo-Mattson was used to obtain IR spectra. LC-HRMS data were
recorded at the Mass Spectrometry Facility at Notre Dame University.
All glassware was flame-dried before use. The 1-aryl-1,3-
dicarbonyl substrate (1 mmol) was dissolved in 15 mL of either
MeCN or CH2Cl2 respectively. Styrene (1.1 mmol) was added
dropwise and the reaction was purged with N2 gas. CAN or CTAN
(2.1 mmol) was dissolved in 5 mL MeCN or CH2Cl2 respectively
and added to the reaction via syringe with stirring. After stirring
at room temperature for 2 h, solvent was removed via rotary
evaporation. Water was added and then extracted three times
with ether. The organic layers were combined, dried with
MgSO4, filtered and concentrated. The a-tetralone products 1a–
4.2. Materials and methods
5a were purified via automated flash chromatography. Com-
pounds 1a–5a were characterized by 1H NMR, 13C NMR, GC-MS,
IR and LC-HRMS. NMR spectra are included in Supplementary
data.
Acetonitrile (MeCN) and methylene chloride (CH2Cl2) were
purified with
a Pure Solv solvent purification system from

B.M. Casey et al. / Tetrahedron 65 (2009) 10762–10768
10767
4.3.2. Synthesis of dihydrofuran derivatives
J¼2.8, 5.8 Hz, anti), 4.50–4.42 (m, 2H), 4.20–4.12 (m, 4H), 2.66–2.54
(m, 4H), 1.21–1.15 (m, 6H). 13C NMR (CDCl3, 125 MHz)
193.9, 193.8,
All glassware was flame-dried before use. The 1-aryl-1,3-dicar-
bonyl substrate (1 mmol) was dissolved in 15 mL of MeOH. Styrene
(1.1 mmol) was added dropwise and the reaction was purged with
N2 gas. CAN (2.1 mmol) was dissolved in 5 mL MeOH and added to
the reaction via syringe with stirring. After stirring at room tem-
perature for 2 h, solvent was removed via rotary evaporation. Water
was added and then extracted three times with ether. The organic
layers were combined, dried with MgSO4, filtered and concentrated.
The dihydrofuran products 1b–5b were purified via automated flash
chromatography. Compounds 1b–5b were characterized by 1H
NMR, 13C NMR, GC-MS, IR and LC-HRMS. NMR spectra are included
in Supplementary data.
d
168.9 (2), 137.2, 137.1, 135.6, 135.5, 134.0, 133.8, 129.2 (2), 129.0 (2),
128.9 (2), 128.8, 128.7, 128.6, 126.4, 126.3, 83.0 (2), 61.9 (2), 50.3, 50.2,
33.5,13.9. MS [m/z (rel int)] 294 (Mþ, 1), 238 (33), 133 (35), 105 (100),
77 (60), 51 (20). IR (KBr) n
(cmꢀ1) 3457, 3357, 3063, 3035, 2983, 2904,
1736, 1688, 1636, 1450, 1274, 1196, 1095, 1021, 855, 755, 696, 592.
LC-HRMS calcd. for C19H19O3 [MþH] 295.1329, found 295.1346.
4.4.6. Ethyl-4,5-dihydro-2,5-diphenyl-3-furancarboxylate (3b)
Light yellow oil. 1H NMR (CDCl3, 500 MHz)
d 7.88–7.85 (m, 2H),
7.46–7.33 (m, 8H), 5.73 (dd, 1H, J¼2.1, 8.7 Hz), 4.18–4.12 (m, 2H),
3.58 (dd, 1H, J¼4.5, 10.8 Hz), 3.16 (dd, 1H, 6.6, 8.6 Hz), 1.21 (t, 3H,
J¼7.2 Hz). 13C NMR (CDCl3, 125 MHz)
d 198.9, 165.2, 164.8, 141.7,
130.4, 129.4, 128.7, 128.1, 127.6, 125.7, 102.1, 82.5, 59.8, 39.9, 14.2. MS
4.4. Characterization of products
[m/z (rel int)] 294 (Mþ, 13), 247 (26), 220 (4), 115 (25), 105 (100), 77
4.4.1. 2-Acetyl-3,4-dihydro-4-phenyl-1(2H)-naphthalenone (1a):
(43). IR (KBr) n
(cmꢀ1) 3658, 3514, 3061, 3033, 2979, 1693, 1628,
mixture of diastereomers
1493, 1452, 1373, 1334, 1241, 1156, 1082, 1029, 928, 828, 758, 694.
LC-HRMS calcd. for C19H19O3 [MþH] 295.1329, found 295.1349.
Light yellow oil. 1H NMR (CDCl3, 500 MHz)
d
7.96–7.88 (m, 4H),
7.67–7.61 (m, 2H), 7.55–7.47 (m, 4H), 7.44–7.30 (m, 8H), 5.83 (t, 1H,
J¼7.2 Hz, syn), 5.75 (dd, 1H, J¼2.3, 6.0 Hz, anti), 4.61–4.56 (m, 2H),
2.58–2.52 (m, 4H), 2.17–2.13 (s, 6H). 13C NMR (CDCl3, 125 MHz)
4.4.7. Methyl-3,4-dihydro-6-fluoro-4-phenyl-1(2H)-
naphthalenone-2-carboxylate (4a): mixture of diastereomers
d
202.2, 195.4, 137.2, 134.3, 134.2, 129.3, 129.1, 129.0, 128.8, 128.7,
Colorless oil. 1H NMR (CDCl3, 500 MHz)
d 8.00–7.94 (m, 4H),
126.3, 83.2, 82.8, 58.7, 58.4, 33.4, 33.3, 28.8, 28.5. MS [m/z (rel int)]
7.43–7.32 (m, 8H), 7.19–7.13 (m, 4H), 5.91 (dd, 1H, J¼3.6, 5.4 Hz,
264 (Mþ, 1), 221 (65), 203 (18), 173 (15), 105 (98), 77 (90), 51 (30). IR
syn), 5.81 (dd, 1H, J¼3.2, 5.6 Hz, anti), 4.47–4.41 (m, 2H), 3.72–3.69
(KBr)
n
(cmꢀ1) 3508, 3448, 3062, 3035, 2962, 2930, 1720, 1635,
(s, 6H). 13C NMR (CDCl3, 125 MHz)
d 192.1 (2), 169.2, 167.2, 165.2 (2),
1555, 1447, 1358, 1274, 1071, 964, 855, 758, 698. LC-HRMS calcd. for
C18H17O2 [MþH] 265.1223, found 265.1225.
137.1, 137.0, 131.5, 131.5 (2), 131.4, 129.3 (2), 129.0 (2), 126.3 (2),
116.2, 116.0, 82.9 (2), 53.0, 50.0, 49.8, 33.6, 33.5. MS [m/z (rel int)]
384 (Mþ, 10), 281 (11), 257 (13), 207 (100), 195 (92), 115 (19), 105
4.4.2. 3-Benzoyl-4,5-dihydro-2-methyl-5-phenyl-furan (1b):
(27), 77 (16). IR (KBr) n
(cmꢀ1) 3472, 3361, 3069, 3033, 2955, 2902,
major isomer
1741, 1687, 1638, 1600, 1506, 1442, 1273, 1240, 1161, 1097, 1009, 852,
744, 700. LC-HRMS calcd. for C18H16FO3 [MþH] 299.1078, found
299.1092.
Yellow oil. 1H NMR (CDCl3, 500 MHz)
d 7.62–7.58 (m, 2H), 7.51–
7.34 (m, 8H), 5.66 (dd, 1H, J¼1.1, 9.0 Hz), 3.51 (ddd, 1H, J¼1.4, 4.1,
10.5 Hz), 3.17 (ddd, 1H, J¼1.4, 5.9, 8.8 Hz), 1.95 (br t, 3H, J¼1.4 Hz).
13C NMR (CDCl3, 125 MHz)
d
168.5, 141.0, 131.1, 128.7, 128.3, 127.8,
4.4.8. Methyl-4,5-dihydro-2-(4-fluoro-phenyl)-5-phenyl-3-
125.8, 83.4, 39.5, 15.5. MS [m/z (rel int)] 264 (Mþ, 36), 221 (15), 203
furancarboxylate (4b)
(8), 171 (9), 105 (94), 91 (17), 77 (100), 51 (35). IR (KBr)
n
(cmꢀ1
)
Colorless oil. 1H NMR (CDCl3, 500 MHz)
d 7.97–7.91 (m, 2H), 7.44–
3448, 3417, 3385, 3355, 3060, 3033, 2927, 1714, 1639, 1563, 1448,
1352, 1274, 1225, 970, 895, 852, 700. LC-HRMS calcd. for C18H17O2
[MþH] 265.1223, found 265.1223.
7.38 (m, 4H), 7.38–7.32 (m,1H), 7.13–7.06 (m, 2H), 5.73 (dd,1H, J¼2.2,
8.6 Hz), 3.70 (s, 3H), 3.58 (dd, 1H, J¼4.6, 10.8 Hz), 3.16 (dd, 1H, J¼6.7,
8.6 Hz). 13C NMR (CDCl3, 125 MHz)
d 165.5, 164.9, 163.9, 162.9, 141.4,
131.7, 131.6, 128.8, 128.2, 125.7, 114.9, 114.7, 101.6, 82.5, 51.1, 39.8. MS
4.4.3. 2-Benzoyl-3,4-dihydro-4-phenyl-1(2H)-naphthalenone (2a)
[m/z (rel int)] 384 (Mþ, 6), 370 (13), 281 (12), 207 (96), 195 (100),105
Yellow oil. 1H NMR (CDCl3, 500 MHz)
d
7.97–7.92 (m, 2H), 7.87–
(42), 77 (39). IR (KBr) n
(cmꢀ1) 3067, 3031, 2949, 2871, 1701, 1621,
7.83 (m, 2H), 7.64–7.56 (m, 2H), 7.52–7.42 (m, 4H), 7.41–7.38 (m,
1507,1442,1341,1240,1156,1085, 913, 841, 759, 700. LC-HRMS calcd.
4H), 5.92 (dd, 1H, J¼3.7, 5.2 Hz), 5.38 (dd, 1H, J¼2.2, 5.5 Hz), 2.72–
for C18H16FO3 [MþH] 299.1078, found 299.1097.
2.59 (m, 2H). 13C NMR (CDCl3, 125 MHz)
d 195.0, 194.9, 137.4, 135.4,
135.2, 134.0, 129.3, 129.1, 129.0 (2), 128.6, 128.5, 126.2, 83.3, 52.4,
4.4.9. Ethyl-3,4-dihydro-4-phenyl-5,6,7-trimethoxy-1(2H)-
33.9. MS [m/z (rel int)] 326 (Mþ, 1), 239 (67), 222 (7), 161 (9), 105
naphthalenone-2-carboxylate (5a): mixture of diastereomers
(100), 77 (58), 51 (11). IR (KBr)
n
(cmꢀ1) 3701, 3619, 3063, 2934,
Colorless oil. 1H NMR (CDCl3, 500 MHz)
d 7.41–7.34 (m, 8H), 7.25,
1693, 1637, 1600, 1569, 1449, 1270, 1189, 1104, 995, 853, 853, 699.
LC-HRMS calcd. for C23H19O2 [MþH] 327.1380, found 327.1391.
7.20 (m, 4H), 5.89 (dd, 1H, J¼5.0, 4.8 Hz, syn), 5.84 (dd, 1H, J¼2.3,
6.0 Hz), 4.46 (dd, 1H, J¼3.9, 5.0 Hz, syn), 4.41 (t, 1H, J¼7.1 Hz, anti),
4.24–4.15 (m, 4H), 3.96–3.88 (m, 18H), 2.64–2.49 (m, 4H), 1.26–1.19
4.4.4. 3-Benzoyl-4,5-dihydro-2,5-diphenyl-furan (2b)
(m, 6H). 13C NMR (CDCl3, 125 MHz)
d 192.6 (2), 169.0 (2), 153.2 (2),
Colorless oil. 1H NMR (CDCl3, 500 MHz)
d
7.51–7.18 (m, 11H), 7.13–
137.3, 137.2, 130.7, 130.6, 129.3, 129.2, 129.0 (2), 126.3, 126.2, 106.2,
106.1, 83.2, 83.1, 62.0, 61.0, 56.3 (2), 50.3, 50.2, 33.8, 14.0 (2). MS
[m/z (rel int)] 298 (Mþ, 8), 265 (6), 170 (16), 123 (100), 95 (25). IR
7.06 (m, 4H), 5.85 (t, 1H, J¼9.8 Hz), 3.72 (dd, 1H, J¼4.8, 10.3 Hz), 3.40
(dd,1H, J¼6.2, 8.9 Hz). 13C NMR (CDCl3,125 MHz)
d 193.4, 165.4, 141.1,
139.0, 131.2, 130.1, 129.5, 128.9, 128.8, 128.3, 127.7 (2), 125.9, 111.8,
(KBr) n
(cmꢀ1) 3644, 3553, 3337, 2978, 2944, 2839, 2255, 1734,
83.2, 41.2. MS [m/z (rel int)] 326 (Mþ,10), 223 (13),134 (51),121 (100),
1681, 1636, 1584, 1502, 1456, 1416, 1332, 1272, 1237, 1125, 1004, 914,
854, 735, 704. LC-HRMS calcd. for C22H25O6 [MþH] 385.1646, found
385.1648.
105 (70), 91 (15), 77 (80), 51 (16). IR (KBr) n
(cmꢀ1) 3698, 3598, 3057,
2955, 2866,1601, 1491, 1447, 1354, 1231, 1112,1016, 918, 879, 695. LC-
HRMS calcd. for C23H19O2 [MþH] 327.1380, found 327.1389.
4.4.10. Ethyl-4,5-dihydro-5-phenyl-2-(3,4,5-trimethoxy-phenyl)-3-
4.4.5. Ethyl-3,4-dihydro-4-phenyl-1(2H)-naphthalenone-2-
furancarboxylate (5b)
carboxylate (3a): mixture of diastereomers
Colorless oil. 1H NMR (CDCl3, 500 MHz)
d 7.44–7.33 (m, 5H),
Light yellow oil. 1H NMR (CDCl3, 500 MHz)
d
7.98–7.91 (m, 4H),
7.33–7.30 (s, 2H), 5.71 (dd,1H, J¼1.8, 8.9 Hz), 4.20–4.13 (m, 2H), 3.90
7.50–7.33 (m, 15H), 5.93 (dd, 1H, J¼3.2, 5.6 Hz, syn), 5.83 (dd, 1H,
(s, 9H), 3.58 (dd, 1H, J¼4.5, 10.8 Hz), 3.16 (dd, 1H, J¼6.6, 8.8 Hz), 1.25

10768
B.M. Casey et al. / Tetrahedron 65 (2009) 10762–10768
3. (a) Nair, V.; Nair, L. G.; George, T. G.; Augustine, A. Tetrahedron 2000, 56, 7607;
(t, 3H, J¼7.1 Hz). 13C NMR (CDCl3, 125 MHz)
d
165.2, 156.0, 152.4,
(b) Jiao, J.; Nguyen, L. X.; Patterson, D. R.; Flowers, R. A. Org. Lett. 2007, 9, 1323.
4. Muathen, H. A. Indian J. Chem. 1991, 30B, 522.
141.6, 128.7, 128.2, 125.7, 124.8, 107.1, 101.8, 82.3, 60.9, 59.8, 56.2,
40.4, 14.4. MS [m/z (rel int)] 298 (Mþ, 1), 105 (100), 77 (60), 51 (25).
5. (a) Roy, S. C.; Mandal, P. K. Tetrahedron 1996, 52, 2193; (b) Hwu, J. R.; Chen, C. N.;
Shiao, S. S. J. Org. Chem. 1995, 60, 856; (c) Baciocchi, E.; Ruzziconi, R. J. Org.
Chem. 1986, 51, 1645; (d) Citterio, A.; Sebastiano, R.; Marion, A.; Santi, R. J. Org.
Chem. 1991, 56, 5328; (e) Lee, Y. R.; Kim, B. S.; Kim, D. H. Tetrahedron 2000, 56,
8845; (f) Lee, Y. R.; Kim, B. S. Tetrahedron Lett. 1997, 38, 2095.
IR (KBr)
n
(cmꢀ1) 3632, 3502, 2944, 2839, 1692, 1635, 1583, 1501,
1459, 1417, 1348, 1293, 1241, 1125, 1094, 1007, 914, 851, 734. LC-
HRMS calcd. for C22H25O6 [MþH] 385.1646, found 385.1651.
6. Zhang, Y.; Raines, A. J.; Flowers, R. A. Org. Lett. 2003, 5, 2003.
7. Zhang, Y.; Raines, A. J.; Flowers, R. A. J. Org. Chem. 2004, 69, 6267.
8. (a) Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1991, 56, 4772; (b) Baciocchi, E.;
Giese, B.; Farshchi, H.; Ruzziconi, R. J. Org. Chem. 1990, 55, 5688; (c) Heiba, E. A.
I.; Dessau, R. M. J. Org. Chem. 1974, 39, 3456.
Acknowledgements
R.A.F. is grateful to the National Institutes of Health
(1R15GM075960-01) for support of this work.
9. See Supplementary data for complete Gaussian reference.
10. (a) Krmzgl, S.; Gren, N.; Yang, S. W.; Cordell, G. A.; Bozok-Johansson, C. J. Nat.
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Nat. Prod. 2004, 67, 1796; (c) Gordaliza, M.; Garcı´a, P. A.; Miguel del Corral, J. M.;
Castro, M. A.; Go´mez-Zurita, M. A. Toxicon 2004, 44, 441.
Supplementary data
11. (a) Forsey, S. P.; Rajapaksa, D.; Taylor, N. J.; Rodrigo, R. J. Org. Chem. 1989, 54,
4280; (b) Garzino, F.; Me´ou, A.; Brun, P. Eur. J. Org. Chem. 2003, 1410.
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.118.
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