Tandem SN2′ nucleophilic substitution/oxidative radical cyclization of aryl substituted allylic alcohols with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/c7ob00620a

A novel and efficient tandem S_N2′ nucleophilic substitution/oxidative radical cyclization reaction of aryl substituted allylic alcohols with 1,3-dicarbonyl compounds has been developed by using Mn(OAc)₃ as an oxidant, which enables t

Full text of DOI:10.1039/c7ob00620a

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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Tandem SN2′ Nucleophilic Substitution/Oxidative Radical
Cyclization of Aryl Substituted Allylic Alcohols with 1,3-Dicarbonyl
Compounds
Received 00th January 20xx,
Accepted 00th January 20xx
Zhen Zhang,a Cheng Li,a Shao-Hua Wang,b Fu-Min Zhang,a Xue Han,a Yong-Qiang Tu,*ac Xiao-Ming
Zhang*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient tandem SN2′ nucleophilic substitution/oxidative radical cyclization reaction of aryl substituted allylic
alcohols with 1,3-dicarbonyl compounds has been developed by using Mn(OAc)3 as an oxidant, which enables the
expeditious synthesis of polysubstituted dihydrofuran (DHF) derivatives in moderate to high yields. The use of weakly
acidic hexafluoroisopropanol (HFIP) as the solvent rather than AcOH has successfully improved the yields and expanded
the substrate scope of this type of radical cyclization reactions. Mechanistic studies confirmed the cascade reaction
process involving a final radical cyclization.
quaternary carbon containing DHFs. In this communication, we
Introduction
present a tandem SN2′ nucleophilic substitution/radical
cyclization process to achieve the synthesis of tetrasubstituted
DHFs from aryl substituted allylic alcohols and 1,3-dicarbonyl
compounds (Scheme 1b). The successful realization of this
highly efficient (up to 98% yield) and diastereoselective
Polysubstituted dihydrofurans (DHFs) are important structural
moieties widely found in a number of biologically important
natural products, as represented by hypholomine B1a and
inoscavin A1b, whose anti-oxidant, anti-inflammatory or
antidiabetic activities have received considerable attention in
related biological studies (Figure 1).2,3 Among the established
methodologies to synthesize DHFs,4 the oxidative radical
cyclization of 1,3-dicarbonyl compounds with alkenes under
transition-metal mediated or metal-free conditions is the most
straightforward and reliable method5 and thus has attracted
continuous attention in recent years.6,7 Despite the numerous
radical cyclization approaches established, the reaction to
functionalize allylic alcohols has proved to be challenging
(Scheme 1a).8 Only low yields were obtained in such radical
transformations due to the use of acetic acid as the solvent to
transformation relies on the employment of HFIP as a solvent.
O
O
O
O
O
OH
OH
HO
O
O
OH
O
O
O
HO
HO
HO
HO
hypholomine B
inoscavin A
Figure 1 Bioactive natural molecules with polysubstituted DHFs
Previous work: oxidative radical cyclization in the synthesis of DHFs
O
R
O
O
OH
Mn(OAc)3, AcOH
80 °
a)
+
C
R
HO
O
dissolve the manganese (
resulted in tedious separation processes. Additionally, these
radical cyclization reactions mainly involve the
Ⅲ
) acetate (Mn(OAc)3),9 which also
R = OEt or Me
R = OEt (35%)
R = Me (26%)
This work: tandem SN2' nucleophilic substitution/oxidative radical
cyclization in the synthesis of tetrasubstituted DHFs
O
OH
O
O
R3
AcO
Mn(OAc)3, HFIP
KOAc/AcOH, 50 °
difunctionalization of the allylic alcohol. An approach to
functionalize both the alkene group as well as its allylic
position would be in high demand because of its potential use
in the construction of more complex tetrasubstituted and
b)
+
R1
R1 = H, alkyl, or aryl
2 = alkyl, alkenyl or aryl
R3 = OMe, OEt, alkyl, or aryl
C
R2
R3
Ar
Ar
R1
20 examples
up to 98% yield
R2
O
R
Scheme 1 Different oxidative radical cyclization reactions of allylic alcohols in the
synthesis of DHFs
Results and discussion
We initiated our study by investigating the radical
cyclization of diphenyl substituted allylic alcohol 1a and ethyl
acetylacetate 2a. When the reaction was conducted in AcOH
with Mn(OAc)3·2H2O being used as the oxidant, DHF 3a was
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obtained in a low yield (41%, Table 1, entry 1). This surprising comparison, the cyclization reactions of monophenyl
outcome stood in contrast with previously reported results, as substituted allylic alcohols were less effective 3f 3h),
(
-
the 1,3-dicarbonyl radical first added to the more substituted especially for substrate 1g with electron-rich phenyl
position of the alkene functionality, resulting in a formal anti- substituent. It is interesting to note that all the three reactions
Markovnikov addition followed by cyclization with the allylic were highly diastereoselective for the formation of the cis-
alcohol to give the tetrasubstituted product. Although the isomers, which must have proceeded via completely different
mechanism of this tandem reaction was not understood yet, stereochemical cyclization courses from the reaction of methyl
the formation of a tetrasubstituted DHF and introduction of an phenyl substituted allylic alcohol 1i that yielded the trans-
acetyl ester group at the terminal alkene position through this dihydrofuran 3i
.
Table 2 Scope of aryl substituted allylic alcohols 1a
single transformation was synthetically valuable. To further
enhance the yield of this reaction and avoid the laborious
separation process of AcOH, other solvents were screened,
and a comparable yield could only be obtained when weakly
acidic HFIP was used as the solvent (entry 2).10 With the
promising result, some acetate additives were next examined
(entries 3-7). Pleasingly, an increase of yield was found in all
cases, and the combination of KOAc and AcOH gave the best
result (95% yield). The employment of HFIP as the solvent was
crucial to the success of this reaction. Replacing HFIP with
isopropanol (IPA) would totally inhibit the reaction (entry 8)
while the use of other fluorosubstituted alcohols like
trifluoroethanol (TFE) would diminish the yield (entry 9). A
screening of other reaction parameters, such as the
temperature and reaction time, did not further improve the
result.
Table 1. Optimization of the oxidative radical cyclization of aryl substituted
allylic alcoholsa
a
b
Isolated yield; The ratio of diastereoisomers was determined by H
1
NMR and the configuration of the major isomers was assigned using
NOE and NOESY correlations.11
A
number of 1,3-dicarbonyl compounds were then
entry
solvent
AcOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
IPA
additive
―
yield (%)b
evaluated under the standard reaction conditions. The results
were summarized in Table 3. Various γ-substituted β-keto
esters were found to be well-tolerated, affording DHFs with
different substituents (3j-
3n), such as isopropyl,12 cyclopropyl,
1
2
3
4
5
6
7
8
9
41
44
64
47
76
79
95
―
70
―
AcOH
Ac2O
phenyl, 2-phenoxyethyl, and 2-ethoxy-2-oxoethyl at C2
position. Generally, the product yields were higher for
NaOAc
KOAc
electron-donating group substituted β-keto esters (2j-2m) than
KOAc & AcOH
KOAc & AcOH
KOAc & AcOH
for the one with electron-withdrawing group (2n). The
successful transformation of β-keto lactone 2o to DHF 3o
would establish the core structure of hypholomine B and
inoscavin A, albeit in moderate yield (51%). Either acyclic or
cyclic 1,3-diketone compounds were also suited for this
tandem reaction. The yields were satisfying for the reactions of
acetylacetone 2p and 1,3-indanedione 2q while relatively
lower for those of cyclic 1,3-diketones 3r and 3s. When
unsymmetrical 1,3-diketone 2t was subjected to the optimized
TFE
a Reaction conditions: 1a (0.1 mmol) was dissolved in 1.0 mL of solvent
followed by addition of Mn(OAc)3·2H2O (0.3 mmol), 2a (0.2 mmol), and
the additive (0.5 mmol for NaOAc or KOAc, 0.2 mL for AcOH or Ac2O),
and the reaction was conducted at 50 °C; Isolated yield. HFIP =
hexafluoroisopropanol, IPA = isopropanol, TFE = trifluoroethanol.
b
With the optimal conditions in hand (Table 1, entry 7), we
then explored the scope and limitation of this transformation.
As can be seen from Table 2, the tandem reactions of a variety
of aryl substituted allylic alcohols performed well, affording
the desired tetrasubstituted DHFs in moderate to high yields
(39-98%). For diphenyl substituted allylic alcohols, the product
conditions, a 1:1 separable regioisomers 3t and 3t′ would be
obtained, indicating a nonselective cyclization process of one
of the carbonyl groups on the allylic position. However, in the
reaction of 1-phenylbutane-1,3-dione 2u
,
the phenyl
substituted carbonyl group would participate in the cyclization
yields were generally higher (3a-3d, up to 98%), regardless of
to generate 3u with excellent regioselectivity.
the electronic nature of the phenyl substituents. However, the
diastereoselectivity for the reaction of allylic alcohol 1e with
different aryl substituents was rather poorly (d. r. 1.8:1). In
Table 3 Scope of 1,3-dicarbonyl compounds 2a
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during the cyclization process. The manganese (
would both interact with the л-electron of the arene and the
basic oxygen atom of the acetoxyl group in structure 3f-C 13
Ⅲ) complex
,
thus placing the two substituents in a cis-position during the
cyclization. While in structure 3i-C, the weak interaction
diminished due to the slight steric hindrance between the
hydrogen and the methyl group. Therefore, the steric effects
would predominate and place the bulkier phenyl group in a cis-
position with the hydrogen, yielding the trans-3i
.
a Isolated yield.1
To further probe the mechanism of this cyclization reaction,
some control experiments were conducted (Scheme 2). When
the reaction was carried out in the absence of Mn(OAc)3·2H2O,
3,3-diphenylallyl acetate 4a was obtained as the sole product
(eq 1), which could smoothly react with ethyl acetylacetate 2a
under the standard conditions to deliver DHF 3a in high yield
Scheme 3 Proposed mechanism of this tandem reaction
Conclusions
In summary, we have successfully developed a novel and
versatile tandem SN2 nucleophilic substitution/oxidative
(eq 2). This result indicated the intermediacy of 4a
,
′
presumably generated via an SN2′ nucleophilic substitution, in
radical cyclization reaction mediated by Mn(OAc)3 for the
synthesis of polysubstituted DHFs, which is applicable to a
wide scope of aryl substituted allylic alcohols and 1,3-
dicarbonyl compounds. The use of HFIP as a solvent instead of
AcOH has improved the yield of the radical reactions and
obviated the laborious separation process. Further studies on
the application of this methodology on nature product
synthesis are underway in our laboratories.
this tandem process. The acetoxy group on 4a, however, was
not necessary for the success of the second cyclization
reaction, as the oxidative radical cyclization of 4b could also
give the DHF product 3v in high yield (eq 3). In addition, when
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to
the reaction system, only 4a was generated (eq 4), signifying a
radical cyclization process in this reaction.
Experimental
General information
All reactions under standard conditions were carried out under
argon and monitored by thin-layer chromatography (TLC) on gel
F254 plates. The silica gel (200-300 meshes) was used for column
chromatography with light petroleum ether (b.p. 60~90 ℃),
dichloromethane and ethyl acetate used as eluents. All solvents
were purified and dried by standard techniques and distilled prior to
use. 1H and 13C NMR spectra were recorded in CDCl3 solution on
Varian Inova -600 MHz, Bruker AM-400 MHz or Varian Mercury-300
MHz instruments and the spectral data were reported in ppm
relative to tetramethylsilane (0.00 ppm) or residual undeuterated
solvent CHCl3 (7.27 ppm) as internal standard for 1H NMR and
deuterated solvent CDCl3 (77.0 ppm) as internal standard for 13C
Scheme 2 Control experiments to investigate the mechanism of this tandem
reaction
On the basis of the above experimental results, a possible
reaction mechanism was proposed (Scheme 3). Under weakly
acidic conditions, an SN2
substituted allylic alcohol
acetate
on the newly formed internal alkene group would deliver
stabilized benzylic radical . After the second oxidation of
radical to carbocation by Mn(OAc)3, the final cyclization
produced DHF . The opposite stereochemical outcomes
′
nucleophilic substitution of aryl
1
NMR. The ratio of diastereoisomers was determined by H NMR of
1
would first take place to give allyl
the crude products. IR spectra were recorded on Nicolet FT-170SX
spectrometer. The MS data were obtained with SHIMADZU GCMS-
QP2010 SE by means of EI (70 eV) technique and signals were given
in m/z with relative intensity (%) in brackets. High-resolution mass
spectral analysis (HRMS) data were measured on a Bruker Daltonics
APEXII 47e FT-ICR spectrometer by means of the ESI technique.
4
. Addition of in situ generated 1,3-dicarbonyl radical
A
B
B
C
3
observed in the reaction of 1f and 1i could be rationalized by
considering two distinct transition structures 3f-C and 3i-C
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Preparation of aryl substituted allylic alcohols 1a-i:
2-phenylbut-3-en-2-ol (1i)14d: Isolated yield: 80 % (355.4 mg).
1
Colorless oil. H NMR (400 MHz, CDCl3, ppm): δ 7.48–7.45 (m, 2H),
All aryl substituted allylic alcohols 1a-i were prepared according to
the literature.14 A typical procedure is given for the synthesis of 1,1-
diphenylprop-2-en-1-ol (1a). To a solution of benzophenone (546.7
mg, 3.0 mmol) in THF (15 mL) at 0 °C was added vinylmagnesium
7.36–7.31 (m, 2H), 7.27–7.22 (m, 1H), 6.17 (dd, J = 17.2, 10.4 Hz,
1H), 5.31-5.26 (m, 1H), 5.15-5.12 (m, 1H), 1.94 (d, J = 2.8 Hz, 1H,
OH), 1.65 (s, 3H).
bromide (4.5 mL, 1.0 M in THF, 1.5 equiv.) under argon atmosphere. Preparation of aryl substituted allylic alcohols 1h:
After the reaction mixture was stirred at 0 °C for 1 h, the resulting
To a solution of crotonaldehyde (0.25 mL, 3.0 mmol) in THF (5 mL)
solution was quenched by saturated aqueous NH4Cl (5 mL) and H2O
(5 mL) and allowed to warm to room temperature. The resulting
mixture was extracted with ethyl acetate (15 mL × 3), washed with
brine (5 mL), dried over Na2SO4 and concentrated in vacuo.
Purification of the residue by neutral silica gel column
chromatography afforded 1a (598.8 mg, 95% yield) as a colorless
oil.
at 0 °C was added phenylmagnesium bromide (4.5 mL, 1.0 M in THF,
1.5 equiv.) under argon atmosphere. After the reaction mixture was
stirred at 0 °C for 1 h, the resulting solution was quenched by
saturated aqueous NH4Cl (1 mL) and H2O (3 mL) and allowed to
warm to room temperature. The resulting mixture was extracted
with ethyl acetate (5 mL × 3), washed with brine (5 mL), dried over
Na2SO4 and concentrated in vacuo. Purification of the residue by
1,1-diphenylprop-2-en-1-ol (1a)14a: Isolated yield: 95 % (598.8 mg). neutral silica gel column chromatography afforded the desired
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.39-7.36 (m, 4H), allylic alcohol 1h (355.4 mg, 80% yield) as a colorless oil.
(E)-1-phenylbut-2-en-1-ol (1h)14e: Isolated yield: 80 % (355.4 mg).
7.34-7.29 (m, 4H), 7.27-7.23 (m, 2H), 6.50 (dd, J = 17.2, 10.4 Hz, 1H),
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.35-7.29 (m, 4H),
5.34-5.29 (m, 2H), 2.29 (s, 1H, OH).
1,1-di([1,1'-biphenyl]-4-yl)prop-2-en-1-ol (1b)14b: Isolated yield: 92 7.27-7.21 (m, 1H), 5.77-5.62 (m, 2H), 5.10 (dd, J = 6.0, 3.6 Hz, 1H),
1
% (999.6 mg). Yellow solid. H NMR (400 MHz, CDCl3, ppm): δ 7.56- 2.20 (d, J = 3.6 Hz, 1H), 1.69 (d, J = 5.6 Hz, 3H).
7.53 (m, 8H), 7.51-7.46 (m, 4H), 7.42-7.38 (m, 4H), 7.38-7.37 (m,
General procedure for cyclization reaction of aryl substituted
2H), 6.62 (dd, J = 17.2, 10.4 Hz, 1H), 5.46 (dd, J = 17.2, 1.2 Hz, 1H),
allylic alcohols 1 with 2:
5.42 (dd, J = 10.6, 1.0 Hz, 1H), 2.45 (s, 1H, OH).
The reaction conditions and results are shown in Tables 1–3. A
1,1-bis(4-fluorophenyl)prop-2-en-1-ol (1c)14a: Isolated yield: 90 %
(664.4 mg). Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.35-
7.31 (m, 4H), 7.06-6.99 (m, 4H), 6.45 (dd, J = 17.0, 10.6 Hz, 1H), 5.34
alcohol 1a (21.0 mg, 0.1 mmol) was dissolved in 1.0 mL of HFIP
(dd, J = 10.6, 1.0 Hz, 1H), 5.29 (dd, J = 17.0, 1.0 Hz, 1H), 2.43 (s, 1H,
typical procedure is given for the reaction of 1,1-diphenylprop-2-en-
1-ol (1a) with ethyl acetoacetate (2a) (Table 1, Entry 7). Allylic
under argon followed by addition of Mn(OAc)3·2H2O (80.4 mg, 0.3
OH).
mmol), KOAc (49.1 mg, 0.5 mmol), 2a (26.0 µL, 0.2 mmol), and
1,1-bis(4-chlorophenyl)prop-2-en-1-ol (1d)14c: Isolated yield: 91 % AcOH (200 µL) at room temperature. The reaction mixture was
(759.0 mg). Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.31- stirred at 50 oC and monitored by TLC. After the complete
7.23 (m, 8H), 6.39 (dd, J = 17.2, 10.8 Hz, 1H), 5.32 (dd, J = 10.4, 0.8 consumption of 1a, the reaction mixture was cooled to room
Hz, 1H), 5.26 (dd, J = 17.2, 0.8 Hz, 1H), 2.40 (s, 1H, OH).
temperature and then quenched with 1.0 mL of saturated aqueous
NaHSO3, diluted with CH2Cl2, and extracted with CH2Cl2 (5 mL × 3).
The combined organic layer was washed with saturated aqueous
Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated
under vacuum. Purification of the residue by column
chromatography on silica gel provided the compound 3a (36.1 mg,
95% yield) as a colorless oil.
1-(4-fluorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-ol
(1e):
Isolated yield: 71 % (549.8 mg). Colorless oil. 1H NMR (400 MHz,
CDCl3, ppm): δ 7.35-7.30 (m, 2H), 7.27-7.23 (m, 2H), 7.01-6.96 (m,
2H), 6.85-6.82 (m, 2H), 6.43 (dd, J = 17.0, 10.6 Hz, 1H), 5.30-5.24 (m,
2H), 3.78 (s, 3H), 2.31 (s, 1H, OH); 13C NMR (100 MHz, CDCl3, ppm):
δ 161.8 (d, J = 245.0 Hz), 158.8, 143.5, 141.6 (d, J = 3.0 Hz), 137.8,
128.6 (d, J = 8.0 Hz), 128.1, 114.8 (d, J = 21.0 Hz), 113.9, 113.5, 78.7,
55.2; 19F NMR (400 MHz, CDCl3, ppm): δ -115.7; IR (neat) 3455,
2929, 1605, 1508, 1249, 1177, 1159, 1035, 832 cm-1; MS (EI) m/z
(%) 258 (M+, 7), 135 (22) 126 (14), 123 (27), 121 (34), 72 (72), 69
(31), 59 (100), 55 (55); HRMS (ESI) Calcd. for C16H15FO2 (M+Na)+:
281.0948, Found 281.0952.
ethyl 4-(acetoxymethyl)-2-methyl-5,5-diphenyl-4,5-dihydrofuran-
3-carboxylate (3a): Isolated yield: 95 % (36.1 mg). Colorless oil. 1H
NMR (400 MHz, CDCl3, ppm): δ 7.58-7.55 (m, 2H), 7.40-7.19 (m, 8H),
4.23-4.11 (m, 3H), 4.00-3.93 (m, 2H), 2.32 (d, J = 1.2 Hz, 3H), 1.74 (s,
3H), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ
170.2, 167.9, 165.1, 144.3, 139.9, 128.2, 128.0, 127.6, 127.4, 126.8,
126.3, 103.3, 93.9, 62.8, 59.7, 49.1, 20.5, 14.7, 14.3; IR (neat) 2924,
1741, 1697, 1382, 1236, 1079, 736, 700 cm-1; MS (EI) m/z (%) 320
1-phenylprop-2-en-1-ol (1f)14d: Isolated yield: 90 % (326.1 mg).
1
Colorless oil. H NMR (400 MHz, CDCl3, ppm): δ 7.35–7.22 (m, 5H),
6.06–5.97 (m, 1H), 5.31 (dt, J = 17.2, 1.2 Hz, 1H), 5.18–5.13 (m, 2H), (100), 274 (41), 231 (34), 205 (54), 165 (37), 115 (12), 105 (25), 77
(11); HRMS (ESI) Calcd. for C23H24O5 (M+Na)+: 403.1516, Found
2.35 (d, J = 3.6 Hz, 1H, OH).
1-(4-methoxyphenyl)prop-2-en-1-ol (1g)14d: Isolated yield: 80 %
(393.8 mg). Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.26-
403.1514.
ethyl 5,5-di([1,1'-biphenyl]-4-yl)-4-(acetoxymethyl)-2-methyl-4,5-
7.23 (m, 2H), 6.87-6.83 (m, 2H), 6.05-5.95 (m, 1H), 5.28 (dt, J = 17.2,
dihydrofuran-3-carboxylate (3b): Isolated yield: 98 % (52.2 mg).
1
1.2 Hz, 1H), 5.14 (dt, J = 10.4, 1.2 Hz, 1H), 5.09 (d, J = 5.6 Hz, 1H),
Colorless oil. H NMR (400 MHz, CDCl3, ppm): δ 7.68-7.31 (m, 18H),
3.76 (s, 3H), 2.49 (s, 1H, OH);
4.24-4.16 (m, 3H), 4.08-4.01 (m, 2H), 2.36 (d, J = 0.4 Hz, 3H), 1.74 (s,
3H), 1.55 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
4 | J. Name., 2012, 00, 1-3
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ppm): δ 170.2, 167.9, 165.1, 143.2, 140.9, 140.4, 140.4, 140.3,
138.9, 128.8, 128.7, 127.5, 127.4, 127.2, 127.1, 127.0, 127.0, 126.7,
126.4, 103.5, 93.8, 62.8, 59.8, 49.2, 20.5, 14.7, 14.4; IR (neat) 2926,
1740, 1698, 1648, 1378, 1238, 1096, 841, 767, 698 cm-1; MS (EI) m/z
(%) 472 (100), 430 (49), 355 (2), 181 (14); HRMS (ESI) Calcd. for
C35H32O5 (M+H)+: 533.2323, Found 533.2321.
(300 MHz, CDCl3, ppm): δ -114.3; IR (neat) 2958, 1742, 1697, 1649,
1510, 1235, 1180, 1095, 1036, 832 cm-1; MS (EI) m/z (%) 368 (100),
326 (48), 297 (35), 253 (49), 239 (24), 196 (13), 170 (10); HRMS (ESI)
Calcd. for C24H25FO6 (M+H)+: 429.1708, Found 429.1709.
ethyl
(4,5-cis)-4-(acetoxymethyl)-2-methyl-5-phenyl-4,5-
dihydrofuran-3-carboxylate (3f): Isolated yield: 65 % (19.8 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.40-7.26 (m, 5H),
5.42 (d, J = 5.2 Hz, 1H), 4.46 (dd, J = 10.8, 3.2 Hz, 1H), 4.23-4.12 (m,
3H), 3.49-3.43 (m, 1H), 2.34 (d, J = 1.2 Hz, 3H), 2.09 (s, 3H), 1.27 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 170.9, 169.9,
165.4, 140.9, 128.7, 128.2, 125.1, 101.1, 86.2, 65.3, 59.7, 50.7, 20.9,
14.4, 14.3; IR (neat) 2925, 1743, 1700, 1643, 1382, 1228, 1095, 700
cm-1; MS (EI) m/z (%) 244 (100), 198 (54), 158 (32), 115 (43), 91
(19); HRMS (ESI) Calcd. for C17H20O5 (M+H)+: 305.1384, Found
305.1383.
ethyl
4-(acetoxymethyl)-5,5-bis(4-fluorophenyl)-2-methyl-4,5-
dihydrofuran-3-carboxylate (3c): Isolated yield: 98 % (40.8 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.52-7.48 (m, 2H),
7.24-7.20 (m, 2H), 7.08-7.03 (m, 2H), 6.96 (t, J = 8.6 Hz, 2H), 4.18
(qd, J = 7.0, 1.0 Hz, 2H), 4.11-4.07 (m, 1H), 3.99-3.89 (m, 2H), 2.30
(d, J = 1.2 Hz, 3H), 1.77 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3, ppm): δ 170.0, 167.5, 164.9, 163.4 (d, J = 39.0 Hz),
161.0 (d, J = 39.0 Hz), 139.9 (d, J = 4.0 Hz), 135.7 (d, J = 4.0 Hz),
128.6 (d, J = 8.0 Hz), 128.1 (d, J = 8.0 Hz), 115.2 (d, J = 22.0 Hz),
114.6 (d, J = 21.0 Hz), 103.4, 93.2, 62.6, 59.9, 49.2, 20.4, 14.6, 14.3;
19F NMR (400 MHz, CDCl3, ppm): δ -113.8, -114.5; IR (neat) 2981,
1742, 1697, 1650, 1604, 1381, 1233, 1093, 835, 735 cm-1; MS (EI)
m/z (%) 356 (100), 314 (29), 270 (25), 240 (16), 201 (27), 123 (18);
HRMS (ESI) Calcd. for C23H22F2O5 (M+H)+: 417.1508, Found
417.1509.
ethyl (4,5-cis)-4-(acetoxymethyl)-5-(4-methoxyphenyl)-2-methyl-
4,5-dihydrofuran-3-carboxylate (3g): Isolated yield: 39 % (13.0 mg).
d.r. > 20:1. Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.23 (d, J
= 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.36 (d, J = 5.2 Hz, 1H), 4.44
(dd, J = 11.4, 3.4 Hz, 1H), 4.25-4.11 (m, 3H), 3.82 (s, 3H), 3.48-3.45
(m, 1H), 2.32 (d, J = 1.2 Hz, 3H), 2.08 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H);
ethyl
4-(acetoxymethyl)-5,5-bis(4-chlorophenyl)-2-methyl-4,5- 13C NMR (100 MHz, CDCl3, ppm): δ 171.0, 169.8, 165.4, 159.6,
dihydrofuran-3-carboxylate (3d): Isolated yield: 98 % (43.9 mg). 133.0, 126.8, 114.1, 101.1, 86.2, 65.3, 59.6, 55.3, 50.4, 20.9, 14.4,
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.48-7.44 (m, 2H), 14.3; IR (neat) 2927, 1742, 1699, 1642, 1515, 1382, 1247, 1094,
7.36-7.32 (m, 2H), 7.27-7.23 (m, 2H), 7.21-7.18 (m, 2H), 4.18 (qd, J = 1034, 833, 772, 737 cm-1; MS (EI) m/z (%) 274 (100), 245 (16), 188
7.2, 0.8 Hz, 2H), 4.09-4.06 (m, 1H), 3.99-3.90 (m, 2H), 2.29 (d, J = 0.8 (17), 145 (21), 115 (16), 77 (10); HRMS (ESI) Calcd. for C18H22O6
Hz, 3H), 1.76 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, (M+H)+: 335.1489, Found 335.1489.
CDCl3, ppm): δ 170.0, 167.4, 164.8, 142.4, 138.1, 134.2, 133.7,
ethyl
4-(1-acetoxyethyl)-2-methyl-5-phenyl-4,5-dihydrofuran-3-
128.6, 128.2, 127.9, 127.7, 103.6, 93.0, 62.5, 59.9, 49.0, 20.4, 14.6,
14.3; IR (neat) 2927, 1742, 1698, 1651, 1234, 1094, 822, 737 cm-1;
MS (EI) m/z (%) 388 (100), 346 (33), 317 (21), 302 (29), 189 (30), 139
(23); HRMS (ESI) Calcd. for C23H22Cl2O5 (M+H)+: 449.0917, Found
449.0923.
carboxylate (3h): Isolated yield: 90 % (28.6 mg). d.r. = 1:1.6.
1
Colorless oil. 3h-A: H NMR (400 MHz, CDCl3, ppm): δ 7.39-7.25 (m,
5H), 5.60 (d, J = 4.4 Hz, 1H), 5.46 (qd, J = 6.4, 4.4 Hz, 1H), 4.23-4.09
(m, 2H), 3.52-3.49 (m, 1H), 2.36 (d, J = 1.6 Hz, 3H), 2.04 (s, 3H), 1.30-
1.22 (m, 6H); 13C NMR (100 MHz, CDCl3, ppm): δ 170.0, 169.9,
ethyl 4-(acetoxymethyl)-5-(4-fluorophenyl)-5-(4-methoxyphenyl)- 165.4, 141.7, 128.7, 128.0, 124.9, 101.7, 83.4, 70.2, 59.7, 54.6, 21.2,
2-methyl-4,5-dihydrofuran-3-carboxylate (3e): Isolated yield: 62 % 14.4, 14.3, 14.2; IR (neat) 2925, 2107, 1263, 1251, 1077, 841, 702
1
(26.6 mg). Colorless oil. 3e-major: H NMR (400 MHz, CDCl3, ppm): cm-1; MS (EI) m/z (%) 255 (100), 239 (10), 165 (10), 105 (14), 73 (73),
δ 7.46-7.42 (m, 2H), 7.26-7.22 (m, 2H), 6.98-6.88 (m, 4H), 4.18 (q, J 77 (11); HRMS (ESI) Calcd. for C18H22O5 (M+Na)+: 341.1359, Found
= 7.0 Hz, 2H), 4.13-4.09 (m, 1H), 3.99-3.89 (m, 2H), 3.82 (s, 3H), 2.30 341.1358; 3h-B: 1H NMR (400 MHz, CDCl3, ppm): δ 7.40-7.26 (m,
(s, 3H), 1.77 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, 5H), 5.54 (d, J = 4.4 Hz, 1H), 5.43 (qd, J = 6.4, 2.8 Hz, 1H), 4.26-4.09
CDCl3, ppm): δ 170.1, 167.7, 165.1, 161.9 (d, J = 245.7 Hz), 159.3, (m, 2H), 3.28-3.25 (m, 1H), 2.32 (d, J = 0.8 Hz, 3H), 2.04 (s, 3H), 1.31-
136.2 (d, J = 8.7 Hz), 128.7 (d, J = 8.0 Hz), 127.6, 114.4 (d, J = 21.3 1.25 (m, 6H); 13C NMR (100 MHz, CDCl3, ppm): δ 170.3, 169.2,
Hz), 113.6, 103.3, 93.5, 62.7, 59.8, 55.3, 48.9, 20.5, 14.7, 14.4; 19F 165.4, 141.5, 128.8, 128.2, 125.2, 101.9, 83.4, 69.7, 59.6, 56.0, 21.1,
17.9, 14.3, 14.2; IR (neat) 2957, 1742, 1699, 1649, 1379, 1248,
1081, 761, 700 cm-1; MS (EI) m/z (%) 211 (100), 165 (35), 105 (8), 73
(30); HRMS (ESI) Calcd. for C18H22O5 (M+H)+: 319.1540, Found
319.1541.
NMR (300 MHz, CDCl3, ppm): δ -115.0; IR (neat) 2958, 1742, 1697,
1648, 1510, 1235, 1180, 1093, 1035, 832 cm-1; MS (EI) m/z (%) 368
(100), 326 (52), 297 (46), 253 (68), 239 (36), 196 (21), 170 (16);
HRMS (ESI) Calcd. for C24H25FO6 (M+H)+: 429.1708, Found 429.1711.
3e-minor: 1H NMR (400 MHz, CDCl3, ppm): δ 7.53-7.49 (m, 2H),
7.15-7.12 (m, 2H), 7.07-7.02 (m, 2H), 6.80-6.77 (m, 2H), 4.17 (q, J =
7.0 Hz, 2H), 4.09-4.05 (m, 1H), 3.99-3.89 (m, 2H), 3.77 (s, 3H), 2.30
(s, 3H), 1.77 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
CDCl3, ppm): δ 170.2, 167.7, 165.1, 162.3 (d, J = 245.3 Hz), 158.9,
140.4, 131.9, 128.1 (d, J = 8.1 Hz), 128.0, 115.1 (d, J = 21.5 Hz),
113.0, 103.3, 93.5, 62.9, 59.8, 55.2, 49.2, 20.6, 14.7, 14.4; 19F NMR
ethyl 4-(acetoxymethyl)-2,5-dimethyl-5-phenyl-4,5-dihydrofuran-
3-carboxylate (3i): Isolated yield: 78 % (24.8 mg). d.r. > 20:1.
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.38-7.33 (m, 4H),
7.30-7.26 (m, 1H), 4.46 (dd, J = 11.6, 2.8 Hz, 1H), 4.28 (dd, J = 11.2,
9.2 Hz, 1H), 4.18-4.04 (m, 2H), 3.51 (d, J = 8.4 Hz, 1H), 2.33 (s, 3H),
2.11 (s, 3H), 1.67 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3, ppm): δ 170.7, 168.6, 165.3, 147.3, 128.4, 127.3, 123.9,
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101.7, 90.4, 62.6, 59.6, 51.8, 24.0, 21.0, 14.5, 14.3; IR (neat) 2980, Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.58-7.55 (m, 2H),
1743, 1698, 1646, 1382, 1234, 1079, 764, 701 cm-1; MS (EI) m/z (%) 7.41-7.21 (m, 8H), 4.23-4.12 (m, 5H), 4.02-3.71 (m, 3H), 3.67 (d, J =
258 (100), 212 (78), 172 (26), 128 (39), 91 (13); HRMS (ESI) Calcd. 0.8 Hz, 1H), 1.76 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H),1.22 (t, J = 7.2 Hz,
for C18H22O5 (M+Na)+: 341.1359, Found 341.1357.
3H); 13C NMR (100 MHz, CDCl3, ppm): δ 170.2, 167.7, 164.5, 162.7,
143.8, 139.7, 128.2, 128.1, 127.6, 127.6, 127.0, 126.5, 105.3, 94.8,
62.6, 61.3, 60.1, 49.2, 34.8, 20.5, 14.3, 14.1; IR (neat) 2927, 1741,
1699, 1654, 1371, 1238, 1073, 760, 701 cm-1; MS (EI) m/z (%) 392
(100), 346 (31), 278 (42), 258 (49), 205 (32), 165 (24), 115 (13), 105
(28); HRMS (ESI) Calcd. for C26H28O7 (M+NH4)+: 470.2173, Found
470.2172.
methyl
4-(acetoxymethyl)-2-isopropyl-5,5-diphenyl-4,5-
dihydrofuran-3-carboxylate (3j): Isolated yield: 84 % (33.1 mg).
White solid. Mp: 108-110 ºC; 1H NMR (400 MHz, CDCl3, ppm): δ
7.57-7.54 (m, 2H), 7.38-7.18 (m, 8H), 4.13 (dd, J = 11.2, 7.2 Hz, 1H),
4.00 (dd, J = 11.2, 7.2 Hz, 1H), 3.90 (dd, J = 11.2, 3.2 Hz, 1H), 3.73-
3.65 (m, 4H), 1.73 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3, ppm): δ 175.7, 170.2, 165.4, 144.1, (6-methyl-4-oxo-2,2-diphenyl-2,3-dihydro-4H-furo[3,2-c]pyran-3-
140.0, 128.1, 127.9, 127.7, 127.4, 126.7, 126.2, 100.9, 93.4, 62.8, yl)methyl acetate (3o): Isolated yield: 51 % (19.2 mg). Yellow solid.
50.9, 48.7, 27.1, 20.5, 19.9, 19.1; IR (neat) 2970, 1741, 1700, 1638, Mp: 168-170 ºC; 1H NMR (400 MHz, CDCl3, ppm): δ 7.46-7.43 (m,
1238, 1066, 737, 701 cm-1; MS (EI) m/z (%) 334 (100), 259 (28), 191 2H), 7.36-7.21 (m, 8H), 6.70 (dd, J = 9.2, 8.0 Hz, 1H), 5.74 (s, 1H),
(29), 165 (22), 71 (31); HRMS (ESI) Calcd. for C24H26O5 (M+H)+: 3.11-3.08 (m, 2H), 2.14 (s, 3H), 2.12 (s, 3H); 13C NMR (100 MHz,
395.1853, Found 395.1852.
CDCl3, ppm): δ 170.8, 169.2, 164.9, 161.6, 141.2, 138.2, 128.1,
128.0, 128.0, 127.9, 127.5, 127.5, 99.4, 95.1, 85.9, 84.9, 27.3, 22.0,
20.2; IR (neat) 2923, 1739, 1724, 1644, 1587, 1239, 743, 702 cm-1;
MS (EI) m/z (%) 316 (100), 239 (30), 152 (42), 105 (74), 77 (30);
HRMS (ESI) Calcd. for C23H20O5 (M+H)+: 377.1384, Found 377.1383.
methyl
4-(acetoxymethyl)-2-cyclopropyl-5,5-diphenyl-4,5-
dihydrofuran-3-carboxylate (3k): Isolated yield: 97 % (38.0 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.48-7.45 (m, 2H),
7.38-7.18 (m, 8H), 4.18 (dd, J = 7.6, 3.6 Hz, 1H), 3.98 (dd, J = 11.2,
7.6 Hz, 1H), 3.91 (dd, J = 11.2, 3.6 Hz, 1H), 3.73 (s, 3H), 2.80-2.73 (m, (4-acetyl-5-methyl-2,2-diphenyl-2,3-dihydrofuran-3-yl)methyl
1H), 1.73 (s, 3H), 1.35-1.30 (m, 1H), 1.05-0.84 (m, 3H); 13C NMR (100 acetate (3p): Isolated yield: 90 % (31.5 mg). Colorless oil. 1H NMR
MHz, CDCl3, ppm): δ 171.5, 170.2, 166.0, 143.8, 140.0, 128.2, 128.0, (400 MHz, CDCl3, ppm): δ 7.55-7.52 (m, 2H), 7.38-7.19 (m, 8H), 4.24
127.6, 127.4, 126.6, 126.2, 102.4, 93.5, 62.8, 50.9, 48.7, 20.5, 9.5, (dd, J = 7.0, 3.8 Hz, 1H), 3.94 (dd, J = 11.4, 7.4 Hz, 1H), 3.87 (dd, J =
8.1, 7.4; IR (neat) 2951, 1740, 1700, 1634, 1382, 1239, 1068, 761, 11.6, 4.0 Hz, 1H), 2.34 (s, 3H), 2.29 (s, 3H), 1.73 (s, 3H); 13C NMR
700 cm-1; MS (EI) m/z (%) 332 (80), 300 (12), 231 (15), 165 (16), 105 (100 MHz, CDCl3, ppm): δ 193.2, 170.2, 166.8, 143.9, 139.6, 128.3,
(37), 69 (100); HRMS (ESI) Calcd. for C24H24O5 (M+H)+: 393.1697, 128.1, 127.7, 127.5, 126.7, 126.2, 115.3, 93.9, 62.8, 48.9, 29.2, 20.5,
Found 393.1695.
15.8; IR (neat) 2925, 1739, 1625, 1386, 1236, 766, 701 cm-1; MS (EI)
m/z (%) 290 (100), 248 (22), 205 (30), 165 (25), 115 (10), 105 (13);
HRMS (ESI) Calcd. for C22H22O4 (M+H)+: 351.1591, Found 351.1590.
ethyl
4-(acetoxymethyl)-2,5,5-triphenyl-4,5-dihydrofuran-3-
carboxylate (3l): Isolated yield: 95 % (42.0 mg). Colorless oil. 1H
NMR (400 MHz, CDCl3, ppm): δ 7.44-7.41 (m, 2H), 7.31-7.14 (m, (4-oxo-2,2-diphenyl-3,4-dihydro-2H-indeno[1,2-b]furan-3
13H), 4.25-4.14 (m, 4H), 4.03-3.92 (m, 3H), 1.63 (s, 3H), 1.30 (t, J = yl)methyl acetate (3q): Isolated yield: 97 % (38.4 mg). Yellow solid.
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 170.4, 164.8, 164.3, Mp: 194-197 ºC; 1H NMR (400 MHz, CDCl3, ppm): δ 7.91-7.88 (m,
143.9, 139.9, 130.8, 129.7, 128.3, 128.1, 127.7, 127.6, 127.5, 126.8, 1H), 7.86-7.79 (m, 3H), 7.30-7.15 (m, 10H), 4.86 (dd, J = 12.0, 6.8 Hz,
126.4, 103.8, 93.4, 62.9, 60.0, 49.5, 20.5, 14.1; IR (neat) 2981, 1740, 1H), 4.53 (dd, J = 11.8, 7.8 Hz, 1H), 3.38 (t, J = 7.4 Hz, 1H), 2.06 (s,
1686, 1631, 1374, 1238, 1096, 763, 697 cm-1; MS (EI) m/z (%) 382 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 195.8, 195.3, 170.7, 142.7,
(31), 296 (10), 105 (100), 77 (21); HRMS (ESI) Calcd. for C28H26O5 141.8, 140.4, 136.4, 135.0, 134.9, 129.6, 128.7, 128.6, 128.6, 127.5,
(M+H)+: 443.1853, Found 443.1851.
127.3, 122.7, 122.6, 59.5, 58.5, 46.3, 39.2, 20.9; IR (neat) 3059,
2925, 1740, 1704, 1226, 766, 738, 707 cm-1; MS (EI) m/z (%) 336
(100), 307 (23), 259 (10), 165 (15), 115 (5), 105 (20); HRMS (ESI)
Calcd. for C26H20O4 (M+NH4)+: 414.1700, Found 414.1699.
ethyl 4-(acetoxymethyl)-2-((benzyloxy)methyl)-5,5-diphenyl-4,5-
dihydrofuran-3-carboxylate (3m): Isolated yield: 90 % (45.0 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.57-7.54 (m, 2H),
7.37-7.18 (m, 13H), 4.50 (s, 2H), 4.19-4.13 (m, 3H), 4.00-3.92 (m, (4-oxo-2,2-diphenyl-2,3,4,5,6,7-hexahydrobenzofuran-3-yl)methyl
2H), 3.81-3.70 (m, 2H), 3.21-3.14 (m, 1H), 3.07-2.99 (m, 1H), 1.71 (s, acetate (3r): Isolated yield: 43 % (15.6 mg). White solid. Mp: 159-
1
3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 162 ºC; H NMR (400 MHz, CDCl3, ppm): δ 7.58-7.54 (m, 2H), 7.42-
170.2, 168.4, 164.8, 144.2, 139.9, 138.2, 128.3, 128.2, 128.0, 127.6, 7.18 (m, 8H), 4.29-4.27 (m, 1H), 4.12 (dd, J = 11.4, 3.8 Hz, 1H), 3.81
127.6, 127.5, 127.4, 126.9, 126.4, 103.9, 94.1, 72.8, 67.0, 62.8, 59.8, (dd, J = 11.4, 8.6 Hz, 1H), 2.68 (dt, J = 18.0, 5.6 Hz, 1H), 2.53-2.26
49.2, 29.2, 20.5, 14.3; IR (neat) 2929, 1741, 1696, 1366, 1238, 1101, (m, 3H), 2.12-2.04 (m, 2H), 1.77 (s, 3H); 13C NMR (100 MHz, CDCl3):
752, 699 cm-1; MS (EI) m/z (%) 440 (28), 277 (17), 203 (17), 165 (11), δ 194.8, 176.3, 170.0, 143.6, 139.5, 128.4, 128.3, 127.8, 127.7,
105 (24), 91 (100); HRMS (ESI) Calcd. for C31H32O6 (M+H)+: 501.2272, 126.7, 126.6, 113.2, 97.5, 62.4, 46.9, 36.7, 24.1, 21.5, 20.5; IR (neat)
Found 501.2269.
2923, 1742, 1640, 1239, 758, 735, 702 cm-1; MS (EI) m/z (%) 302
(100), 238 (12), 196 (37), 183 (48), 137 (72), 105 (63); HRMS (ESI)
Calcd. for C23H22O4 (M+H)+: 363.1591, Found 363.1590.
ethyl 4-(acetoxymethyl)-2-(2-ethoxy-2-oxoethyl)-5,5-diphenyl-4,5-
dihydrofuran-3-carboxylate (3n): Isolated yield: 52 % (23.5 mg).
6 | J. Name., 2012, 00, 1-3
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ARTICLE
(4-oxo-2,2-diphenyl-3,4,5,6,7,8-hexahydro-2H-cyclohepta[b]furan- 14.4; IR (neat) 2977, 2929, 1696, 1650, 1448, 1379, 1221, 1079,
3-yl)methyl acetate (3s): Isolated yield: 64 % (24.1 mg). Colorless 1014, 952, 773, 699 cm-1; MS (EI) m/z (%) 322 (M+, 3), 280 (100),
1
oil. H NMR (400 MHz, CDCl3, ppm): δ 7.53-7.51 (m, 2H), 7.38-7.19 248 (23), 206 (38), 205 (99), 165 (53), 115 (13), 105 (26), 77 (18);
(m, 8H), 4.33-4.30 (m, 1H), 4.00-3.88 (m, 2H), 2.79 (dt, J = 18.8, 6.0 HRMS (ESI) Calcd. for C21H22O3 (M+H)+: 323.1642, Found 323.1645.
Hz, 1H), 2.63-2.53 (m, 3H), 1.94-1.90 (m, 3H), 1.89-1.70 (m, 1H),
1.69 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 196.5, 170.6, 170.2,
General procedure for 4a:
Substrate 1a (21.0 mg, 0.1 mmol) was dissolved in 1.0 mL of HFIP
144.0, 139.8, 128.2, 128.0, 127.6, 127.4, 126.7, 126.3, 115.9, 94.1,
under argon followed by addition of KOAc (49.1 mg, 0.5 mmol) and
62.3, 49.2, 44.1, 30.4, 24.2, 22.8, 20.5; IR (neat) 2932, 1739, 1616,
AcOH (200 µL) at room temperature. The reaction mixture was
stirred at 50 oC and monitored by TLC. After the complete
1390, 1241, 764, 701 cm-1; MS (EI) m/z (%) 316 (100), 303 (12), 232
(17), 191 (14), 165 (17), 115 (8), 105 (30), 55 (12); HRMS (ESI) Calcd.
for C24H24O4 (M+H)+: 377.1747, Found 377.1746.
consumption of 1a, the reaction mixture was cooled to room
temperature and then quenched with 1.0 mL of water, diluted with
(4-acetyl-5-isobutyl-2,2-diphenyl-2,3-dihydrofuran-3-yl)methyl
acetate (3t): Isolated yield: 40 % (15.7 mg). Colorless oil. 1H NMR
CH2Cl2, and extracted with CH2Cl2 (5 mL × 3). The combined organic
layer was washed with saturated aqueous Na2CO3 and brine, dried
(400 MHz, CDCl3, ppm): δ 7.54-7.52 (m, 2H), 7.38-7.21 (m, 8H), 4.25
over anhydrous Na2SO4 and concentrated under vacuum.
(dd, J = 7.4, 3.4 Hz, 1H), 3.95 (dd, J = 11.2, 7.6 Hz, 1H), 3.84 (dd, J =
Purification of the residue by column chromatography on silica gel
11.4, 3.8 Hz, 1H), 2.47 (dd, J = 15.6, 6.8 Hz, 1H), 2.38 (dd, J = 15.6,
provided the compound 4a (22.2 mg, 88% yield) as a colorless oil.
6.8 Hz, 1H), 2.33 (s, 3H), 2.18-2.10 (m, 1H), 1.73 (s, 3H), 0.93-0.90
3,3-diphenylallyl acetate (4a)15: Isolated yield: 88 % (22.2 mg).
(m, 6H); 13C NMR (100 MHz, CDCl3, ppm): δ 195.8, 170.3, 166.1,
Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.41-7.33 (m, 3H),
144.0, 139.7, 128.2, 128.0, 127.7, 127.5, 126.7, 126.2, 115.1, 93.7,
7.30-7.23 (m, 5H), 7.20-7.17 (m, 2H), 6.18 (t, J =7.2 Hz, 1H), 4.64 (d,
63.0, 49.8, 48.8, 25.0, 22.7, 22.6, 20.5, 15.9; IR (neat) 2957, 2927,
1741, 1620, 1383, 1235, 756, 700 cm-1; MS (EI) m/z (%) 332 (100),
J = 7.2 Hz, 2H), 2.07 (s, 3H).
General procedure for 1a with 2a by the addition of TEMPO:
276(17), 248 (19), 205 (21), 165 (22), 115 (11), 85 (26), 57 (43);
HRMS (ESI) Calcd. for C25H28O4 (M+H)+: 393.2060, Found 393.2058.
Substrate 1a (21.0 mg, 0.1 mmol) was dissolved in 1.0 mL of HFIP
under argon followed by addition of Mn(OAc)3·2H2O (80.4 mg, 0.3
mmol), KOAc (49.1 mg, 0.5 mmol), 2a (26.0 µL, 0.2 mmol), TEMPO
(31.3 mg, 0.2 mmol), and AcOH (200 µL) at room temperature. The
reaction mixture was then stirred at 50 oC and monitored by TLC.
(5-methyl-4-(3-methylbutanoyl)-2,2-diphenyl-2,3-dihydrofuran-3-
yl)methyl acetate (3t′): Isolated yield: 40 % (15.7 mg). Colorless oil.
1H NMR (400 MHz, CDCl3, ppm): δ 7.51-7.48 (m, 2H), 7.36-7.20 (m,
8H), 4.26 (dd, J = 6.8, 3.6 Hz, 1H), 3.96 (dd, J = 11.6, 7.2 Hz, 1H), 3.85
(dd, J = 11.4, 3.8 Hz, 1H), 2.64 (dd, J = 14.0, 7.2 Hz, 1H), 2.52 (dd, J = After the complete consumption of 1a, the reaction mixture was
13.4, 7.4 Hz, 1H), 2.31 (s, 3H), 2.17-2.09 (m, 1H), 1.72 (s, 3H), 1.01
(d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3,
cooled to room temperature and then quenched with 1.0 mL of
saturated aqueous NaHSO3, diluted with CH2Cl2, and extracted with
ppm): δ 193.2, 170.3, 169.5, 143.8, 139.8, 128.2, 128.1, 127.7, CH2Cl2 (5 mL × 3). The combined organic layer was washed with
127.4, 126.6, 126.4, 115.9, 93.5, 62.9, 48.4, 37.7, 29.4, 27.3, 22.6,
22.3, 20.5; IR (neat) 2963, 2933, 1741, 1701, 1637, 1237, 1066, 760,
700 cm-1; MS (EI) m/z (%) 332 (100), 247 (27), 191 (38), 165 (38),
115 (15), 105 (32), 57 (32); HRMS (ESI) Calcd. for C25H28O4 (M+H)+:
393.2060, Found 393.2059.
saturated aqueous Na2CO3 and brine, dried over anhydrous Na2SO4
and concentrated under vacuum. Purification of the residue by
column chromatography on silica gel provided compound 4a (21.2
mg, 84% yield) as a colorless oil.
(4-acetyl-2,2,5-triphenyl-2,3-dihydrofuran-3-yl)methyl
acetate
Acknowledgements
(3u): Isolated yield: 52 % (21.4 mg). Yellow solid. Mp: 137-140 ºC;
1H NMR (400 MHz, CDCl3, ppm): δ 7.63-7.61 (m, 2H), 7.53-7.21 (m,
13H), 4.43 (dd, J = 7.0, 3.4 Hz, 1H), 4.18 (dd, J = 11.4, 7.0 Hz, 1H),
4.00 (dd, J = 11.4, 3.4 Hz, 1H), 1.87 (s, 3H), 1.75 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm): δ 193.8, 170.3, 166.1, 143.7, 139.6, 131.0,
130.6, 129.4, 128.5, 128.4, 128.2, 127.8, 127.5, 126.6, 126.3, 116.5,
62.7, 49.3, 29.7, 28.8, 20.6; IR (neat) 2924, 1740, 1620, 1448, 1235,
760, 700 cm-1; MS (EI) m/z (%) 352 (45), 164 (13), 105 (100), 77 (43);
HRMS (ESI) Calcd. for C27H24O4 (M+H)+: 413.1747, Found 413.1746.
We would like to thank the Natural Science Foundation of
China (No. 21502080, 21202073, 21290180, 21272097,
21372104, and 21472077), the “111” Program of MOE, and the
Project of MOST (2012ZX 09201101-003) for their financial
support.
Notes and references
1
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2,4-dimethyl-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate
(3v): Isolated yield: 95 % (30.6 mg). Colorless oil. 1H NMR (400 MHz,
CDCl3, ppm): δ 7.54-7.52 (m, 2H), 7.35-7.31 (m, 2H), 7.29-7.25 (m,
5H), 7.23-7.19 (m, 1H), 4.24-4.10 (m, 2H), 3.91 (dd, J = 13.6, 6.8 Hz,
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127.8, 127.7, 126.9, 126.4, 126.2, 109.3, 94.7, 59.4, 44.5, 17.8, 14.7,
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