Catalytic nazarov reaction of aryl vinyl ketones via binary acid strategy

Article abstract of DOI:10.1021/jo302451b

We describe herein a viable binary acid strategy for the catalytic Nazarov reaction of aryl vinyl ketones. Simply combining a Lewis acid and a Bronsted acid led to a dramatic enhancement of the catalytic activity in the Nazarov reaction of aryl vinyl β-ketoesters. The obtained optimal binary acid catalyst In(OTf)₃/diphenyl phosphoric acid (DPP) can be applied to a range of aryl vinyl ketones with good activity. A trend of reactivity has also been summarized on the basis of mapping of the substituents.

Full text of DOI:10.1021/jo302451b

Article
pubs.acs.org/joc
Catalytic Nazarov Reaction of Aryl Vinyl Ketones via Binary Acid
Strategy
Zhi-Guo Xi,† Lihui Zhu,‡ Sanzhong Luo,*,‡ and Jin-Pei Cheng†
†Department of Chemistry and State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, 300071, China
‡Beijing National Laboratory for Molecule Sciences (BNLMS), CAS Key Laboratory for Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 China
S
* Supporting Information
ABSTRACT: We describe herein a viable binary acid strategy
for the catalytic Nazarov reaction of aryl vinyl ketones. Simply
combining a Lewis acid and a Brønsted acid led to a dramatic
enhancement of the catalytic activity in the Nazarov reaction
of aryl vinyl β-ketoesters. The obtained optimal binary acid
catalyst In(OTf)3/diphenyl phosphoric acid (DPP) can be
applied to a range of aryl vinyl ketones with good activity. A
trend of reactivity has also been summarized on the basis of
mapping of the substituents.
In this binary acid catalysis, the synergistic integration of a
Brønsted acid and a metal catalyst would lead to mutually
enhanced acidity/electrophilicity and meanwhile provide multi-
ple sites for substrate binding and activation as a result of weak
coordinating behaviors between the acid moiety and the metal
center. These features inspire us to explore its application in the
Nazarov reaction wherein an acid-initialized 4π-electrocycliza-
tion and a sequence of proton transfers are key mechanistic
steps. Herein, we reported a remarkably active binary acid
catalyst In(OTf)3/phosphoric acid for the Nazarov cyclization
reaction of aryl vinyl ketones.
INTRODUCTION
■
Natural products have been and continue to serve as inspiration
for developing synthetic methodology. Indane-containing
natural products as illustrated in Scheme 1 have recently
become a prevalent type of natural products with promising
pharmaceutical profiles, and the total synthesis of these natural
products and their analogues is hence of significant synthetic
interest.1 One of the easily conceived and also the most
straightforward strategies for the construction of these indane
skeletons is the Nazarov cyclization of aryl vinyl ketones. As a
versatile C−C formation reaction, the Nazarov cyclization
reaction has demonstrated fascinating power in building
cyclopentenone-containing natural or unnatural products.2
Despite the extensive exploration of Nazarov-type chemistry,
aryl vinyl ketones remain difficult substrates with notoriously
sluggish reactivity, not to mention the unaddressed issues in
controlling enantioselectivity in this type of reactions.3 Usually,
stoichiometric or superstoichiometric amounts of Brønsted or
Lewis acids are required to promote the Nazarov cyclization of
aryl vinyl ketones.1c,4 Based on a “polarizing strategy”, the
Frontier group has developed catalysts such as Cu(II),5 Pd(II),6
RESULTS AND DISCUSSION
■
Screening and Optimization. Our studies commenced
with a model reaction of aryl vinyl ketone 1a, which has been
previously studied.5−7 A range of Lewis acids have been first
examined. The previously reported Lewis acids such as
Cu(OTf)2 and Sc(OTf)3 were indeed viable catalysts for the
reaction, albeit with rather low activity at room temperature
(Table 1, entries 2 and 4). Indium Lewis acids also worked very
well in this reaction, and In(OTf)3 was eventually identified as a
more active Lewis acid delivering quantitative conversion in 72
h at ambient temperature (Table 1, entries 6−11). To our
delight, the combined use of a Brønsted acid such as diphenyl
phosphoric acid diester (DPP) led to a dramatic rate
enhancement in the reactions (Table 1, entries 3, 5, and 7 vs
2, 4, and 6, respectively). For example, when In(OTf)3 was
used together with DPP, the reaction time for complete
conversion was sharply reduced from 72 h to 10 min,
corresponding to an over 400 times rate increase compared
to that using only In(OTf)3! Similar rate enhancement has also
Ir(III),7 and Sc(OTf)3/stoichiometric LiClO4 for Nazarov
8
cyclization reactions, and these catalysts have also been
examined in the Nazarov reactions of several aryl vinyl ketones.
The Sarpong group and the Yamamoto group also found AlCl3
and AuCl3/AgSbF6 as efficient catalysts for aryl vinyl ketones,
respectively.9 Though initial successes have been achieved,
those catalytic systems are still suffering from low activity and
consequently of narrow scopes. A simple, general, and effective
catalyst for cyclization of aryl vinyl ketones remains to be
further exploited in Nazarov chemistry.
Building upon the known combined acid principles,10 we
have recently been developing binary acid catalysis as a
combinatorial approach for strong acid/electrophilic catalysis.11
Received: November 8, 2012
© XXXX American Chemical Society
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Scheme 1. Nazarov Strategy in the Synthesis of Indane-Containing Natural Products
a
Table 1. Screening of Lewis Acids
Scheme 2. Possible Catalytic Mode of Binary Acid Catalyst
b
entry
Lewis acid
Brønsted acid
time (h)
conv (%)
1
2
no
DPP
no
24
NR
trace
92
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
In(OTf)3
In(OTf)3
InF3
72
3
DPP
no
24
4
72
70
5
DPP
no
1
>99
>99
>99
trace
83
study also suggests a cationic indium complex as the catalytic
species in indium halides catalyzed reactions.13 In addition, the
resulted multi acidic centers may also contribute in effective
activation of the substrate (Scheme 2).11f
6
72
7
DPP
DPP
DPP
DPP
DPP
TfOH
10 min
1
8
9
InCl3
0.5
With In(OTf)3 as the optimal Lewis acid, the reaction was
further optimized. Other Brønsted acids including carboxylic
acid (Table 2, entries 1, 3, and 4) and sulfonic acid (Table 2,
entry 2) have been first examined, and phosphoric acid turned
out to be the optimal Brønsted acid in terms of catalytic
activity. The binary acid catalyst In(OTf)3/DPP generally
worked well in chlorinated solvents such as dichloromethane
and 1,2-dichloroethane (Table 2, entries 5 and 6), while the
reactions in MeCN and toluene (Table 2, entries 7 and 8) were
slightly slower. In contrast, the reaction did not occur in ethyl
ether and THF (Table 2, entries 9 and 10). The catalyst
loading can be decreased to 2 mol % with only slight loss of
activity (1 h, quantitative conversion, Table 2, entry 11). At 2
mol % loading of the Lewis acid, the possible impact of Lewis
acid/Brønsted acid ratio has also been examined. Variations of
the ratio from 1:1 to 1:4 indicated that the 1:2 molar ratio of
In(OTf)3 and DPP is optimal and the reaction exhibited
inferior performance under an either lower or higher molar
ratio (Table 2, entry 13 vs 12, 14, and 15). Last but not least,
the use of chiral phosphoric acid has also been examined with a
hope of attaining enantioselective control.3 Unfortunately, our
initial attempt with chiral phosphoric acids did not lead to any
chiral inductions, though the catalytic activity was still
maintained (Table 2, entries 16 and 17). At this point, we
chose to focus on exploring the synthetic potential of this
binary acid catalysis in this paper, and a catalytic asymmetric
version is pursued further in separated studies.
10
11
12
InBr3
10 min
10 min
30 min
>99
>99
80
InI3
none
a
Reactions were carried out on a 0.05 mmol scale (substrate 1a) in 0.5
mL of DCM at 25 °C; only trans-diastereoisomer product was
b
observed. Reaction conversion was determined by 1H NMR. NR: no
reaction.
been clearly noted in the cases with Cu(OTf)2 and Sc(OTf)3.
The impressive reactivity enhancement highlights the syner-
gistic combination of the Lewis acid and the Brønsted acid in
the catalysis of the Nazarov reaction; note that Brønsted acid
DPP only was virtually inactive for the reaction (Table 1, entry
1).
In a control reaction, the use of only TfOH (20 mol %),
which may be in situ generated from metal triflate and DPP, as
the possible active catalytic species has been examined. Though
TfOH only with 20 mol % loading is quite active in the
reaction, the activity is considerably inferior to that of the
metal/weak acid combination (Table 1, entry 12 vs 7). This
result together with the observations that InBr3 and InI3
performed equally well when combined with DPP (Table 1,
entries 10 and 11) suggests that both metal and proton play
roles in the catalysis, and the contribution from in situ
generated strong Brønsted acid, if present, is minor.
Mechanistically, this synergistic binary acid effect likely stems
from the enhanced electrophilicity as a result of complexation
of the metal center with the Brønsted acid ligand, leading to a
cationic Indium(III) complex (Scheme 2).10 Similar ligand
enhanced Lewis acidity is well-known12 and a recent theoretical
Substrate Scope. With the optimized conditions in hand,
we embarked on testing the substrate scope of this method-
ology (Table 3). The bulkiness of the α-substituted ester group
demonstrates no obvious impact on the reactivity. Both
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a
reaction proceeded very slowly at room temperature. This is
not quite unexpected since there have been no reports on the
successful cyclizations of electron-deficient β-aryl substituted
aryl vinyl ketoesters so far. Delightfully, when the temperature
was elevated to 40 °C, the Nazarov reaction of these
challenging substrates proceeded smoothly to give good to
excellent yields under our binary acid catalysis (Table 3, entries
8−12). The reaction of β-furan- and β-vinyl-substituted 1e and
1n worked very well to deliver the desired adducts in high
yields (Table 3, entries 4 and 13). The cyclization of a β-alkyl-
substituted 1o has also been examined in the catalysis of
In(OTf)3/DPP (10 mol %), and the reaction proceeded quite
well at 40 °C to give the desired adduct 2o in 85% yield (Table
3, entry 14). In all cases, the Nazarov products were isolated as
dominant trans-diastereoisomers, and no cis-isomer was
observed.5 The trans-adducts mainly exist in their ketoester
form, and in several cases particularly with substrates bearing β-
electron-deficient aryl group on the enone moieties, e.g., 1i−l,
the Nazarov adducts in their enol ester form were observed in
Table 2. Optimization of Reaction Parameters
b
conv
entry
Lewis acid
In(OTf)3
Brønsted acid
L-proline
solvent
time (h)
(%)
1
2
DCM
DCM
6
1
NR
c
In(OTf)3
camphorsulfonic
acid
>99
3
4
5
6
7
8
9
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
mandelic acid
benzoic acid
DPP
DCM
DCM
DCM
DCE
1
95
75
5.5
10 min
10 min
10 min
10 min
10 min
>99
>99
65
DPP
DPP
MeCN
toluene
DPP
92
DPP
ethyl
ether
NR
1
10
11
In(OTf)3
DPP
THF
10 min
1
NR
varied ratios by H NMR.
In(OTf)3 (2
mol %)
DPP (4 mol %)
DCM
>99
In the Nazarov reaction with aryl vinyl ketones, the general
reactivity pattern regarding variations on the aryl part remains
obscure. For the first time, we have surveyed the substituent
effect of the aryl group. Interestingly, it was found that the
electron-donating group on the meta-position of the aryl group
is vital for the substrates to undergo Nazarov cyclization
effectively. For example, while the reaction with meta-methoxyl
group substituted 1p reacted smoothly at room temperature to
furnish the desired product as a regioisomeric mixture (85:15
favoring the adduct para to the methoxyl group as illustrated),
those bearing an o- or p-methoxyl group such as 1q and 1r are
inert even at elevated temperature for 72 h (Table 3, entry 15
vs entries 16 and 17). This observation is clearly in line with the
typical electrophilic aromatic substitution pattern that reaction
preferentially occurs para- or ortho- to the electron-donating
group. In further explorations, we could extend our binary acids
strategy to Nazarov substrates 1s and 1t bearing a naphthyl
moiety (Table 3, entries 18 and 19). Interestingly, the Nazarov
product 2t mainly exists in its enol form. When the aryl moiety
was replaced by an N-methyl-protected indolyl ring, our binary
acid system was still applicable, albeit demanding elevated
temperature and relatively longer reaction time (Table 3, entry
20).
12
13
14
15
In(OTf)3 (2
mol %)
DPP (2 mol %)
DPP (4 mol %)
DPP (6 mol %)
DPP (8 mol %)
DCM
DCM
DCM
DCM
0.5
0.5
0.5
0.5
23
64
31
30
In(OTf)3 (2
mol %)
In(OTf)3 (2
mol %)
In(OTf)3 (2
mol %)
c
c
16
17
In(OTf)3
In(OTf)3
(S)-BPPA
(S)-PFPA
DCM
DCM
10 min
10 min
>99
>99
a
Reactions were carried out on a 0.05 mmol scale (substrate 1a) in 0.5
mL of DCM at 25 °C; when 2 mol % of Lewis acid was loaded,
reactions were carried out on a 0.1 mmol scale (substrate 1a). Only
b
trans-product was observed. Reaction conversion was determined by
c
1H NMR; <5% ee. Enantiomeric excess was determined by Chiral
HPLC (Column: chiral AD, elute: iPrOH/hexane = 30/70, rate: 1
mL/min).
CONCLUSION
■
In conclusion, we have developed a simple and effective binary
acid catalytic strategy for the Nazarov reactions of aryl vinyl
ketones. The identified optimal binary acid catalyst In(OTf)3/
DPP demonstrates good performance in a broad range of
substrates, with activity comparable to the so far best catalyst
IrIII complex.5 One advantage is that our catalytic system is
insensitive to air or moisture and is operationally simple and
flexible, and hence, it is of practical interest. Besides its wide
substrate scope, this method also offers a new opportunity to
bring about a catalytic asymmetric variant for the Nazarov
reaction of aryl vinyl ketones by judicious selection of active
(chiral) Lewis acid, chiral Brønsted acid, and their combina-
tions.
reactions of 1b and 1c proceeded smoothly to give the desired
products with high yields (Table 3, entries 1 and 2). After a
prolonged reaction time, decarboxylation of the Nazarov
products 2b and 2c was observed. This provides a convenient
pathway for the synthesis of decarboxylated Nazarov adduct,
since the expected Nazarov cyclization with substrates lacking
the ester group did not occur under the present conditions.
Previously, it has been shown that β-aryl substituents on the
enone part influence the reactivity significantly.3e,5−8 In our
work, a similar trend of reactivity, i.e., more electron-rich β-aryl
substituent reacts faster, was also observed. The electron-rich β-
aryl-substituted aryl vinyl ketoesters underwent the Nazarov
reaction at room temperature smoothly to give excellent yields
(Table 3, entries 3 and 5−7). As for the electron-deficient β-
aryl-substituted aryl vinyl ketoesters such as 1i−l, the Nazarov
EXPERIMENTAL SECTION
■
The Nazarov substrates were synthesized following a published
procedure of Knoevenagel condensation between β-ketoesters with
corresponding aldehydes.5b,14 1a5a and 1b15 are known compounds.
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a
Table 3. Substrate Scope
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Table 3. continued
a
Reactions were carried out on a 0.1 mmol scale (substrate 1) with In(OTf)3/2 DPP (2 mol %) in 0.5 mL of DCM at 25 °C; 10 mol % of catalyst
b
c
loading in entries 7−12, 14, 16, 17, and 19. TMP-2,4,6 = 2,4,6-trimethoxylphenyl. Isolated yield. Only trans products were obtained. Data in
parentheses refers to the keto/enol ratio determined by H NMR. Ratio of regioisomers, major isomer is shown.
d
1
1c: 1.75 g, 82% yield; yellow solid; mp 126−128 °C; 1H NMR (300
MHz, CDCl3) δ 8.14 (s, 1H), 7.46 (dd, J = 8.10, 1.62 Hz, 1H), 7.42
(d, J = 1.56 Hz, 1H), 6.77 (d, J = 8.10 Hz, 1H), 6.00 (s, 2H), 5.95 (s,
2H), 5.86−5.73 (m, 1H), 5.18−5.08 (m, 2H), 4.63- 4.60 (m, 2H),
3.76 (s, 3H), 3.50 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 192.0,
166.5, 163.7, 159.8, 151.1, 147.8, 135.9, 132.8, 132.1, 128.2, 125.3,
117.6, 108.4, 107.7, 105.1, 101.7, 90.3, 65.4, 55.4, 54.8; IR (KBr, cm−1)
1710, 1663, 1604,1440, 1251, 1209, 1129, 1034, 417; HRMS (SIMS-
FT-ICRMS) m/z [M + H]+ calcd for C23H23O8 427.1393, found
427.1385.
1672, 1592, 1456, 1431, 1256, 1204, 1155, 1064; HRMS (EI-TOF) m/
z M+ calcd for C20H20O5 340.1311, found 340.1311.
1
1h: 920 mg, 56% yield; white solid; mp 68−70 °C; H NMR (300
MHz, CDCl3) δ 7.96 (s, 1H), 7.34−7.23 (m, 2H), 7.30−7.18 (m, 3H),
7.10 (d, J = 2.28 Hz, 2H), 6.64 (t, J = 2.28 Hz, 1H), 3.77 (s, 6H), 3.75
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 195.2, 165.5, 161.2, 142.9,
137.9, 132.9, 130.9, 130.5, 130.3, 128.9, 106.9, 106.6, 55.6, 52.7; IR
(KBr, cm−1) 1632, 1456, 1426, 1254, 1203, 1155, 543, 445; HRMS
(ESI) m/z [M + Na]+ calcd for C19H18O5Na 349.1052, found
349.1045.
1
1d: 1.23 g, 58% yield; yellow solid; mp 144−146 °C; 1H NMR (300
MHz, CDCl3) δ 8.13 (s,1 H), 7.07 (d, J = 2.28 Hz, 2H), 6.58 (t, J=
2.28 Hz, 1H), 5.95 (s, 2H), 3.77 (s, 6H), 3.76 (s, 3H), 3.70 (s, 3H),
3.50 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 193.2, 167.3, 163.8 160.7,
159.8, 139.7, 136.0, 128.1, 106.5, 105.5, 105.3, 90.4, 55.6, 55.5, 54.8,
52.3; IR (KBr, cm−1) 1715, 1672, 1600, 1459, 1339, 1254, 1207, 1157,
1129, 1060, 815, 442, 412; HRMS (SIMS-FT-ICRMS) m/z [M + H]+
calcd for C22H25O8 417.1549, found 417.1537.
1i: 830 mg, 48% yield; light yellow solid; mp 70−72 °C; H NMR
(300 MHz, CDCl3) δ 7.89 (s, 1H), 7.36−7.31 (m, 2H), 7.07 (d, J =
2.34 Hz, 2H), 6.96−6.89 (m, 2H), 6.63 (t, J = 2.28 Hz, 1H), 3.77 (s,
6H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 195.2, 165.5, 165.4,
162.1, 161.2, 141.5, 137.8, 132.4, 132.3, 130.7, 130.6, 129.2, 129.1,
116.3, 116.0, 106.9, 106.6, 55.6, 52.7; IR (KBr, cm−1) 2953, 2842,
1721, 1674, 1602, 1509, 1429, 1298, 1259, 1064, 1009, 927, 839, 736,
517; HRMS (EI-TOF) m/z M+ calcd for C19H17O5F 344.1060, found
344.1061.
1
1e: 1.08 g, 69%yield; white solid; mp 104−106 °C; H NMR (300
1
1j: 912 mg, 51% yield; yellow solid; mp 124−126 °C; H NMR
MHz, CDCl3) δ 7.67 (s,1 H), 7.31 (d, J = 1.50 Hz, 1H), 7.09 (d, J=
2.40 Hz, 2H), 6.65 (d, J = 2.40 Hz, 2H), 6.37 (q, J = 1.80 Hz, 1H),
3.80 (s, 6H), 3.73 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 194.2,
165.5, 161.1, 149.3, 146.4, 138.4, 128.4, 126.8, 118.0, 112.6, 106.9,
106.2, 55.7, 52.7; IR (KBr, cm−1) 1720, 1677, 1626, 1592, 1551, 1457,
1247, 1206, 1155, 1063, 750; HRMS (ESI) m/z [M + Na]+ calcd for
C17H16O6Na 339.0845, found 339.0840.
(300 MHz, CDCl3) δ 7.89 (s, 1H), 7.25 (q, J = 8.67 Hz, 4H), 7.08 (d,
J = 2.31 Hz, 2H), 6.65 (t, J = 2.25 Hz, 1H), 3.79 (s, 6H), 3.76 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 195.0, 165.3, 161.3, 141.4, 137.7, 136.7,
131.5, 131.5, 131.4, 129.3, 107.0, 106.7, 55.7, 52.8; IR (KBr, cm−1)
1721, 1670, 1591, 1428, 1254, 1203, 1157; HRMS (ESI) m/z [M +
Na]+ calcd for C19H17O5ClNa 383.0662, found 383.0653.
1
1
1f: 1.24g, 66% yield; white solid; mp 115−117 °C; H NMR (300
1k: 1.12g, 55% yield; white solid; mp 122−124 °C; H NMR (300
MHz, CDCl3) δ 7.90 (s, 1H), 7.30 (d, J = 8.79 Hz, 2H), 7.12 (d, J =
2.28 Hz, 2H), 6.76 (d, J = 8.82 Hz, 2H), 6.65 (t, J = 2.25 Hz, 1H), 3.79
(s, 6H), 3.75 (s, 3H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
195.8, 165.8, 161.5, 161.2, 142.7, 138.1, 132.4, 128.2, 125.5, 114.4,
107.0, 106.6, 55.7, 55.4, 52.6; IR (KBr, cm−1) 1668, 1601, 1512, 1256,
1172, 1155, 829, 523, 497, 453; HRMS (ESI) m/z [M + Na]+ calcd for
C20H20O6Na 379.1158, found 379.1151.
MHz, CDCl3) δ 7.86 (s, 1H), 7.37 (d, J = 8.55 Hz, 2H), 7.19 (d, J =
8.52 Hz, 2H), 7.06 (d, J = 2.31 Hz, 2H), 6.64 (t, J = 2.28 Hz, 2H),
3.78(s, 6H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 195.0, 165.3,
161.3, 141.4, 137.7, 132.2, 131.8, 131.6, 125.1, 107.0, 106.7, 55.7, 52.8;
IR (KBr, cm−1) 2953, 2360, 1712, 1612, 1484, 1306, 1205, 1147, 1010,
833, 737, 554; HRMS (EI-TOF) m/z M+ calcd for C19H17O5Br
404.0259, found 404.0257.
1g: 980 mg, 58% yield; light yellow solid; mp 80−82 °C; 1H NMR
(300 MHz, CDCl3) δ 7.92 (s, 1H), 7.24 (d, J = 8.16 Hz, 2H), 7.11 (d,
J = 2.31 Hz, 2H), 7.05 (d, J = 8.07 Hz, 2H), 6.64 (t, J = 2.31 Hz, 1H),
3.78 (s, 6H), 3.75 (s, 3H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 195.5, 165.7, 161.2, 143.0, 141.2, 138.0, 130.4, 130.1, 129.7, 129.7,
107.0, 106.6, 55.6, 52.6, 21.5; IR (KBr, cm−1) 2925, 2360, 2342, 1716,
1l: 1.32g, 71% yield; white solid; mp 145−147 °C; H NMR (300
1
MHz, CDCl3) δ 8.10 (d, J = 8.79 Hz, 2H), 7.96 (s, 1H), 7.50 (d, J =
8.79 Hz, 2H), 7.04 (d, J = 2.22 Hz, 2H), 6.66 (t, J = 2.22 Hz, 1H), 3.80
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 194.1, 164.7, 161.3, 148.4,
139.7, 139.1, 137.4, 134.9, 130.7, 124.1, 107.0, 106.8, 55.7, 53.1; IR
(KBr, cm−1) 2923, 2850, 2360, 1721, 1669, 1593, 1523, 1462, 1347,
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1255, 1205, 1158, 1064, 1009, 853, 816; HRMS (EI-TOF) m/z M+
calcd for C19H17O7N 371.1005, found 371.1006.
159.7, 141.2, 134.7, 132.4, 131.7, 129.6, 128.6, 128.5, 128.0, 127.0,
125.7, 118.8, 115.0, 104.7, 90.9, 55.8, 55.6; IR (KBr, cm−1) 2942, 2843,
2360, 1667, 1588, 1471, 1417, 1335, 1274, 1207, 1151, 1126, 1059,
1025, 1001, 955, 818, 738, 703, 479, 442, 418, 404; HRMS (EI-TOF)
m/z M+ calcd for C24H19F3O5 444.1185, found 444.1183.
1m: 810 mg, 41% yield; white solid; mp 78−80 °C; 1H NMR (300
MHz, CDCl3) δ 7.94 (s, 1H), 7.47 (dd, J = 18.06, 8.49 Hz, 4H), 7.07
(d, J = 2.28 Hz, 2H), 6.65 (t, J = 2.28 Hz, 1H), 3.78 (s, 6H), 3.77 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 194.5, 165.1, 161.3, 140.9, 137.7,
136.3, 133.5, 132.1, 131.6, 130.3, 125.9 (q, J = 3.8 Hz), 107.0, 106.7,
106.4, 55.7, 52.9; IR (KBr, cm−1) 2954, 2841, 1722, 1673, 1593, 1462,
1429, 1356, 1325, 1262, 1205, 1156, 1125, 1068, 1015, 927, 847, 736,
705, 595; HRMS (EI-TOF) m/z M+ calcd for C20H17O5F3 394.1028,
found 394.1025.
1
1u: 400 mg, 42% yield; light yellow solid; mp 141−143 °C; H
NMR (300 MHz, CDCl3) δ 8.48−8.37 (m, 1H), 8.06 (s, 1H), 7.36 (s,
1H), 7.25 (d, J = 3.33 Hz, 3H), 5.90 (s, 2H), 4.22 (q, J = 7.10 Hz, 2H),
3.71 (s, 3H), 3.65 (s, 3H), 3.56 (s, 6H), 1.21 (t, J = 7.10 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 188.0, 167.3, 163.1, 159.7, 137.6, 136.9,
134.1, 130.9, 126.6, 123.0, 122.6, 122.2, 116.7, 109.5, 105.8, 90.2, 61.0,
55.3, 55.1, 33.3, 14.3; IR (KBr, cm−1) 1708, 1603, 1527, 1464, 1334,
1249, 1207, 1157, 1127, 1034, 750, 458, 409; HRMS (SIMS-FT-
ICRMS) m/z [M + H]+ calcd for C24H26NO6 424.1760, found
424.1750.
1
1n: 650 mg, 45% yield; yellow solid; mp 100−102 °C; H NMR
(300 MHz, CDCl3) δ 7.69 (d, J = 11.76 Hz, 1H), 7.39−7.35 (m, 2H),
7.33−7.27 (m, 3H), 7.07 (d, J = 2.10 Hz, 2H), 7.03 (d, J = 15.51 Hz,
1H), 6.82−6.64 (m, 2H), 3.82 (s, 6H), 3.73 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 194.2, 165.6, 161.1, 144.1, 144.0, 138.9, 135.6, 130.9,
129.8, 128.9, 127.8, 122.9, 107.1, 106.4, 55.7, 52.5; IR (KBr, cm−1)
2360, 2341, 1717, 1669, 1592, 1235, 1204, 1156, 669, 421; HRMS (EI-
TOF) m/z M+ calcd for C21H20O5 352.1311, found 352.1312.
General Procedure for the Nazarov Reaction. To a mixture of
In(OTf)3 (1.12 mg, 0.002 mmol) and diphenyl phosphate (DPP)
(1.00 mg, 0.004 mmol) was added andydrous DCM (0.2 mL). After
the mixture was stirred for 0.5 h at room tempreture, a solution of
Nazarov substrates (0.1 mmol) in DCM (0.3 mL) was added to the
catalyst solution. The reaction was carried out at room temperature
and monitored by TLC. After the indicated reaction time, the reaction
mixture was directly purified by column chromatography on silica gel
with petroleum/ethyl acetate (2:1 to 10:1) to give the Nazarov
products. Nazarov product 2a5a is a known compound.
1
1o: 1.62g, 83% yield; colorless oil; H NMR (300 MHz, CDCl3) δ
7.10 (t, J = 7.92 Hz, 1H), 7.00 (d, J = 2.22 Hz, 2H), 6.64 (t, J = 2.19
Hz, 1H), 3.78 (s, 6H), 3.66 (s, 3H), 2.07 (p, J = 7.62 Hz, 2H), 0.99 (t,
J = 7.50 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.2, 165.0, 161.1,
149.5, 138.5, 132.7, 106.8, 106.3, 55.6, 52.3, 23.2, 12.9; IR (KBr, cm−1)
2968, 2936, 2874, 2839, 2359, 2340, 1728, 1675, 1593, 1457, 1432,
1362, 1317, 1294, 1242, 1206, 1157, 1065, 773, 675; HRMS (EI-TOF)
m/z M+ calcd for C15H18O5 278.1154, found 278.1155.
2b: 39.8 mg, 96% yield; colorless oil; 1H NMR (300 MHz, CDCl3)
δ 7.08 (s, 1H), 6.52 (s, 1H), 6.19 (s, 1H), 6.00 (broad, 3H), 5.39 (d, J
= 3.69 Hz, 1H), 4.3−4.10 (m, 2H), 3.93 (d, J = 3.78 Hz, 1H), 3.86 (s,
3H), 3.80 (s, 3H), 3.44 (s, 3H), 1.27 (t, J = 7.08 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 198.3, 170.0, 160.8, 159.6, 159.1, 156.5, 154.6,
148.1, 129.5, 109.4, 104.7, 102.3, 102.2, 91.5, 90.9, 61.4, 60.4, 56.3,
55.6, 38.0, 14.3; IR (KBr, cm−1) 1733, 1701, 1607, 1469, 1294, 1205,
1149, 1118, 1035, 413; HRMS (ESI) m/z [M + Na]+ calcd for
C22H22O8Na 437.1212, found 437.1205.
1
1p: 450 mg, 38% yield; yellow solid; mp 171−173 °C; H NMR
(300 MHz, CDCl3) δ 8.15 (s, 1H), 7.50−7.47 (m, 2H), 7.33−7.27 (m,
1H), 7.06−7.02 (m, 1H), 5.95 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.69
(s, 3H) 3.48 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 193.4, 167.3,
163.7, 159.8, 159.6, 139.0, 136.0, 129.2, 128.2, 121.9, 119.2, 112.6,
105.1, 90.3, 55.5, 55.4, 54.8, 52.2; IR (KBr, cm−1) 1712, 1674, 1601,
1467, 1435, 1337, 1260, 1209, 1159, 1129, 814, 734, 403; HRMS
(SIMS-FT-ICRMS) m/z [M + H]+ calcd for C21H23O7 387.1444,
found 387.1441.
2c: 39.2 mg, 92% yield; colorless oil; 1H NMR (300 MHz, CDCl3)
δ 7.08 (s, 1H), 6.52 (s, 1H), 6.18 (s, 1H), 6.00 (s, 3H), 5.97−5.84 (m,
1H), 5.40 (d, J = 3.69 Hz, 1H), 5.32 (dd, J = 17.22, 1.44 Hz, 1H), 5.20
(dd, J = 10.47, 1.23 Hz, 1H), 4.75−4.56 (m, 2H), 3.98 (d, J = 3.78 Hz,
1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.44 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 198.0, 169.7, 160.9, 159.5, 159.1, 156.5, 154.6, 148.1, 132.1,
129.4, 118.1, 109.3, 104.7, 102.3, 91.4, 90.8, 60.2, 56.3, 55.5, 55.4, 38.0;
IR (KBr, cm−1) 1737, 1698, 1607, 1470, 1456, 1294, 1118, 1035, 938,
816; HRMS (ESI) m/z [M + Na]+ calcd for C23H22O8Na 449.1212,
found 449.1206.
1
1q: 600 mg, 50% yield; yellow solid; mp 132−134 °C; H NMR
(300 MHz, CDCl3) δ 8.13 (s, 1H), 7.86 (d, J = 8.85 Hz, 2H), 6.86 (d,
J = 8.88 Hz, 2H), 5.93 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.68 (s,
3H), 3.47 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 192.5, 167.5, 163.6,
162.9, 159.7, 135.7, 131.0, 130.8, 128.4, 113.4, 105.2, 90.2, 55.5, 55.4,
54.7, 52.2; IR (KBr, cm−1) 1712, 1680, 1603, 1264, 1159, 1128, 741;
HRMS (SIMS-FT-ICRMS) m/z [M + H]+ calcd for C21H23O7
387.1444, found 387.1441.
1
1r: 540 mg, 45% yield; yellow solid; mp 126−128 °C; H NMR
2d: 41.3 mg, 99% yield; colorless oil; 1H NMR (300 MHz, CDCl3)
δ 6.80 (d, J = 2.04 Hz, 1H), 6.54 (d, J = 2.04 Hz, 1H), 6.17 (d, J = 2.16
Hz, 1H), 5.96 (d, J = 2.13 Hz, 1H), 5.42 (d, J = 2.76 Hz, 1H), 3.88 (s,
3H), 3.81−3.79 (m, 4H), 3.77 (s, 3H), 3.73 (s, 3H), 3.60 (s, 3H), 3.38
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.6, 170.2, 161.0, 160.2,
159.3, 159.0, 157.5, 139.8, 137.7, 110.1, 106.2, 96.5, 91.4, 91.3, 60.9,
56.6, 55.9, 55.8, 55.4, 52.6, 35.6; IR (KBr, cm−1) 1739, 1711, 1607,
1454, 1360, 1308, 1149, 1118, 1035,814, 736, 634, 502; HRMS (ESI)
m/z [M + Na]+ calcd for C22H24O8Na 439.1369, found 439.1357.
2e: 29.8 mg, 94% yield; colorless oil; 1H NMR (300 MHz, CDCl3)
δ 6.82 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.25 (dd, J = 3.0,
1.9 Hz, 1H), 6.01 (d, J = 3.1 Hz, 1H), 5.02 (d, J = 2.85 Hz, 1H), 3.83
(s, 3H), 3.80 (d, J = 2.91 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 198.1, 168.6, 162.3, 157.9, 153.7, 141.8,
137.4, 135.6, 110.4, 107.0, 106.4, 97.0, 60.7, 56.0, 55.9, 53.1, 39.4; IR
(KBr, cm−1) 2954, 2842, 1722, 1612, 1495, 1437, 1357, 1309, 1205,
1152, 1037, 1012, 934, 848, 736, 601; HRMS (ESI) m/z [M + Na]+
calcd for C17H16O6Na 339.0845, found 339.0837.
(300 MHz, CDCl3) δ 8.06 (dd, J = 1.68 Hz, 1H), 7.77 (s, 1H), 7.50−
7.43 (m 1H), 7.05−6.95 (m, 2H), 5.98 (s, 2H), 3.81 (s, 3H), 3.75 (s,
3H), 3.66 (s, 3H), 3.42 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 190.6,
167.2, 162.9, 159.7, 159.3, 133.9, 133.8, 131.9, 131.1, 127.1, 120.7,
112.4, 105.6, 90.5, 55.9, 55.4, 54.9, 51.8; IR (KBr, cm−1) 1719, 1654,
1603, 1459, 1254, 1207, 1157, 1129, 1023, 760, 422; HRMS (SIMS-
FT-ICRMS) m/z [M + H]+ calcd for C21H23O7 387.1444, found
387.1439.
1s: 1.23 g, 61% yield; yellow solid; mp 146−148 °C; 1H NMR (300
MHz, CDCl3) δ 8.41(s,1 H), 8.25(s,1 H), 8.04 (dd, J = 8.55, 1.50 Hz,
1H), 7.92−7.85 (m, 3H), 7.59−7.48 (m, 2H), 5.93 (s, 2H), 3.74 (s,
3H), 3.67 (s, 3H), 3.44 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 193.8,
167.5, 163.7, 159.8, 136.3, 135.5, 135.2, 132.7, 130.5, 129.8, 128.3,
128.2, 128.0, 127.9, 126.6, 124.8, 105.2, 90.4, 55.5, 54.9, 52.3; IR (KBr,
cm−1) 1666, 1604, 1466, 1211, 1157, 1126, 406; HRMS (SIMS-FT-
ICRMS) m/z [M + H]+ calcd for C24H23O6 407.1495, found
407.1488.
1t: 1.32 g, 72% yield; a mixture of E/Z isomers (E/Z ≈ 1:4,
determined by 1H NMR); yellow solid; mp 57−59 °C; 1H NMR (300
MHz, CDCl3) 8.40 (s, 1H), 8.34 (s, 1.20H), 8.04−7.81 (m, 5H), 7.70
(s, 0.32H), 7.62−7.44 (m, 2.5H), 6.11 (s, 0.40H), 5.92 (s, 2H), 3.84
(s, 0.59H), 3.75 (s, 1.12H), 3.74 (s, 3H), 3.49 (s, 6H); 13C NMR (75
MHz, CDCl3) for the Z isomer: 192.9, 181.2, 165.7, 160.6, 141.5,
135.6, 134.4, 132.6, 130.6, 130.2, 129.7, 128.4, 128.3, 127.9, 126.7,
124.5, 105.3, 90.5, 55.6, 55.0; for the E isomer: 194.8, 180.7, 164.9,
1
2f: 35.1 mg, 98% yield; colorless oil; H NMR (300 MHz, CDCl3)
7.00−6.92 (m, 2H), 6.84 (d, J = 2.04 Hz, 1H), 6.82−6.75 (m, 2H),
6.66 (d, J = 2.07 Hz, 1H), 4.88 (d, J = 2.88 Hz, 1H), 3.85 (s, 3H), 3.77
(s, 3H), 3.76 (s, 3H), 3.64 (s, 3H), 3.58 (d, J = 2.88 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 199.2, 169.0, 162.1, 158.5, 157.9, 138.7,
137.6, 134.5, 128.2, 114.1, 107.1, 96.6, 64.3, 55.9, 55.8, 55.3, 52.9, 45.3;
IR (KBr, cm−1) 1648, 1636, 1559, 1541, 1507, 1456, 467, 417; HRMS
F
dx.doi.org/10.1021/jo302451b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ESI) m/z [M + Na]+ calcd for C20H20O6Na 379.1158, found
379.1155.
1325, 1067, 1018, 935, 837, 794, 738, 683, 602, 554; HRMS (EI-TOF)
m/z M+ calcd for C20H17O5F3 394.1028, found 394.1028.
1
2g: 33.7 mg, 99% yield; white solid, containing a inseparable enol
2n: 32 mg, 92% yield; yellow oil; H NMR (300 MHz, CDCl3) δ
1
isomer (keto/enol = 86:14); data for the keto isomer H NMR (300
7.40−7.16 (m, 5H), 6.82 (d, J = 2.04 Hz, 1H), 6.69 (d, J = 2.07 Hz,
1H), 6.50 (d, J = 15.72 Hz, 1H), 6.25 (dd, J = 15.79, 7.81 Hz, 1H),
4.53 (dd, J = 7.81, 2.39 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.79 (s,
3H), 3.62 (d, J = 2.94 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 198.6,
169.0, 162.1, 158.2, 137.6, 137.3, 137.1, 131.3, 129.2, 128.7, 127.6,
126.4, 106.8, 96.9, 61.1, 55.9, 55.8, 52.9, 43.6; IR (KBr, cm−1) 2955,
2839, 2359, 2340, 1715, 1614, 1496, 1308, 797, 749, 694, 472, 457,
444, 423; HRMS (EI-TOF) m/z M+ calcd for C21H20O5 352.1311,
found 352.1311.
MHz, CDCl3) δ 7.06 (d, J = 8.04 Hz, 2H), 6.94 (d, J = 8.04 Hz, 2H),
6.85 (d, J = 2.01 Hz, 1H), 6.66 (d, J = 2.04 Hz, 1H), 4.89 (d, J = 2.82
Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.65 (s, 3H), 3.59 (d, J = 2.85 Hz,
1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 199.2, 169.0, 162.1,
157.9, 139.4, 138.6, 137.6, 136.5, 129.4, 127.1, 107.1, 96.67 (s), 64.3,
55.9, 55.8, 52.9, 45.7, 21.2; IR (KBr, cm−1) 2955, 2925, 1740, 1714,
1613, 1495, 1310, 1206, 1151, 934, 834, 420; HRMS (EI-TOF) m/z
M+ calcd for C20H20O5 340.1311, found 340.1313.
2o: 23.7 mg, 85% yield; light yellow oil; 1H NMR (300 MHz,
CDCl3) δ 6.74 (d, J = 1.74 Hz, 1H), 6.65 (d, J = 1.71 Hz, 1H), 3.83 (s,
3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.65 (dt, J = 9.15 Hz, 2.85 Hz, 1H),
3.37 (d, J = 2.67 Hz, 1H), 2.20−2.12 (m, 1H), 1.52−1.47 (m, 1H),
0.87 (t, J = 7.41 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 199.5, 169.9,
161.6, 157.9, 139.5, 137.6, 106.5, 96.6, 59.7, 55.8, 55.6, 52.7, 42.6, 26.2,
11.3; IR (KBr, cm−1) 2962, 2360, 2340, 1744, 1713, 1614, 1495, 1456,
1435, 1362, 1323, 1293, 1205, 1151, 1038, 847, 666, 419, 405; HRMS
(EI-TOF) m/z M+ calcd for C15H18O5 278.1154, found 278.1153.
2p: 36.4 mg, 94% yield; white solid (containing an inseparable
regioisomer); data for the major isomer: 1H NMR (300 MHz, CDCl3)
δ 7.18 (d, J = 1.20 Hz, 1H), 7.07 (d, J = 2.25 Hz, 2H), 6.19 (d, J = 2.25
Hz, 1H), 6.01 (s, 1H), 5.46 (d, J = 3.72 Hz, 1H), 4.01 (d, J = 3.72 Hz,
1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.39 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 200.3, 170.3, 160.6, 159.2, 151.4,
136.0, 128.80, 126.1, 124.5, 116.4, 115.6, 109.8, 104.9, 91.6, 91.3, 90.8,
60.4, 55.6, 55.4, 55.3, 52.6 37.5; IR (KBr, cm−1) 2942, 2839, 1714,
1591, 1455, 1267, 1024, 985, 952, 813, 737, 583; HRMS (ESI) m/z
[M + Na]+ calcd for C21H22O7Na 409.1263, found 409.1258.
2s: 36.7 mg, 95% yield; corlorless oil; 1H NMR (300 MHz, CDCl3)
δ 7.87 (t, J = 8.45 Hz, 2H), 7.77 (s, 2H), 7.59−7.47 (m, 1H), 7.46−
7.31 (m, 1H), 6.27 (d, J = 2.19 Hz, 1H), 5.92−5.89 (m, 2H), 4.02 (s,
3H), 3.91 (d, J = 2.79 Hz, 1H), 3.76 (s, 6H), 3.21 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 200.1, 170.3, 160.7, 159.7, 158.7, 158.1, 137.4,
133.3, 130.2, 128.9, 128.7, 126.8, 125.5, 119.5, 110.2, 91.6, 91.1, 61.1,
56.4, 55.4, 55.1, 52.7, 37.8; IR (KBr, cm−1) 1737, 1704, 1608, 1457,
1334, 1204, 1149, 1118, 816, 752, 737; HRMS (ESI) m/z [M + Na]+
calcd for C24H22O6Na 429.1314, found 429.1302.
2t: 29 mg, 65% yield; a mixture of enol/keto esters with the enol
form as the major product (enol/keto = 93:7); yellow solid; 1H NMR
(300 MHz, CDCl3) δ 13.79 (s, 1H), 8.06 (d, J = 8.31 Hz, 1H), 7.88
(d, J = 8.04 Hz, 1H), 7.85 (s, 2H), 7.56 (t, J = 7.08 Hz, 1H), 7.44 (t, J
= 7.59 Hz, 1H), 6.27 (d, J = 2.25 Hz, 1H), 6.13 (d, J = 1.50 Hz, 1H),
5.85 (d, J = 2.28 Hz, 1H), 4.08 (s, 3H), 3.75 (s, 3H), 3.25 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 199.4, 160.7, 159.6, 158.2, 154.9, 137.3,
134.4, 129.7, 129.1, 129.0, 128.9, 127.2, 125.8, 118.8, 117.7, 109.4,
91.9, 91.2, 56.3, 55.7, 55.3, 36.5, 29.9; IR (KBr, cm−1) 1673, 1606,
1469, 1285, 1203, 1118, 799, 757, 536, 502, 473, 443, 417; HRMS (EI-
TOF) m/z M+ calcd for C24H19F3O5 444.1185, found 444.1187.
2u: 34.2 mg, 81% yield; yellow oil; 1H NMR (300 MHz, CDCl3) δ
7.98−7.90 (m, 1H), 7.29−7.22 (m, 3H), 6.20 (d, J = 2.22 Hz, 1H),
6.04 (d, J = 2.19 Hz, 1H), 5.56 (d, J = 3.00 Hz, 1H), 4.33−4.17 (m,
2H), 4.08 (d, J = 3.00 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.44 (s,
3H), 3.40 (s, 3H), 1.31 (t, J = 7.11 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 188.3, 170.5, 170.2, 161.2, 160.0, 158.8, 143.4, 123.2, 122.4,
121.9, 121.3, 117.4, 109.9, 105.9, 91.2, 90.9, 65.7, 61.4, 56.3, 55.8, 55.5,
33.8, 30.2, 14.5; IR (KBr, cm−1) 2360, 2341, 1731, 1684, 1457, 1119,
727, 668; HRMS (ESI) m/z [M + Na]+ calcd for C24H25NNaO6
446.1580, found 446.1578.
2h: 29.1 mg, 89% yield; pink solid, containing a inseparable enol
1
isomer (keto/enol =94:6); data for the keto isomer: H NMR (300
MHz, CDCl3) δ 7.30−7.14 (m, 3H), 7.07−7.04 (m, 2H), 6.86 (d, J =
2.04 Hz, 1H), 6.66 (d, J = 2.07 Hz, 1H), 4.93 (d, J = 2.91 Hz, 1H),
3.85 (s, 3H), 3.78 (s, 3H), 3.63 (s, 3H), 3.61 (d, J = 2.94 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 199.0, 168.9, 162.2, 157.9, 142.4, 138.4,
137.7, 128.7, 127.3, 127.0, 107.1, 96.7, 64.2, 55.9, 55.7, 53.0, 46.0; IR
(KBr, cm−1) 1647, 1636, 560; HRMS (ESI) m/z [M + Na]+ calcd for
C19H18O5Na 349.1052, found 349.1041.
2i: 32.8 mg, 95% yield; light yellow oil, containing a inseparable
1
enol isomer (keto/enol = 83:17); data for the keto isomer H NMR
(300 MHz, CDCl3) δ 7.05−6.90 (m, 5H), 6.85 (d, J = 1.89 Hz, 1H),
6.66 (d, J = 1.95 Hz, 1H), 4.91 (d, J = 3.00 Hz, 1H), 3.85 (s, 3H), 3.78
(s, 3H), 3.64 (s, 3H), 3.56 (d, J = 3.00 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 198.7, 168.8, 162.3, 157.8, 138.2, 138.0, 137.6, 128.8, 128.7,
115.7, 115.47, 107.17, 96.8, 64.1, 56.0, 55.7, 53.0, 45.3; IR (KBr, cm−1)
2954, 2842, 2360, 1711, 1619, 1510, 1360, 1309, 1231, 1152, 1029,
934, 842, 794, 738, 564; HRMS (EI-TOF) m/z M+ calcd for
C19H17O5F 344.1060, found 344.1059.
2j: 34.6 mg, 96% yield; pink solid, containing an inseparable enol
1
isomer (keto/enol = 88:12); data for the keto isomer H NMR (300
MHz, CDCl3) δ 7.24−7.21 (m, 2H), 7.01−6.98 (m, 2H), 6.85 (d, J =
1.78 Hz, 1H), 6.67 (d, J = 1.95 Hz, 1H), 4.90 (d, J = 3.0 Hz, 1H), 3.86
(s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.55 (d, J = 3.30 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 198.5, 168.7, 162.4, 157.8, 141.0, 137.7,
137.6, 132.7, 128.9, 128.7, 128.6, 128.5, 107.1, 96.8, 63.9, 56.0, 55.7,
53.0, 45.3; IR (KBr, cm−1) 1650, 1636, 429; HRMS (ESI) m/z [M +
Na]+ calcd for C19H17O5ClNa 383.0662, found 383.0652.
2k: 38.1 mg, 94% yield; pink solid, containing a inseparable enol
1
isomer (keto/enol = 86:14); data for the keto isomer H NMR (300
MHz, CDCl3) δ 7.38 (d, J = 1.74 Hz, 1H), 7.36 (d, J = 1.77 Hz, 1H),
6.96−6.92 (m, 2H), 6.84 (d, J = 2.04 Hz, 1H), 6.66 (d, J = 2.04 Hz,
1H), 4.88 (d, J = 3.03 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.64 (s,
3H), 3.54 (d, J = 3.09 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 198.5,
168.7, 162.4, 157.8, 141.5, 137.7, 137.6, 131.8, 131.0, 129.8, 129.0,
120.8, 107.1, 96.8, 63.9, 56.0, 55.7, 53.0, 45.4; IR (KBr, cm−1) 2953,
2360, 1713, 1612, 1484, 1307, 1205, 1147, 1010, 833, 737, 554;
HRMS (EI-TOF) m/z M+ calcd for C19H17O5Br 404.0259, found
404.0253.
2l: 30.0 mg, 80% yield; light yellow oil, containing a inseparable
1
enol isomer (keto/enol = 77:23); data for the keto isomer H NMR
(300 MHz, CDCl3) δ 8.15 (s, 1H), 8.12 (s, 1H), 7.27 (d, J = 1.23 Hz,
1H), 7.24 (d, J = 1.95 Hz, 1H), 6.88 (d, J = 2.01 Hz, 1H), 6.69 (d, J =
2.04 Hz, 1H), 5.04 (d, J = 3.30 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H),
3.65 (s, 3H), 3.57 (d, J = 3.33 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
197.7, 168.3, 162.7, 157.6, 149.9, 147.1, 137.7, 136.4, 128.8, 128.2,
124.1, 123.4, 107.1, 97.1, 63.4, 56.0, 55.7, 53.2, 45.5; IR (KBr, cm−1)
2956, 2360, 1721, 1612, 1519, 1452, 1347, 1311, 1150, 1014, 845, 738,
701, 559; HRMS (EI-TOF) m/z M+ calcd for C19H17O7N 371.1005,
found 371.1021.
2m: 33.4 mg, 85% yield; pink solid, containing an inseparable enol
1
isomer (keto/enol = 85:15); data for the keto isomer: H NMR (300
ASSOCIATED CONTENT
MHz, CDCl3) δ 7.52 (d, J = 8.13 Hz, 2H), 7.18 (d, J = 8.10 Hz, 2H),
6.87 (d, J = 2.07 Hz, 1H), 6.67 (d, J = 2.07 Hz, 1H), 4.98 (d, J = 3.12
Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.64 (s, 3H), 3.56 (d, J = 3.15 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 198.2, 168.6, 162.5, 157.8, 146.5,
137.7, 137.2, 129.6, 128.3, 127.7, 125.8, 125.7, 107.1, 96.9, 63.7, 56.0,
55.7, 53.1, 45.7; IR (KBr, cm−1) 2955, 2842, 1722, 1656, 1620, 1461,
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds reported. This
material is available free of charge via the Internet at http://
pubs.acs.org.
G
dx.doi.org/10.1021/jo302451b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Lv, J.; Cheng, J.-P.; Luo, S. Chem. Asian J. 2012, 7, 2569. (g) Lv, J.;
Zhong, X.; Cheng, J.-P.; Luo, S. Acta Chim. Sin. 2012, 70, 1518−1522.
(12) Beutner, G. L.; Denmark, S. E. Angew. Chem., Int. Ed. 2008, 47,
1560−1638.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luosz@iccas.ac.cn.
(13) Zhao, L.-G.; Zhang, J.-J.; Yu, Z.-X. J. Org. Chem. 2012, 77,
8527−8540.
Notes
The authors declare no competing financial interest.
(14) For the synthesis of aliphatic substituted substrates, see: Liu, W.;
Liu, J.; Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org. Lett. 2011, 13,
6272.
(15) Canterbury, D. P.; Herrick, I. R.; Um, J.; Houk, K. N.; Frontier,
A. J. Tetrahedron 2009, 65, 3165.
ACKNOWLEDGMENTS
■
This project was supported by the Ministry of Science and
Technology (2012CB821600), the Natural Science Foundation
of China (NSFC 20972163, 21202170 and 21025208), and the
Chinese Academy of Sciences.
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