Metal-Free Radical Oxidative Annulation of Ynones with Alkanes to Access Indenones

Article abstract of DOI:10.1021/acs.joc.6b00072

The benzoyl peroxide (BPO) promoted carboannulation of ynones with alkanes is developed, affording a series of 2-alkyl-3-aryl indenones in moderate to good yields. The procedure involves direct functionalization of alkane C(sp³)-H and arene C(s

Full text of DOI:10.1021/acs.joc.6b00072

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Article
Metal-free Radical Oxidative Annulation of
Ynones with Alkanes to Access Indenones
Changduo Pan, Bifan Huang, Weiming Hu, Xiaomei Feng, and Jin-Tao Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00072 • Publication Date (Web): 03 Feb 2016
Downloaded from http://pubs.acs.org on February 3, 2016
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The Journal of Organic Chemistry
Metal-free Radical Oxidative Annulation of Ynones with Alkanes to
Access Indenones
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a
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Changduo Pan,* Bifan Huang, Weiming Hu, Xiaomei Feng and Jin-Tao Yu*
a
School of Chemistry & Environmental Engineering, Jiangsu University of Technology, Changzhou 213001, P. R.
China
b
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology,
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Changzhou University, Changzhou 213164, P. R. China
panchangduo@jsut.edu.cn; yujintao@cczu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the
journal that you are submitting your paper to)
ABSTRACT
The benzoyl peroxide (BPO)-promoted carboannulation of ynones with alkanes is developed, affording a series of
2-alkyl-3-aryl indenones in moderate to good yields. The procedure undergoes direct functionalization of alkane
3
2
C(sp )–H and arene C(sp )–H bonds under metal-free conditions, providing a favorable approach for indenones
synthesis.
INTRODUCTION
1
Indenones are significant carbocycles that are prevalent in bioactive molecules and natural products. Consequently,
2-5
plenty of methods have been well established in the construction of indenone frameworks. Among them,
2
-4
transition-metal catalyzed approaches have been proved with superexcellent advances in recent decades. For
example, the annulation reactions between alkynes and ortho-bifunctionalized aryl aldehydes, esters, nitriles or
3
alcohols have well been developed as efficient synthetic strategies towards a variety of indenones (Scheme 1, eq 1).
However, those prefunctionalizated substrates are not commercially available, and their syntheses are always time and
cost consuming tasks. Delightfully, the direct C-H activation/annulation of aryl aldehydes, nitriles or amides with
4
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internal alkynes catalyzed by rhodium or MeOTf arose as efficient and atom-economic options (Scheme 1, eq 2).
Ynones are important structural motifs and synthetic intermediates in organic chemistry that can be conveniently
6
prepared by the Sonogashira coupling of acyl chlorides with terminal alkynes. Using 1,3-diarylpropynones as
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substrates, Pale and Sommer developed the synthesis of 3-aryl indenone derivatives via superacids-promoted
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intramolecular cyclization. However, the substrate scope is limited due to harsh reaction conditions. In 2011, Zou and
Zhang successfully generated the 3-phosphonylated and thiolated indenones by manganese(III)-mediated radical
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addition of phosphorus- and sulfur-centered radicals to 1,3-diarylpropynones. Although significant achievements have
been made, new protocols for the synthesis of diverse indenones with readily available substrates under mild and
metal-free conditions are still highly desired.
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Scheme 1. Construction of Indenones.
Construction of carbon-carbon bonds through direct C-H functionalization has drawn great attention during recent
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decades owing to its step- and atom-economy with environmental sustainability. Compared with C(sp )-H bond, the
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activation of C(sp )-H bond is more challenging for its relatively strong bond dissociation energy (BDE) with low
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polarity. Fortunately, radical reaction has demonstrated as an effective tool in organic synthesis and provides
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promising avenue to the direct functionalization of C(sp )-H bond. In view of the abundance and easily availability of
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alkanes, the direct functionalization of inert C(sp )–H bonds of alkanes through radical pathway has attracted
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considerable attentions. In addition, the alkyl radical induced annulation has been successfully utilized to construct
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heterocyclic compounds. To our knowledge, synthesis of indenones through radical C(sp )-H bond activation of
alkanes has not been reported. Herein, we describe the benzoyl peroxide (BPO) induced radical annulation of ynones
with alkanes to afford 2,3-difunctionalized indenone derivatives under metal-free conditions (Scheme 1, eq 4).
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RESULTS AND DISCUSSION
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Initially, 1,3-diphenyl-2-propyn-1-one (1a) was chosen as the model substrate to obtain the optimal reaction
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conditions. To our delight, when tert-butyl peroxide (DTBP) was used as the oxidant in cyclohexane (2a) under 120 C,
the desired product 2-cyclohexyl-3-phenyl-indenone (3aa) was obtained in 39% isolated yield (Table 1, entry 1). An
increase in temperature turned out futile to get higher yields (Table 1, entry 2). Next, other common oxidants, such as
TBHP, BPO and DCP were tested, and BPO gave the best result with a yield of 56% (Table 1, entry 4). Further
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optimization showed that the reaction performed the best efficiency at 100 C, providing a 69% yield of the product
(
Table 1, entry 6). The reaction became sluggish if the amount of oxidant was decreased and no reaction occurred in
the absence of any oxidant (Table 1, entries 8-9).
Table 1. Selected Results for Screening the Optimized Reaction Conditions.
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Entry
Oxidant
DTBP
DTBP
TBHP
BPO
T ( C)
Yield (%)
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56
DCP
trace
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BPO
BPO
BPO
--
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b
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0
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Reaction conditions: 1a (0.2 mmol), oxidant (3 equiv) in 2a (2 mL) at indicated temperature under air, 24 h. BPO (2 equiv). DTBP = tert-Butyl peroxide,
TBHP = tert-butyl hydroperoxide, BPO = benzoyl peroxide, DCP = dicumyl peroxide.
Next, we explored the scopes and limitations of this radical oxidative annulation process. Firstly, ynones with
different substituents on 1- or 3- aryls were applied as substrates to react with cyclohexane 2a, as shown in Figure 1.
As expected, substrates with methyl, halogen, methoxy or trifluoromethyl on either phenyl ring of the
1
,3-diaryl-2-propynones all proceeded well and afforded the corresponding 3-aryl-2-cyclohexyl indenones in moderate
to good yields (3aa–3la, Figure 1). The reaction is insensitive to the steric hindrance, for substrate with
ortho-substituent resulted in similar yield with the para-substituted one (3ca vs 3ba). This phenomenon was further
confirmed by regioselectivity study using aryl ynone bearing a meta-methoxy substituted
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a
Figure 1. Scope of the Ynones.
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Reaction conditions: 1 (0.2 mmol), BPO (3 equiv) in 2a (2 mL) at 100 C under air, 24 h. 1 mmol scale. The ratio of the isomers was
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determined by H NMR.
phenyl, with the generation of two isomers in a 1:1 ratio (3oa & 3oa’). Delightly, the procedure was mild enough to
tolerate amine and ester groups (3ma & 3na). Notably, the tolerance of halide substituents such as F and Cl, provides
possibilities for further functionalizations (3ea, 3fa, 3ja-3la). A slightly decreased reactivity was observed for the
reaction of ynone with strong electron deficient trifluoromethyl group (3ga). The practicability of this procedure was
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The Journal of Organic Chemistry
further evaluated by conducting the reaction on a 1 mmol scale, and the product 3aa was obtained in a comparable
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63% yield. Unfortunately, only trace of products were detected when ynones with 3-alkyl substituents, such as
4,4-dimethyl-1-phenylpent-2-yn-1-one (R’ = t-Bu) and 1-phenylhept-2-yn-1-one (R’ = n-Bu) were subjected to the
procedure.
Afterwards, the reactions of 1,3-diaryl-2-propynones with various alkanes were examined. As shown in Figure 2,
cyclopentane, cycloheptane and cyclooctane all worked well, providing the corresponding indenones in moderate to
good yields. Particularly, when acyclic alkanes, such as pentane and 2-methylbutane were subjected to the reaction,
isomeric mixtures were generated in moderate yields with a preference of 3° > 2° >> 1° carbons was observed (3ae, &
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3af).
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Figure 2. Substrate Scope of the Reaction.
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Reaction conditions: 1 (0.2 mmol), BPO (3 equiv) in 2a (2 mL) at 100 C under air, 24 h. The ratios of the isomers were determined by
H NMR.
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In order to understand the reaction mechanism of this radical annulation process, control experiments were carried
out as shown in Scheme 2. When the radical scavenger 2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or
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2,6-di-tert-butyl-4-methylphenol (BHT) was added under the standard conditions, the reaction was completely
inhibited, which strongly suggests a radical intermediate is involved. Moreover, a large kinetic isotope effect (k /k =
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.1) was observed, which reveals the C(sp )-H bond cleavage of cyclohexane is the rate-determining step (Scheme 2,
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see Supporting Information for details).
Scheme 2. Mechanism Studies.
Scheme 3. The Proposed Mechanism.
Based on the above mentioned experimental results, the proposed mechanism is outlined in Scheme 3. Initially,
thermal homolytic cleavage of BPO produces the benzoyl radical, which abstracts a hydrogen atom of cyclohexane to
form a cyclohexanyl radical 4 as well as benzoic acid. This is the rate-determining step as confirmed by the large KIE.
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The Journal of Organic Chemistry
Next, selective addition of the cyclohexanyl radical to the α-position of the C=O bond in ynone 1a produces vinyl
radical 5. Immediately, 5 undergoes intramolecular radical addition to arene and generates another radical intermediate
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6. Finally, after releasing of a H atom, indenone 3aa is formed along with one equivalent of benzoic acid. Moreover,
benzoic acid was detected by GCMS to confirm the above mechanism (see Supporting Information).
CONCLUSION
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In conclusion, we have developed a versatile BPO-promoted radical oxidative annulation of ynones with alkanes
under metal-free conditions. The reaction tolerates a series of functional groups such as halogen, methoxy,
trifluoromethyl, amine and ester group well, giving 2-alkyl-3-aryl indenones in moderate to good yields. Additionally,
this transformation is insensitive to the steric hindrance as well as the electro nature of the substituents on either phenyl
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ring of the 1,3-diaryl-2-propynones. The procedure undergoes direct functionalization of alkane C(sp )–H and arene
2
C(sp )–H bonds under metal-free conditions, providing a favorable approach for indenones synthesis.
EXPERIMENTAL SECTION
General Information: All chemicals were used as received without further purification unless stated otherwise.
NMR spectra were recorded at ambient temperature on a 300, 400 or 500 MHz NMR spectrometer. Chemical shifts (δ)
are given in ppm relative to TMS, the coupling constants J are given in Hz. HRMS were recorded on a TOF LC/MS
equipped with electrospray ionization (ESI) probe operating in positive or negative ion mode. IR spectra were recorded
on a spectrometer using KBr discs.
6c
Experimental Procedure for the Synthesis of Ynones: To a 50 mL round-bottom flask were added PdCl (PPh )
2
3 2
(14 mg, 0.02 mmol), CuI (19 mg, 0.1 mmol), and triethylamine (10 mL). The flask was flushed with nitrogen and the
terminal acetylene (5.0 mmol) was added to the stirred suspension, followed by immediate drop-wise addition of acyl
o
chloride (6.5 mmol). After stirring at 25 C for 12 h, water (10 mL) was added. The resulting solution was extracted
with diethyl ether (3 × 20 mL) and the organic layers were combined and dried over anhydrous MgSO . The solvent
4
was removed under vacuum, and the residue was purified by flash column chromatography on silica gel.
Experimental Procedure for the Oxidative Annulation of Ynone with Alkane to access Indenones: Under air,
ynone 1 (0.2 mmol), BPO (0.6 mmol, 144 mg) and alkane 2 (2 mL) were added into the tube and sealed. The reaction
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mixture was vigorously stirred at 100 C for 24 h. Then, the solvent was evaporated under reduced pressure and the
residue was purified by preparative TLC or flash column chromatography to afford the desired products.
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2
-Cyclohexyl-3-phenyl-1H-inden-1-one (3aa): Flash column chromatography on a silica gel (petroleum ether/ethyl
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acetate = 50:1) gives a yellow oil (39.7 mg, 69%). R = 0.38 (Silica gel, petroleum ether/ethyl acetate = 50:1). H NMR
f
(
CDCl , 400 MHz): δ 7.55-7.51 (m, 2H), 7.49-7.44 (m, 2H), 7.41-7.39 (m, 2H), 7.29-7.26 (m, 1H), 7.21-7.17 (m, 1H),
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.90 (d, J = 7.1 Hz, 1H), 2.52-2.46 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.74 (m, 2H), 1.67-1.58 (m, 3H), 1.33-1.14 (m,
13
1
H). C{ H} NMR (CDCl , 75 MHz): δ 198.2, 154.6, 145.7, 139.0, 133.1, 133.0, 130.9, 128.9, 128.7, 128.2, 127.9,
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22.2, 120.4, 35.9, 31.1, 26.5, 25.7. IR (cm ) ν 3058, 2925, 2852, 1703, 1609, 1595, 1454, 1361, 1330, 1166, 1080,
+
002. HRMS (ESI) m/z calcd for C H O (M+H) 289.1587, found 289.1585.
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2-Cyclohexyl-5-methyl-3-phenyl-1H-inden-1-one (3ba): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (44.1 mg, 73%). R = 0.38 (Silica gel, petroleum ether/ethyl acetate =
f
1
50:1). H NMR (CDCl , 400 MHz): δ 7.55-7.52 (m, 2H), 7.49-7.45 (m, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.34 (d, J = 7.2
3
Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 2.51-2.44 (m, 1H), 2.29 (s, 3H), 1.90-1.81 (m, 2H), 1.76-1.73 (m, 2H),
13
1
1.67-1.57 (m, 3H), 1.32-1.14 (m, 3H). C{ H} NMR (CDCl , 75 MHz): δ 197.9, 154.1, 146.2, 144.0, 139.4, 133.2,
3
−
1
128.8, 128.7, 128.5, 128.1, 127.9, 122.3, 121.7, 35.9, 31.1, 26.6, 25.7, 22.0. IR (cm ) ν 3054, 2925, 2852, 1702, 1603,
+
1
3
491, 1449, 1356, 1327, 1277, 1189, 1096, 1006. HRMS (ESI) m/z calcd for C H O (M+H) 303.1743, found
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03.1744.
-Cyclohexyl-7-methyl-3-phenyl-1H-inden-1-one (3ca): Flash column chromatography on a silica gel (petroleum
2
ether/ethyl acetate = 50:1) gives a yellow oil (44.7 mg, 74%). R = 0.35 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
0:1). H NMR (CDCl , 300 MHz): δ 7.54-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.8
3
Hz, 1H), 6.72 (d, J = 7.1 Hz, 1H), 2.54 (s, 3H), 2.50-2.40 (m, 1H), 1.92-1.71 (m, 4H), 1.65-1.55 (m, 3H), 1.27-1.10 (m,
1
3
1
3
1
1
H). C{ H} NMR (CDCl , 75 MHz): δ 199.6, 153.6, 146.2, 138.9, 137.2, 133.3, 132.3, 131.5, 128.7, 128.6, 128.0,
3
−
1
27.1, 118.4, 35.9, 31.1, 26.6, 25.8, 17.1. IR (cm ) ν 3059, 2920, 2851, 1704, 1609, 1492, 1455, 1362, 1275, 1188,
+
026. HRMS (ESI) m/z calcd for C H O (M+H) 303.1743, found 303.1745.
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2-Cyclohexyl-5-methoxy-3-phenyl-1H-inden-1-one (3da): Flash column chromatography on a silica gel
(
petroleum ether/ethyl acetate = 30:1) gives a yellow oil (46.4 mg, 73%). R = 0.32 (Silica gel, petroleum ether/ethyl
f
1
acetate = 30:1). H NMR (CDCl , 400 MHz): δ 7.54-7.50 (m, 2H), 7.48-7.44 (m, 1H), 7.42-7.36 (m, 3H), 6.58 (d, J =
3
7.9 Hz, 1H), 6.46 (s, 1H), 3.80 (s, 3H), 2.52-2.45 (m, 1H), 1.91-1.81 (m, 2H), 1.76-1.73 (m, 2H), 1.66-1.57 (m, 3H),
13
1
1.32-1.14 (m, 3H). C{ H} NMR (CDCl , 75 MHz): δ 196.7, 164.2, 152.4, 148.5, 140.6, 133.0, 128.8, 128.7, 128.0,
3
−
1
1
1
24.0, 123.7, 109.7, 109.4, 55.6, 36.1, 31.1, 26.5, 25.7. IR (cm ) ν 3028, 2976, 2921, 1702, 1657, 1450, 1427, 1382,
+
330, 1220, 1089, 1047. HRMS (ESI) m/z calcd for C H O (M+H) 319.1693, found 319.1691.
2
2
23
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2
-Cyclohexyl-5-fluoro-3-phenyl-1H-inden-1-one (3ea): Flash column chromatography on a silica gel (petroleum
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ether/ethyl acetate = 50:1) gives a yellow oil (43.4 mg, 71%). R = 0.37 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
1
0:1). H NMR (CDCl , 400 MHz): δ 7.56-7.46 (m, 3H), 7.44-7.41 (m, 1H), 7.37 (d, J = 7.3 Hz, 2H), 6.84-6.80 (m,
3
13
1
H), 6.62 (d, J = 8.0 Hz, 1H), 2.53-2.47 (m, 1H), 1.89-1.74 (m, 4H), 1.61-1.58 (m, 2H), 1.32-1.14 (m, 4H). C{ H}
NMR (CDCl , 75 MHz): δ 196.3, 166.3 (d, J = 251.9 Hz), 152.5, 149.1 (d, J = 10.9 Hz), 140.5, 132.5, 129.1, 128.9,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
27.8, 126.7 (d, J = 3.0 Hz), 123.9 (d, J = 9.8 Hz), 113.5 (d, J = 22.9 Hz), 109.4 (d, J = 25.4 Hz), 36.0, 31.0, 26.5, 25.7.
−
1
IR (cm ) ν 3069, 2926, 2853, 1706, 1597, 1492, 1470, 1449, 1353, 1331, 1202, 1115, 1078, 1006. HRMS (ESI) m/z
+
calcd for C H FO (M+H) 307.1493, found 307.1495.
21 20
5-Chloro-2-cyclohexyl-3-phenyl-1H-inden-1-one (3fa): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (43.1 mg, 67%). R = 0.37 (Silica gel, petroleum ether/ethyl acetate =
f
1
50:1). H NMR (CDCl , 400 MHz): δ 7.56-7.47 (m, 3H), 7.38-7.36 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H),
3
1
3
1
2.52-2.46 (m, 1H), 1.88-1.74 (m, 4H), 1.64-1.57 (m, 2H), 1.32-1.14 (m, 4H). C{ H} NMR (CDCl , 75 MHz): δ 196.0,
3
−
1
153.5, 147.7, 140.3, 139.3, 132.4, 129.2, 129.0, 128.9, 127.8, 127.7, 123.1, 121.2, 36.0, 31.0, 26.4, 25.7. IR (cm ) ν
068, 2926, 2852, 1706, 1604, 1593, 1449, 1350, 1323, 1166, 1066, 1006. HRMS (ESI) m/z calcd for C H ClO
3
21
20
+
(
M+H) 323.1197, found 323.1193.
2-Cyclohexyl-3-phenyl-5-(trifluoromethyl)-1H-inden-1-one (3ga): Flash column chromatography on a silica gel
(
petroleum ether/ethyl acetate = 50:1) gives a yellow oil (39.9 mg, 56%). R = 0.34 (Silica gel, petroleum ether/ethyl
f
1
acetate = 50:1). H NMR (CDCl , 300 MHz): δ 7.59-7.56 (m, 1H), 7.55-7.48 (m, 4H), 7.40-7.37 (m, 2H), 7.10 (s, 1H),
3
13
1
2
1
1
1
.55-2.45 (m, 1H), 1.91-1.73 (m, 4H), 1.63-1.56 (m, 2H), 1.30-1.12 (m, 4H). C{ H} NMR (CDCl , 75 MHz): δ 196.7,
3
54.3, 146.5, 134.7 (q, J = 31.9 Hz), 133.6, 132.2, 129.4, 129.0, 127.8, 125.8 (q, J = 4.2 Hz), 123.6 (q, J = 270.0 Hz),
−
1
22.0, 116.9 (q, J = 3.6 Hz), 36.0, 30.9, 26.4, 25.7. IR (cm ) ν 3058, 2928, 2854, 1708, 1610, 1492, 1449, 1427, 1374,
+
316, 1261, 1162, 1130, 1054, 1007. HRMS (ESI) m/z calcd for C H F O (M+H) 357.1461, found 357.1465.
2
2
20 3
2-Cyclohexyl-3-(p-tolyl)-1H-inden-1-one (3ha): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (44.1 mg, 73%). R = 0.35 (Silica gel, petroleum ether/ethyl acetate =
f
1
50:1). H NMR (CDCl , 400 MHz): δ 7.44 (d, J = 7.0 Hz, 1H), 7.35-7.25 (m, 5H), 7.18 (t, J = 7.2 Hz, 1H), 6.93 (d, J =
3
13
1
7.2 Hz, 1H), 2.53-2.46 (m, 4H), 1.93-1.84 (m, 2H), 1.77-1.74 (m, 2H), 1.68-1.57 (m, 3H), 1.31-1.18 (m, 3H). C{ H}
NMR (CDCl , 75 MHz): δ 198.3, 154.8, 145.7, 138.9, 138.7, 133.0, 131.0, 130.0, 129.4, 128.1, 127.8, 122.0, 120.4,
3
−
1
3
5.9, 31.0, 26.6, 25.8, 21.5. IR (cm ) ν 3025, 2925, 2852, 1702, 1601, 1509, 1451, 1329, 1276, 1183, 1111, 1002.
+
HRMS (ESI) m/z calcd for C H O (M+H) 303.1743, found 303.1744.
22
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2
-Cyclohexyl-3-(4-methoxyphenyl)-1H-inden-1-one (3ia): Flash column chromatography on a silica gel
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
petroleum ether/ethyl acetate = 50:1) gives a yellow oil (45.1 mg, 71%). R = 0.31 (Silica gel, petroleum ether/ethyl
f
1
acetate = 30:1). H NMR (CDCl , 400 MHz): δ 7.43 (d, J = 6.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.30-7.26 (m, 1H),
3
7
2
1
2
3
.21-7.17 (m, 1H), 7.43 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 7.1 Hz, 1H), 3.91 (s, 3H), 2.53-2.47 (m, 1H), 1.94-1.85 (m,
13
1
H), 1.78-1.75 (m, 2H), 1.67-1.57 (m, 2H), 1.35-1.15 (m, 4H). C{ H} NMR (CDCl , 75 MHz): δ 198.2, 160.1, 154.5,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
−
1
45.8, 138.4, 132.9, 131.1, 129.4, 128.1, 125.2, 122.0, 120.4, 114.1, 55.3, 36.0, 31.1, 26.6, 25.8. IR (cm ) ν 3034,
+
924, 2851, 1701, 1607, 1509, 1453, 1330, 1250, 1176, 1032, 1001. HRMS (ESI) m/z calcd for C H O (M+H)
2
2
23
2
19.1693, found 319.1692.
-(4-Chlorophenyl)-2-cyclohexyl-1H-inden-1-one (3ja): Flash column chromatography on a silica gel (petroleum
3
ether/ethyl acetate = 50:1) gives a yellow oil (42.5 mg, 66%). R = 0.35 (Silica gel, petroleum ether/ethyl acetate =
f
1
50:1). H NMR (CDCl , 400 MHz): δ 7.50 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 6.8 Hz, 1H), 7.34-7.27 (m, 3H), 7.22-7.18
3
13
1
(m, 1H), 6.86 (d, J = 7.1 Hz, 1H), 2.48-2.40 (m, 1H), 1.89-1.74 (m, 4H), 1.65-1.56 (m, 3H), 1.30-1.17 (m, 3H). C{ H}
NMR (CDCl , 75 MHz): δ 197.8, 153.3, 145.4, 139.4, 134.8, 133.2, 131.5, 130.7, 129.3, 129.1, 128.3, 122.4, 120.2,
3
−
1
3
6.0, 31.1, 26.5, 25.7. IR (cm ) ν 3064, 2926, 2852, 1704, 1605, 1489, 1450, 1329, 1277, 1166, 1091, 1014, 1001.
+
HRMS (ESI) m/z calcd for C H ClO (M+H) 323.1197, found 323.1193.
21
20
2-Cyclohexyl-3-(4-fluorophenyl)-1H-inden-1-one (3ka): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (42.2 mg, 69%). R = 0.35 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
1
1
1
1
0:1). H NMR (CDCl , 300 MHz): δ 7.45-7.42 (m, 1H), 7.40-7.34 (m, 2H), 7.30-7.16 (m, 4H), 6.86 (d, J = 7.1 Hz,
3
13
1
H), 2.48-2.38 (m, 1H), 1.91-1.72 (m, 4H), 1.66-1.54 (m, 3H), 1.33-1.11 (m, 3H). C{ H} NMR (CDCl , 75 MHz): δ
3
97.9, 162.9 (d, J = 247.3 Hz), 153.6, 145.5, 139.2, 133.2, 130.8, 129.9 (d, J = 8.1 Hz), 129.0 (d, J = 3.4 Hz), 128.3,
−
1
22.3, 120.3, 115.9 (d, J = 21.4 Hz), 35.9, 31.1, 26.5, 25.7. IR (cm ) ν 3069, 2926, 2852, 1704, 1600, 1507, 1451,
+
329, 1227, 1156, 1002. HRMS (ESI) m/z calcd for C H FO (M+H) 307.1493, found 307.1495.
2
1
20
2-Cyclohexyl-3-(3-fluorophenyl)-1H-inden-1-one (3la): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (41.0 mg, 67%). R = 0.34 (Silica gel, petroleum ether/ethyl acetate =
f
1
50:1). H NMR (CDCl , 300 MHz): δ 7.52-7.42 (m, 2H), 7.31-7.06 (m, 5H), 6.87 (d, J = 7.1 Hz, 1H), 2.50-2.39 (m,
3
1
3
1
1H), 1.90-1.72 (m, 4H), 1.63-1.55 (m, 3H), 1.34-1.11 (m, 3H). C{ H} NMR (CDCl , 75 MHz): δ 197.8, 162.8 (d, J =
3
245.7 Hz), 153.1 (d, J = 2.0 Hz), 145.4, 139.5, 135.2 (d, J = 7.8 Hz), 133.3, 130.6, 129.9 (d, J = 8.3 Hz), 128.4, 123.7
−
1
(
d, J = 3.0 Hz), 122.4, 120.3, 115.9 (d, J = 20.9 Hz), 115.0 (d, J = 21.8 Hz), 35.9, 31.0, 26.5, 25.7. IR (cm ) ν 3069,
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2
926, 2853, 1706, 1601, 1580, 1485, 1452, 1363, 1330, 1264, 1219, 1143, 1003. HRMS (ESI) m/z calcd for C H FO
21
20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(M+H) 307.1493, found 307.1495.
Methyl 4-(2-cyclohexyl-1-oxo-1H-inden-3-yl)benzoate (3ma): Flash column chromatography on a silica gel
(petroleum ether/ethyl acetate = 10:1) gives a yellow oil (44.3 mg, 64%). R = 0.52 (Silica gel, petroleum ether/ethyl
f
1
acetate = 5:1). H NMR (CDCl , 300 MHz): δ 8.19 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.4 Hz, 3H), 7.31-7.25 (m, 1H),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1
1
1
.22-7.17 (m, 1H), 6.84 (d, J = 7.1 Hz, 1H), 3.97 (s, 3H), 2.48-2.38 (m, 1H), 1.88-1.73 (m, 4H), 1.66-1.55 (m, 2H),
13
1
.28-1.09 (m, 4H). C{ H} NMR (CDCl , 75 MHz): δ 197.7, 166.6, 153.4, 145.4, 139.8, 137.8, 133.3, 130.6, 130.4,
3
−
1
30.0, 128.4, 128.0, 122.5, 120.3, 52.3, 36.0, 31.1, 26.5, 25.7. IR (cm ) ν 3062, 2932, 2856, 1708, 1591, 1473, 1448,
+
360, 1267, 1222, 1146, 1021. HRMS (ESI) m/z calcd for C H O (M+H) 347.1642, found 347.1647.
23 23
3
2-Cyclohexyl-3-(4-(dimethylamino)phenyl)-1H-inden-1-one (3na): Flash column chromatography on a silica gel
(petroleum ether/ethyl acetate = 10:1) gives a red oil (44.3 mg, 67%). R = 0.42 (Silica gel, petroleum ether/ethyl
f
1
acetate = 10:1). H NMR (CDCl , 300 MHz): δ 7.39 (d, J = 7.0 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.28-7.23 (m, 1H),
3
7.18-7.13 (m, 1H), 7.04 (d, J = 7.1 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 3.05 (s, 6H), 2.61-2.51 (m, 1H), 2.01-1.88 (m,
1
3
1
2H), 1.78-1.73 (m, 2H), 1.60-1.56 (m, 2H), 1.33-1.13 (m, 4H). C{ H} NMR (CDCl , 75 MHz): δ 198.4, 155.1, 150.7,
3
−
1
145.6, 137.1, 132.6, 131.7, 129.3, 127.9, 121.7, 120.6, 120.3, 111.7, 40.2, 36.0, 31.0, 26.6, 25.8. IR (cm ) ν 3047,
+
2925, 2848, 1705, 1473, 1451, 1356, 1276, 1180, 1021. HRMS (ESI) m/z calcd for C H NO (M+H) 332.2009,
2
3
26
found 332.2017.
2-Cyclohexyl-6-methoxy-3-phenyl-1H-inden-1-one
(3oa)
and
2-cyclohexyl-7-methoxy-3-phenyl-1H-inden-1-one (3oa’): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 30:1) gives a yellow oil (43.8 mg, 69%). R = 0.32 (Silica gel, petroleum ether/ethyl acetate =
f
1
3
1
0:1). H NMR (CDCl , 300 MHz), for 3oa: δ 7.54-7.30 (m, 5H), 7.18-7.09 (m, 1H), 7.05-7.04 (m, 1H), 6.80-6.77 (m,
3
H), 3.50 (s, 3H), 2.47-2.37 (m, 1H), 1.90-1.71 (m, 4H), 1.61-1.48 (m, 2H), 1.28-1.04 (m, 4H); for 3oa’: δ 7.54-7.30
(m, 5H), 7.18-7.09 (m, 1H), 6.90-6.87 (m, 1H), 6.70-6.67 (m, 1H), 3.80 (s, 3H), 2.34-2.23 (m, 1H), 1.90-1.71 (m, 4H),
13
1
1.61-1.48 (m, 2H), 1.28-1.04 (m, 4H). C{ H} NMR (CDCl , 75 MHz): δ 198.2, 197.9, 160.5, 155.9, 155.5, 153.2,
3
138.4, 137.9, 137.5, 135.3, 133.2, 133.0, 130.1, 128.9, 128.7, 128.0, 127.9, 127.8, 127.5, 121.2, 119.4, 115.7, 115.4,
−
1
110.1, 55.8, 55.7, 35.9, 35.6, 31.1, 31.0, 26.6, 26.5, 25.7. IR (cm ) ν 3025, 2972, 2923, 1698, 1452, 1424, 1378, 1325,
+
1222, 1094, 1042. MS (EI): 318 (M ).
2-Cyclopentyl-3-phenyl-1H-inden-1-one (3ab): Flash column chromatography on a silica gel (petroleum ether
1
/ethyl acetate = 50:1) gives a yellow oil (33.4 mg, 61%). R = 0.37 (Silica gel, petroleum ether/ethyl acetate = 50:1). H
f
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NMR (CDCl , 400 MHz): δ 7.55-7.51 (m, 2H), 7.48-7.41 (m, 4H), 7.30-7.26 (m, 1H), 7.21-7.17 (m, 1H), 6.94 (d, J =
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
7
.1 Hz, 1H), 2.89-2.81 (m, 1H), 1.98-1.83 (m, 4H), 1.79-1.72 (m, 2H), 1.58-1.55 (m, 2H). C{ H} NMR (CDCl , 75
3
−1
MHz): δ 197.8, 155.1, 145.6, 137.7, 133.1, 133.0, 131.2, 128.9, 128.1, 128.0, 122.2, 120.3, 36.3, 32.2, 26.4. IR (cm )
+
ν 3052, 2920, 2850, 1703, 1632, 1609, 1470, 1455, 1361, 1173, 1028. HRMS (ESI) m/z calcd for C H O (M+H)
2
0
19
275.1430, found 275.1432.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-Cycloheptyl-3-phenyl-1H-inden-1-one (3ac): Flash column chromatography on a silica gel (petroleum ether
1
/
ethyl acetate = 50:1) gives a yellow oil (38.6 mg, 64%). R = 0.36 (Silica gel, petroleum ether/ethyl acetate = 50:1). H
f
NMR (CDCl , 400 MHz): δ 7.55-7.51 (m, 2H), 7.48-7.43 (m, 2H), 7.41-7.39 (m, 2H), 7.29-7.26 (m, 1H), 7.19 (t, J =
3
7.3 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 2.65-2.60 (m, 1H), 2.02-1.89 (m, 2H), 1.79-1.75 (m, 2H), 1.68-1.53 (m, 5H),
13
1
1.41-1.27 (m, 3H). C{ H} NMR (CDCl , 125 MHz): δ 198.2, 152.9, 145.9, 140.7, 133.1, 133.0, 130.9, 128.9, 128.7,
3
−
1
128.1, 127.9, 122.2, 120.5, 37.3, 33.4, 27.9, 27.7. IR (cm ) ν 3058, 2921, 2854, 1704, 1608, 1596, 1456, 1443, 1361,
+
1273, 1175, 1113, 1028. HRMS (ESI) m/z calcd for C H O (M+H) 303.1743, found 303.1744.
2
2
23
2-Cyclooctyl-3-phenyl-1H-inden-1-one (3ad): Flash column chromatography on a silica gel (petroleum ether/ethyl
1
acetate = 50:1) gives a yellow oil (41.1 mg, 65%). R = 0.37 (Silica gel, petroleum ether/ethyl acetate = 50:1). H NMR
f
(
CDCl , 300 MHz): δ 7.55-7.38 (m, 6H), 7.29-7.23 (m, 1H), 7.19-7.14 (m, 2H), 6.91 (d, J = 7.1 Hz, 1H), 6.72 (s, 1H),
3
1
3
1
2
1
.78-2.69 (m, 1H), 2.02-1.89 (m, 2H), 1.75-1.67 (m, 2H), 1.63-1.38 (m, 10H). C{ H} NMR (CDCl , 75 MHz): δ
3
98.3, 152.8, 145.9, 141.5, 133.1, 130.8, 129.5, 128.9, 128.6, 128.1, 127.9, 122.2, 120.5, 34.6, 32.3, 26.4, 26.2. IR
−1
(
cm ) ν 3055, 2925, 2851, 1696, 1592, 1466, 1449, 1377, 1327, 1177, 1158, 1025. HRMS (ESI) m/z calcd for
+
C H O (M+H) 317.1900, found 317.1906.
23
25
2-Cyclopentyl-5-methyl-3-phenyl-1H-inden-1-one (3bb): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (36.3 mg, 63%). R = 0.36 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
0:1). H NMR (CDCl , 400 MHz): δ 7.55-7.51 (m, 2H), 7.48-7.40 (m, 3H), 7.34 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2
3
Hz, 1H), 6.73 (s, 1H), 2.87-2.79 (m, 1H), 2.30 (s, 3H), 1.95-1.82 (m, 4H), 1.77-1.73 (m, 2H), 1.57-1.54 (m, 2H).
13
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C{ H} NMR (CDCl , 75 MHz): δ 197.7, 154.6, 146.0, 144.0, 138.1, 133.1, 129.4, 128.85, 128.80, 128.7, 128.0,
3
−
1
122.2, 121.6, 36.3, 32.1, 26.4, 22.0. IR (cm ) ν 3061, 2952, 2867, 1702, 1603, 1470, 1448, 1358, 1274, 1175, 1113,
+
1027. HRMS (ESI) m/z calcd for C H O (M+H) 289.1587, found 289.1589.
21
21
2-Cyclopentyl-5-methoxy-3-phenyl-1H-inden-1-one (3db): Flash column chromatography on a silica gel
(
petroleum ether/ethyl acetate = 30:1) gives a yellow oil (37.8 mg, 62%). R = 0.31 (Silica gel, petroleum ether/ethyl
f
1
acetate = 30:1). H NMR (CDCl , 400 MHz): δ 7.53-7.39 (m, 6H), 6.59-6.56 (m, 1H), 6.50 (s, 1H), 3.81 (s, 3H),
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.89-2.80 (m, 1H), 1.97-1.81 (m, 4H), 1.77-1.71 (m, 2H), 1.57-1.54 (m, 2H). C{ H} NMR (CDCl , 75 MHz): δ 196.6,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
−1
64.2, 152.8, 148.2, 139.3, 132.9, 128.8, 128.7, 128.1, 124.1, 123.9, 109.6, 106.3, 55.6, 36.4, 32.2, 26.4. IR (cm ) ν
066, 2953, 2867, 1700, 1612, 1597, 1474, 1448, 1365, 1284, 1221, 1178, 1092, 1026. HRMS (ESI) m/z calcd for
+
C H O (M+H) 305.1536, found 305.1539.
21
21
2
2
-Cyclopentyl-5-fluoro-3-phenyl-1H-inden-1-one (3eb): Flash column chromatography on a silica gel (petroleum
0
1
2
3
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8
9
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1
2
3
4
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7
8
9
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7
8
9
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4
5
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7
8
9
0
ether/ethyl acetate = 50:1) gives a yellow oil (35.6 mg, 61%). R = 0.35 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
1
2
0:1). H NMR (CDCl , 400 MHz): δ 7.55-7.39 (m, 6H), 6.85-6.80 (m, 1H), 6.67-6.64 (m, 1H), 2.90-2.81 (m, 1H),
3
1
3
1
.96-1.82 (m, 4H), 1.79-1.74 (m, 2H), 1.58-1.53 (m, 2H). C{ H} NMR (CDCl , 75 MHz): δ 196.2, 166.3 (d, J =
3
51.9 Hz), 152.9 (d, J = 2.3 Hz), 148.9 (d, J = 9.3 Hz), 139.3, 132.4, 129.2, 128.8, 127.9, 126.9 (d, J = 3.0 Hz), 123.9
−
1
(d, J = 9.7 Hz), 113.5 (d, J = 22.8 Hz), 109.3 (d, J = 25.5 Hz), 36.4, 32.2, 26.4. IR (cm ) ν 3056, 2953, 2867, 1706,
+
1596, 1469, 1443, 1364, 1203, 1115, 1079, 1027. HRMS (ESI) m/z calcd for C20H18FO (M+H) 293.1336, found
293.1338.
5-Chloro-2-cyclopentyl-3-phenyl-1H-inden-1-one (3fb): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (35.7 mg, 58%). R = 0.34 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
6
0:1). H NMR (CDCl , 400 MHz): δ 7.56-7.52 (m, 2H), 7.50-7.46 (m, 1H), 7.41-7.36 (m, 1H), 7.19-7.16 (m, 1H),
3
1
3
1
.91 (s, 1H), 2.89-2.81 (m, 1H), 1.96-1.82 (m, 4H), 1.79-1.74 (m, 2H), 1.57-1.56 (m, 2H). C{ H} NMR (CDCl , 75
3
MHz): δ 196.5, 154.9, 147.4, 139.3, 139.1, 132.4, 129.3, 129.2, 128.9, 127.9, 127.7, 123.1, 121.1, 36.3, 32.2, 26.4. IR
−1
(
cm ) ν 3052, 2920, 2867, 1706, 1604, 1593, 1456, 1409, 1354, 1164, 1066, 1028. HRMS (ESI) m/z calcd for
+
C20H18ClO (M+H) 309.1041, found 309.1045.
2
-Cyclopentyl-3-(p-tolyl)-1H-inden-1-one (3hb): Flash column chromatography on a silica gel (petroleum ether
1
/
ethyl acetate = 50:1) gives a yellow oil (35.7 mg, 62%). R = 0.36 (Silica gel, petroleum ether/ethyl acetate = 50:1). H
f
NMR (CDCl , 400 MHz): δ 7.53 (d, J = 7.0 Hz, 2H), 7.33-7.26 (m, 5H), 7.20-7.16 (m, 1H), 6.95 (d, J = 7.0 Hz, 2H),
3
1
3
1
2
.90-2.82 (m, 1H), 2.46 (s, 3H), 1.98-1.83 (m, 4H), 1.78-1.72 (m, 2H), 1.58-1.52 (m, 2H). C{ H} NMR (CDCl , 75
3
MHz): δ 198.1, 155.2, 145.5, 139.0, 137.3, 133.0, 131.3, 130.0, 129.4, 128.1, 127.9, 122.1, 120.3, 36.3, 32.1, 26.4,
−
1
21.5. IR (cm ) ν 3025, 2952, 2867, 1703, 1601, 1509, 1456, 1454, 1356, 1275, 1173, 1112, 1020. HRMS (ESI) m/z
+
calcd for C H O (M+H) 289.1587, found 289.1588.
2
1
21
2-Cyclooctyl-5-methyl-3-phenyl-1H-inden-1-one (3bd): Flash column chromatography on a silica gel (petroleum
ether/ethyl acetate = 50:1) gives a yellow oil (44.9 mg, 68%). R = 0.33 (Silica gel, petroleum ether/ethyl acetate =
f
1
5
0:1). H NMR (CDCl , 400 MHz): δ 7.56-7.52 (m, 2H), 7.49-7.45 (m, 1H), 7.42-7.39 (m, 2H), 7.33 (t, J = 7.2 Hz,
3
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H), 6.98 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 2.77-2.70 (m, 1H), 2.30 (s, 3 H), 2.02-1.93 (m, 2H), 1.77-1.70 (m, 2H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
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3
3
3
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3
3
3
4
4
4
4
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4
4
4
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5
5
5
5
5
5
5
5
5
5
6
13
1
.66-1.57 (m, 4H), 1.54-1.41 (m, 6H). C{ H} NMR (CDCl , 75 MHz): δ 198.0, 152.4, 146.4, 144.0, 141.9, 133.2,
3
−1
29.5, 128.8, 128.6, 128.5, 128.0, 122.2, 121.8, 34.7, 32.3, 26.4, 26.2, 22.0. IR (cm ) ν 3036, 2920, 2851, 1702, 1604,
+
471, 1444, 1356, 1275, 1183, 1098, 1026. HRMS (ESI) m/z calcd for C H O (M+H) 331.2056, found 331.2061.
2
4
27
2-Cyclooctyl-5-methoxy-3-phenyl-1H-inden-1-one (3dd): Flash column chromatography on a silica gel
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(petroleum ether/ethyl acetate = 30:1) gives a yellow oil (45.6 mg, 66%). R = 0.29 (Silica gel, petroleum ether/ethyl
f
1
acetate = 30:1). H NMR (CDCl , 400 MHz): δ 7.54-7.50 (m, 2H), 7.47-7.43 (m, 1H), 7.41-7.38 (m, 3H), 6.57 (d, J =
3
7
.9 Hz, 1H), 6.49 (s, 1H), 3.80 (s, 3 H), 2.77-2.71 (m, 1H), 2.02-1.93 (m, 2H), 1.75-1.69 (m, 2H), 1.65-1.40 (m, 10H).
13
1
C{ H} NMR (CDCl , 75 MHz): δ 191.9, 164.2, 150.5, 148.7, 143.1, 133.0, 128.7, 128.6, 128.0, 124.0, 123.7, 109.8,
3
−
1
109.3, 55.6, 34.8, 32.3, 26.42, 26.40, 24.2. IR (cm ) ν 3046, 2920, 2850, 1699, 1611, 1598, 1473, 1445, 1364, 1284,
+
1219, 1180, 1093, 1027. HRMS (ESI) m/z calcd for C H O (M+H) 347.2006, found 347.2002.
2
4
27
2
3ae: 2-(Pentan-2-yl)-3-phenyl-1H-inden-1-one (C2) & 2-(pentan-3-yl)-3-phenyl-1H-inden-1-one (C3) (ratio C2 :
C3 = 3:2): Preparative TLC (petroleum ether/ethyl acetate = 50:1) gives a yellow oil (35.3 mg, 64%). R = 0.42 (Silica
f
1
gel, petroleum ether/ethyl acetate = 50:1). H NMR (CDCl , 300 MHz): δ 7.54-7.50 (m, 2H), 7.48-7.43 (m, 2H),
3
7
1
1
1
1
.40-7.39 (m, 2H), 7.31-7.28 (m, 1H), 7.22-7.19 (m, 1H), 6.91-6.86 (m, 1H), 2.72-2.67 (m, 0.6H), 2.39-2.35 (m, 0.4H),
1
3
1
.81-1.47 (m, 3H), 1.27-1.22 (m, 3H), 0.85-0.76 (m, 4H). C{ H} NMR (CDCl , 125 MHz): δ 198.2, 157.3, 155.4,
3
45.9, 145.8, 138.8, 137.1, 133.2, 133.16, 131.13, 133.0, 130.9, 130.8, 128.9, 128.7, 128.68, 128.65, 128.2, 127.9,
−1
27.8, 122.2, 120.4, 120.3, 40.2, 37.3, 30.6, 26.7, 21.3, 19.9, 13.9, 12.8. IR (cm ) ν 3059, 2958, 2928, 2870, 1703,
+
608, 1596, 1456, 1443, 1361, 1279, 1169, 1068, 1027. MS (EI): 276 (M ).
3af: 2-(2-methylbutyl)-3-phenyl-1H-inden-1-one (C1),
2-tert-Pentyl-3-phenyl-1H-inden-1-one (C2),
2
-(3-methylbutan-2-yl)-3-phenyl-1H-inden-1-one (C3) and 2-isopentyl-3-phenyl-1H-inden-1-one (C4) (ratio
C1:C2:C3:C4 = 3:12:8:3): Preparative TLC (petroleum ether/ethyl acetate = 50:1) gives a yellow oil (32.0 mg, 58%).
1
R = 0.41 (Silica gel, petroleum ether/ethyl acetate = 50:1). H NMR (CDCl , 400 MHz): δ 7.54-7.50 (m, 1H),
f
3
7
.48-7.38 (m, 4H), 7.31-7.15 (m, 3H), 6.89-6.87 (m, 0.4H), 6.49-6.47 (m, 0.56H), 2.30-2.25 (m. 0.3H), 2.15-2.13 (m,
0.3H), 1.98-1.91 (m, 0.4H), 1.77-1.71 (m, 1.2H), 1.26-1.24 (m, 0.9H), 1.06 (s, 3.3H), 1.01-0.97 (m, 0.9H), 0.92-0.90
13
1
(m, 1H), 0.83-0.77 (m, 2.7H). C{ H} NMR (CDCl , 75 MHz), δ 198.7, 155.8, 147.9, 145.9, 140.2, 139.2, 135.4,
3
133.5, 133.2, 130.8, 129.8, 129.4, 128.8, 128.7, 128.3, 128.2, 128.1, 127.9, 127.8, 122.2, 121.9, 120.4, 120.3, 38.3,
−
1
3
1
7.7, 34.4, 33.8, 31.5, 28.7, 25.7, 22.3, 21.1, 18.1, 9.8, 8.4. IR (cm ) ν 3056, 2953, 2925, 2872, 1701, 1602, 1592,
+
453, 1444, 1363, 1272, 1162, 1031. MS (EI): 276 (M ).
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ACKNOWLEDGMENT
The Journal of Organic Chemistry
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We thank the National Natural Science Foundation of China (No. 21202013), Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology (BM2012110) and Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center for financial supports.
Supporting Information:
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Mechanism studies, H and C NMR spectra of compounds 3aa-3oa, 3ab-3af. This material is available free of charge
via the Internet at http://pubs.acs.org.
REFERENCE
1
(a) Morrell, A.; Placzek, M.; Parmley, S.; Grella, B.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2007,
50, 4388. (b) Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A. J. Med. Chem. 1989, 32, 2163. (c) Ahn, J.;
Shin, M.; Jung, S.; Kang, S.; Kim, K.; Rhee, S.; Jung, W.; Yang, S.; Kim, S.; Woo, J.; Lee, J.; Cheon, H.; Kim, S.
J. Med. Chem. 2006, 49, 4781.
2 (a) Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129,
766. (b) Chen, X.; Jin, J.; Wang, N.; Lu, P.; Wang, Y. Eur. J. Org. Chem. 2012, 4, 824. (c) Butkevich, A.;
5
Ranieri, B.; Meerpoel, L.; Stansfield, I.; Angibaud, P.; Corbu, A.; Cossy, J. Org. Biomol. Chem. 2014, 12, 728.
(a) Larock R. C.; Doty, M. J. Org. Chem. 1993, 58, 4579. (b) Larock, R. C.; Tian, Q. Pletnev, A. J. Am. Chem.
Soc. 1999, 121, 3238. (c) Pletenv, A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. (d) Liu, C.; Korivi,
R. P.; Cheng, C.-H. Chem. Eur. J. 2008, 14, 9503. (e) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227. (f)
Miura, T.; Murakami, M. Org. Lett. 2005, 7, 3339. (g) Rao, M.; Dhanorkar, R. Tetrahedron 2014, 70, 8067. (h)
Feng, J.; Lu, G.; Lv, M.; Cai, C. J. Org. Chem. 2014, 79, 10561.
3
4
5
(a) Li, B.; Wang, H.; Zhu, Q.; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51, 3948. (b) Chen, S.; Yu, J.-T.; Jiang, Y.;
Chen, F.; Cheng, J. Org. Lett. 2013, 15, 4754. (c) Qi, Z.; Wang, M.; Li, X. Org. Lett. 2013, 15, 5440.
(a) Yu, X.; Zou, S.; Zhao, P.; Xi, C. Chem. Commun. 2014, 50, 2775. (b) Zhao, P.; Liu, Y.; Xi, C. Org. Lett. 2015,
17, 4388.
6 (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977, 777. (b) Cox, R.; Ritson, D.; Dane, T.; Berge, J.;
Charmantc, J.; Kantacha, A. Chem. Commun. 2005, 1037. (c) She, Z.; Niu, D.; Chen, L.; Gunawan, M. A.;
Shanja, X.; Hersh, W.; Chen, Y. J. Org. Chem. 2012, 77, 3627. (d) Chen L.; Li, C.-J. Org. Lett. 2004, 6, 3151.
7
(a) Vasilyev, A. V.; Walspeuger, S.; Pale, P.; Sommer, J. Tetrahedron Lett. 2004, 45, 3379. (b) Vasilyev, A. V.;
Walspeuger, S.; Haouas, M.; Sommer, J.; Pale, P.; Rudenko, A. P. Org. Biomol. Chem. 2004, 2, 3483. (c)
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Vasilyev, A. V.; Walspeuger, S.; Pale, P.; Sommer, J.; Haouas, M.; Rudenko, A. P. Russ. J. Org. Chem. 2004, 40,
769.
Page 16 of 16
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5
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5
5
5
5
5
5
6
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8
9
(a) Pan, X.-Q.; Zou, J.-P.; Zhang, G.-L.; Zhang, W. Chem. Commun. 2010, 46, 1721. (b) Zhou, J.; Zhang, G.-L.;
Zou, J.-P.; Zhang, W. Eur. J. Org. Chem. 2011, 3412.
For selected recent reviews, see: (a) Girard, S. A.; Knauber, T. Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74. (b)
Xie, J.; Pan, C.; Abdukader, A. Zhu, C. Chem. Soc. Rev. 2014, 43, 5245. (c) Kumar, R.; Van der Eycken, E. V.
Chem. Soc. Rev. 2013, 42, 1121. (d) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (e) Yang, L.; Huang,
H. Chem. Rev. 2015, 115, 3468. (f) Yu, J.-T.; Pan, C. Chem. Commun. 2016, 52, 2220. (g) Narayan, R.; Matcha,
K.; Antonchick, A. P. Chem. Eur. J. 2015, 21, 14678. (h) Sun, C.-L. Shi, Z.-J. Chem. Rev. 2014, 114, 9219.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10 (a) Wille, U. Chem. Rev. 2013, 113, 813. (b) Majumdar, K. C.; Basuy, P. K.; Chattopadhyay, S. K. Tetrahedron
2007, 63, 793. (c) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron 2005, 61, 10603. (d)
Majumdar, K. C.; Basu, P. K.; Gonzalez, A. Curr. Org. Chem. 2009, 13, 599.
11 Reviews: (a) Zhang, S.; Zhang, F.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40, 1937. (b) Hancock, A.; Schiesser, C.
Chem. Commun. 2013, 49, 9892. (c) Tang, S.; Liu, K.; Liu, C.; Lei, A. Chem. Soc. Rev. 2015, 44, 1070.
3
1
1
2
Selected reports on metal-free functionalization of C(sp )–H bond of alkane: (a) Ni, S.; Zhang, Y.; Xie, C.; Mei,
H.; Han, J.; Pan, Y. Org. Lett. 2015, 17, 5524, and references cited therein. (b) Zhao, J.; Fang, H.; Song, R.; Zhou,
J.; Han, J.; Pan, Y. Chem. Commun. 2015, 51, 599. (c) Zhang, H.; Pan, C.; Jin, N.; Gu, Z.; Hu, H.; Zhu, C. Chem.
Commun. 2015, 51, 1320.
3 (a) Qiu, J.; Jiang, B.; Zhu, Y.; Hao, W.; Wang, D.; Sun, J.; Wei, P.; Tu, S.-J.; Li, G. J. Am. Chem. Soc. 2015, 137,
928. (b) Sha, W.; Yu, J.-T.; Jiang, Y.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 9179. (c) Li, Z.; Zhang, Y.;
8
Zhang, L.; Liu, Z.-Q. Org. Lett. 2014, 16, 382. (d) Zhang, H.; Gu, Z.; Xu, P.; Hu, H.; Cheng, Y.; Zhu, C. Chem.
Commun. 2016, 52, 477.
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